Overview

Clinical Phenotype: Alzheimer's Disease, Multiple Conditions
Reference Assembly: GRCh37/hg19
Position: Chr19:45411941 T>C
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs429358
Coding/Non-Coding: Coding
DNA Change: Allele
Expected RNA Consequence: Allele
Expected Protein Consequence: Allele
Codon Change: TGC to CGC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4
Research Models: 2

Findings

This variant, one of the three common alleles of the APOE gene, is the major known risk factor for late-onset Alzheimer’s disease (LOAD), with a high degree of penetrance in homozygous form. It is found in at least half and as much as 75 percent of all LOAD patients. Unlike other variants associated with a high risk of disease, APOE4 is common, with a global frequency of 14 to 25 percent. The risk it confers appears to vary between populations, with people of East Asian ancestry being more vulnerable, those of European ancestry less, and those of African or Hispanic ancestry even less (see table below). The largest datasets are from studies of Caucasian populations, in which APOE4 increases AD risk in a dose-dependent manner with one allele raising risk about threefold, and two alleles elevating it 10- to 15-fold (for reviews, see Belloy et al., 2019; Yamazaki et al., 2019; Serrano-Pozo et al., 2021; Koutsodendris et al., 2021; Martens et al., 2022).

APOE4 was originally studied in the context of blood lipids and cardiovascular disease and first characterized at the protein level as one of three inherited ApoE isoforms with unique cysteine/arginine combinations at two positions eventually identified as 130 and 176 (Weisgraber et al., 1981; Zannis and Breslow, 1981). With arginines at both positions, ApoE4 is the most basic of the three species and was designated 4 based on its migration upon isoelectric focusing (see Nomenclature Notes below). It is likely that APOE4 is the ancestral form of APOE which gave rise to APOE2 and APOE3 (Hanlon and Rubinsztein 1995; Seixas et al., 1999; Fullerton et al., 2000; Abondio et al., 2019). 

APOE4’s ties to LOAD date back to the early 1990s, when a linkage study of multiple affected families revealed a disease-associated locus on chromosome 19, which then led to pinpointing of the APOE4 allele (Corder et al., 1993; Saunders et al., 1993; Strittmatter et al., 1993; Poirier et al., 1993). Since then, several large association studies have confirmed and extended these findings (Coon et al., 2007; Grupe et al., 2007; GWAS catalog). Overall, the population risk that can be attributed to APOE4 has been estimated at 20 percent (Reyes-Dumeyer et al., 2022), following a semi-dominant pattern of inheritance with moderate penetrance (Genin et al., 2011; see also May 2024 news). APOE4 status alone still outperforms polygenic risk scores in predicting dementia risk, despite the steady improvement of the latter, including multiple genome-wide variants (Yu et al., 2023).

In homozygous form, APOE4 has even been proposed to be a genetic cause of AD pathology with near full penetrance (May 2024 news, Fortea et al., 2024). The proposal is based on data from more than 13,000 individuals, most of European ancestry, indicating that nearly all APOE4 homozygotes had abnormal CSF Aβ42, and 75 percent had positive amyloid scans by age 65. By age 80, 88 percent were positive for the two biomarkers, as well as for CSF p-tau181. On average, memory problems had emerged by age 65. However, clinical penetrance was not assessed in this study. Importantly, other studies indicate the risk of homozygotes developing mild cognitive impairment or dementia due to AD is only 30 to 55 percent (Qian et al., 2017).

APOE4 Effects on AD Onset and Progression

APOE4 modifies the age of AD onset, with carriers’ symptoms emerging about five years earlier than those of non-carriers (Sando et al., 2008; De Rojas et al., 2021). Consistent with the earlier onset of symptoms, amyloid and tau pathologies were shifted towards younger ages, six and two years, respectively, in a longitudinal PET study (Therneau et al., 2021). Moreover, APOE4 carriers in the early stages of AD had higher levels of Aβ oligomers in cerebrospinal fluid than non-carriers with their kinetics suggesting an earlier start of the disease process (Blömeke et al., 2024). In APOE4 homozygotes, the acceleration is even more pronounced. One study found that onset occurred about a decade earlier than in non-carriers, CSF Aβ42 levels were already low by the late 40s, and by the early 50s, amyloid-PET and CSF p-tau181 readings were abnormal (May 2024 news, Fortea et al., 2024). Consistent with these findings, alterations in brain lipid metabolism associated with APOE4 appear to emerge early, possibly preceding amyloid plaques (Apr 2023 conference news; Mares et al., 2024).

APOE4 also seems to accelerate onset in individuals with familial LOAD (Reyes-Dumeyer 2022) or AD associated with Down syndrome, despite the already severe amyloid burden caused by chromosome 21 trisomy (Bejanin et al., 2021; July 2021 news). Moreover, individuals with young-onset dementia (Hendriks et al., 2024; Jan 2024 news) or sporadic early onset AD (Hammers et al., 2023) are more likely to be homozygous for APOE4. Also, in autosomal-dominant AD (ADAD), data from PSEN1 E280A (Paisa) carriers revealed an age-related acceleration of cognitive decline associated with APOE4 (Langella et al., 2023). However, the allele's effects on ADAD may vary based on mutation type (Almkvist et al., 2022).

Whether and under what circumstances APOE4 affects disease progression remains uncertain, although most studies suggest it accelerates it. For example, faster cognitive decline has been reported in carriers versus non-carriers (e.g., Jutten et al., 2021; Qian et al., 2021; but see Katzourou et al., 2021), as well as shorter disease duration (e.g., Vermunt et al., 2019). Imaging studies suggest APOE4 accelerates the atrophy of brain areas affected by AD, increases the rate of amyloid deposition, and enhances and accelerates tau deposition (for review see Koutsodendris et al., 2021, Steward et al., 2023). It may affect certain stages of disease more than others, however. For example, APOE4 appears to contribute more to conversion from the amyloid negative/tau negative (A-T-) state to A+T-, than from A+T- to A+T+ (Altmann et al., 2024). Another study found phosphorylated tau interacting preferentially with synaptic proteins and cellular transport components in the frontal cortex of APOE4 homozygotes, a possible  indication of ApoE4 facilitating the spread of tau pathology (Thierry et al., 2024). Independently of its effects on neuropathology, APOE4 may speed up cognitive decline (Qian et al., 2021; Qian et al., 2023). 

APOE4-Related AD and its Modulation

Interestingly, APOE4-related AD appears to be distinct from APOE4-unrelated AD (Vogel et al., 2021; Apr 2021 news; Frisoni et al., 2021). Proteomic, transcriptomic, and metabolomic analyses of cerebrospinal fluid, brain tissue, plasma, and cerebral organoids derived from patient stem cells have all revealed APOE4-dependent profiles, including a unique signature of disease progression (e.g., Dai et al., 2018; Zhao et al., 2020; Konijnenberg et al., 2020; Madrid et al., 2021; Chang et al., 2022; Das et al., 2023; Brase et al., 2023; Frick et al., 2023; Oveisgharan et al., 2024; Shvetcov et al., 2024; Dammer et al., 2024).  Hallmarks of APOE4-related AD include particularly  high levels of tau pathology and atrophy in the medial temporal lobe (Emrani et al., 2020; La Joie et al., 2021), changes in the structural relationships between sites of early tau pathology and the white matter through which they project (Wearn et al., 2024), association of AD phenotypes with plasma inflammation markers (Tao et al., 2023), as well as altered blood-brain barrier function, cerebral blood flow, and meningeal lymphatics (Montagne et al., 2020; May 2020 news; Chen et al., 2021; Sep 2022 conference news, Sun et al., 2023; Jun 2023 news). Of note, some of these alterations—for example those in brain connectivity—may be due to compensatory mechanisms that shape brain function early on (e.g., Cacciaglia et al., 2022).

Moreover, age and genetic factors, including gender, modify APOE4’s effects on AD risk, having a stronger influence on people between the ages of 60 and 75, and on women, whose risk peaks at an earlier age than that of men (Farrer et al., 1997; Bickeböller et al., 1997; Altmann et al., 2014; Neu et al., 2017; Sep 2017 news; Nemes et al., 2023; Belloy et al., 2023). APOE4’s effects on cortical Aβ load, however, may extend into very old ages, as suggested in a preprint (Rohde et al., 2023). Sex differences are also observed in biomarkers of pathology, particularly in cerebrospinal fluid tau, with women having higher levels than men in amyloid-positive individuals (Hohman et al., 2018; May 2018 news). Disease stage is also relevant, with one study showing higher CSF phospho-tau levels in women than men, but only during pre-dementia stages of disease (Babapour Mofrad et al., 2020). In addition, women carriers appear to be particularly susceptible to tau pathology (Feb 2019 news; Nov 2019 news). Interestingly, differences in brain structure between individuals—especially in the hippocampus and default network which are particularly vulnerable to AD—appear to also help shape APOE4-associated AD risk (Savignac et al., 2022).

Clues to the molecular underpinnings of gender-associated differences are beginning to emerge from experimental systems. For example, one mouse study suggested that follicle-stimulating hormone, which rises in post-menopausal females, may contribute to APOE4 vulnerability (Xiong et al., 2023).  Also, a genetic variant that regulates microglial activation was identified as a gender-specific modifier of APOE4 AD risk (July 2022 news; Jiang et al., 2022). Interestingly, a search for DNA methylation patterns associated with APOE4 and AD revealed an abundance of genes encoding proteins of the estrogen response pathway (Panitch et al., 2024). 

Environmental factors also modify APOE4’s effects. For example, infections, in particular by the herpes virus, may boost AD risk (Apr 2021 conference news), while a healthy lifestyle may reduce it (e.g., Jia et al., 2023). However, many such effects are complex and not well understood, with some studies suggesting negligible effects (e.g., Neuffer et al., 2024). Healthy lifestyle choices, for example, may need to be adopted early in life to be protective against APOE4-associated risk (e.g., Aug 2019 news). Indeed, alterations tied to APOE4 expression at the molecular, cellular, and behavioral levels have been detected decades before disease onset (e.g., Oct 2015 news; Dec 2021 news). Also of note, APOE4 may itself modulate the effects of environmental factors, such as  education (e.g., Rajabli et al., 2024; Glans et al., 2024).

The Role of Other Variants in APOE4 Pathogenicity

APOE4’s effect on AD risk is modulated by other genetic factors and some studies suggest these modifiers are abundant. Several have been traced to the APOE region, which includes APOE and a few neighboring genes, while others are far-flung, including variants in other chromosomes (e.g., Kim et al., 2020; Dec 2020 news; Ebenau et al., 2021; Huq et al., 2021; Nazarian et al., 2022; Nazarian et al., 2022; Sep 2022 news).

An example of a nearby modulator is APOE R269G, a rare variant within APOE itself that is co-inherited with APOE4. In a large association study including more than 500,000 participants, it was associated with a twofold reduction in AD risk (June 2022 news; Le Guen et al., 2022). Although its biological effect is unknown, it is suspected to have a direct effect on ApoE function, possibly altering lipid binding and/or oligomerization. Another APOE variant, APOE R154S (Christchurch), may also modulate APOE4 toxicity. In human neurons derived from induced pluripotent stem cells (iPSCs) and a tauopathy mouse model, homozygous Christchurch rescued APOE4-associated tau pathology and, in the mouse model, it also protected against APOE4-driven neurodegeneration and neuroinflammation in a gene dose-dependent manner (Nelson et al., 2023). 

Klotho-VS, a set of two polymorphisms, F352V and C370S, in the longevity gene Klotho, offers an example of a distant modulator. In heterozygous form, Klotho-VS cuts APOE4 AD risk by approximately a third (Erickson et al., 2019; Belloy et al., 2020; Apr 17 news). It appears to accomplish this by lowering amyloid-dependent tau accumulation (Aug 2020 news; Neitzel et al., 2021). Even in non-demented APOE4 carriers, Klotho-VS has been associated with reduced amyloid and tau pathologies (Belloy et al., 2021; Driscoll et al., 2021; Ali et al., 2022; see also Grøntvedt et al., 2022). The relationships between Klotho-VS, ApoE, and AD are complex, however. For example, Klotho heterozygosity has also been reported to slow down cognitive decline specifically in male AD patients who do not carry APOE4 (Chen et al., 2023). 

Other variants that may temper APOE4’s damaging effects include P522R in the phospholipase Cγ2 (PLCG2) gene (van der Lee et al., 2019; May 2019 news; Kleineidam et al., 2020), variants in Wnt signaling genes (Lin et al., 2021; Sep 2021 news), and a variant in the IL1RL1 gene that alters microglial activation (July 2022 news; Jiang et al., 2022). In addition, a common variant of the hemoglobin scavenger haptoglobin that also binds to ApoE and is thought to protect ApoE from oxidation (Bai et al., 2023), the P3S variant of the mitochondrial-derived peptide humanin prevalent among individuals of Ashkenazi ancestry (Miller et al., 2024), rare variants in the fibronectin-1 gene (May 2024 news, Bhattarai et al., 2024), and polymorphisms in genes and inter-genic regions neighboring APOE (see APOE region) have been identified as additional modifiers of APOE4.  Expression levels of certain genes (VGF, SPECC1L, HLA-DRA, and RANBP3L) may also help shape APOE4-associated AD risk (Branciamore et al., 2024).

Of note, APOE4 may itself act as a modulator of the effects of variants. For example, the penetrance of loss-of-function variants in the SORL1 gene, another strong genetic risk factor for AD, appears to be increased by the presence of APOE4 alleles in a dose-dependent manner (Schramm et al., 2022).   

APOE4 and Ancestry

Interestingly, ancestry plays an important role in determining APOE4 consequences (table below shows data from comparative studies). Since the mid-1990s, there have been reports of a weaker effect of APOE4 on AD risk in people of African ancestry compared with Caucasians (Maestre et al., 1995; Tang et al., 1996; Farrer et al., 1997). Also, APOE4 has been found to confer higher risk in East Asians, and lower risk in Hispanics, compared with whites (see Harerimana et al., 2022 for review). Large studies including tens of thousands of individuals support these observations (e.g., Belloy et al., 2023; Rajabli et al., 2023; Choi et al., 2019). Ancestry-based differences have also been reported in the association of APOE4 with AD endophenotypes, such as amyloid PET levels (Ali et al., 2023).

Efforts to identify the genetic regions responsible for differences in AD risk have revealed nearby sequences, also known as local ancestry regions (LAR), in the APOE region (e.g., Rajabli et al., 2018; Babenko et al., 2018; Rajabli et al., 2022), with some studies pinpointing variants of interest (Zhang et al., 2018; Choi et al., 2019; Nuytemans et al., 2022; Granot-Hershkovitz et al., 2023). Although the mechanisms underlying the associations remain unclear, modulation of APOE gene expression is a likely candidate. For example, a study of single-nuclei RNA in the frontal cortices of APOE4 homozygotes indicated that carriers of European LARs expressed higher levels of APOE4 than carriers of African LARs (Griswold et al., 2021). 

Many questions about how ancestry shapes APOE4's effects on AD risk remain. One challenge is disentangling the contributions of environmental factors. Indeed, modifiable risk factors which often vary between groups of different ancestries—such as lower education levels, smoking, and physical inactivity—appear to exacerbate the effects of APOE4 on dementia. Moreover, as reported in a preprint, the effectiveness of different methods to measure modifiable risks also varies between populations (Andrews et al., 2024).

Another challenge is dissecting the roles of different ancestries in admixed populations, such as Hispanic groups. The effects of African and European local and global ancestries have been examined in Hispanics, as well as the potential contributions of Amerindian ancestry, sometimes yielding conflicting results (Blue et al., 2019; Marca-Ysabel et al., 2021; Belloy et al., 2023). Moreover, some studies have failed to find ancestry-associated differences in the effects of APOE4 on AD and AD-related cognitive decline, or have failed to confirm the APOE region as the source of these differences (e.g., Knopman et al., 2009; Sawyer et al., 2009; Mezlini et al., 2020; Curtis, 2021, Mukadam et al., 2022). Differences in demographic variables, sample sizes, analytical and statistical methodologies, measures of cognition, and racial bias in assessing dementia have been proposed as factors accounting for these discrepancies. Also of note, methodological limitations are potentially relevant to many APOE association studies. For example, the variability in the reliability of widely used APOE genotyping methods may result in irreproducible findings (Belloy et al., 2022).

APOE4 is more prevalent in Africans and Oceanians than in Europeans, particularly non-Finnish Europeans, with Asians and Hispanics/Latinos having the lowest frequency (Kamboh et al., 1995; Wang et al., 2021; gnomAD v2.1.1, Sep 2022).

Non-AD Neurological Disorders

APOE4 has also been associated with non-AD pathologies and conditions. Some of them often accompany AD (see Belloy et al., 2019), such as cerebral amyloid angiopathy (CAA; e.g., Premkumar et al., 1996;  Rannikmäe et al., 2014; Reiman et al., 2020), the more severe inflammatory form of CAA (Grangeon et al., 2022), and AD psychosis (DeMichele-Sweet et al., 2021). Also, APOE4 homozygosity has been associated with a modest increase in risk for ischemic cerebrovascular disease (Rasmussen et al., 2023), a condition which can co-occur with CAA. Other conditions are independent of AD, including some neuropathologies associated with transactive response DNA-binding protein of 43 kDa (TDP-43), such as limbic-predominant age-related TDP-43 encephalopathy (LATE) and hippocampal sclerosis (e.g., Yang et al., 2018; Dugan et al., 2021), as well as negative outcomes after traumatic brain or spinal cord injury (e.g., Atherton et al., 2022; Feigen et al., 2024; Schneider et al., 2024). Moreover, APOE4 appears to increase the risk of impaired cognition and multiple neurodegenerative proteinopathies (Walker and Richardson 2022, Maldonado-Díaz et al., 2024). 

Interestingly, in Parkinson’s disease (PD), APOE4 has been associated with a change in the progression of the disease. APOE4 appears to accelerate cognitive decline (Paul et al., 2016; Tan et al., 2020; Liu et al., 2021) and, in carriers with a high amyloid burden, hasten motor deterioration (Pu et al., 2021). Also of note, although a substantial number of PD patients develop AD pathology, a preprint suggests APOE4 may drive PD dementia by a mechanism independent of AD pathology (Wu et al., 2023). 

Multiple studies have reported associations between APOE4 and dementia with Lewy bodies (e.g., Hardy et al., 1994; Tsuang et al., 2013; Guerreiro et al., 2017; Dec 2017 news). However, while some studies suggest this association is due to the common co-occurrence of Lewy body (LB) pathology with AD pathology (e.g., Kaivola et al., 2022), others suggest APOE4 affects the two pathologies independently of each other (e.g., Tsuang et al., 2013; Wu et al., 2024). Consistent with the former possibility, a large GWAS meta-analysis, indicated APOE4 is associated with risk of AD⁺LB^– and AD⁺LB⁺ compared with AD^–LB^–, but not with risk of AD^–LB⁺ compared with AD^–LB^– or risk of AD⁺LB⁺ compared with AD⁺LB^– (Talyansky et al., 2023). Of note, at least one TDP-43opathy appears to be unaffected by APOE4: a large meta-analysis including 4,000 amyotrophic lateral sclerosis cases and 10,000 controls found no association between the allele and the disease (Govone et al., 2014).

Several studies have reported significant associations between APOE4 and age-related cognitive decline (e.g., Davies et al., 2014; Raj et al., 2016; Corley et al, 2022; Tomassen et al., 2022; Rietman et al., 2022), with all cognitive domains tested, particularly memory, being affected (e.g., Kang et al., 2023, Pettigrew et al., 2023, Sun et al., 2023; Jun 2023 news). Interestingly, some of the declines appeared to be mitigated by cognitive reserve (Pettigrew et al., 2023) and APOE4's negative impact on baseline memory appeared to be stronger in women than in men (Walters et al., 2023). Also, in a study of several cohorts with different neurodegenerative and cerebrovascular disorders, APOE4 carriers performed consistently worse on tests of verbal memory and visuospatial skills, regardless of their diagnoses (Dilliott et al., 2021). 

Importantly, several studies have indicated APOE4 exerts little or no effect on baseline general cognitive function (e.g., Davies et al., 2018, Rietman et al., 2022, Rahman et al., 2024, Daly et al., 2024). A study of nearly 10,000 English individuals aged 17–85 years, for example, identified associations with performance in 11 cognitive tests, as well as age-by-APOE interaction effects, but none survived correction for multiple testing (Rahman et al., 2024)

Nevertheless, cognitively unimpaired APOE4 carriers may be more prone to some neuropathological and functional alterations. One study, for example, identified APOE4 carriership as distinctive of a subgroup of cognitively healthy individuals with signs of accelerated brain aging (Skampardoni et al., 2024). Also, APOE4 has been associated with more rapid loss of slow-wave sleep (Himali et al., 2023) and reduced duration of rapid eye movement (REM) sleep (André et al., 2024) during normal aging. Moreover, p-tau181 levels in plasma were elevated in a group of APOE4 carriers who remained healthy after age 85 (Cooper et al., 2024) and, as reported in a preprint, cognitively healthy centenerian carriers tended to have higher Aβ loads than non-carriers (although half of the carriers had Aβ levels below those associated with AD, suggesting resilience to Aβ accumulation; Rohde et al., 2023). Another study found alterations in the functional connectivity of the default mode network in young carriers (Kucikova et al., 2023). Age-dependent association of APOE4 with smaller hippocampal volumes has also been reported (Fortea et al., 2024; Chaloemtoem et al., 2024) . Moreover, two studies tied APOE4 to reductions in white matter integrity in cognitively healthy carriers (Heise et al., 2024; Tato-Fernández et al., 2024). Indeed, APOE4-associated brain changes have been reported even among infants and young children (Dec 2013 news).

In some instances, however, APOE4 may be neurologically protective. For example, some studies indicate it decreases the risk of age-related macular degeneration (e.g., Fritsche et al., 2016; Rasmussen et al., 2022) and, as suggested in a preprint, progressive supranuclear palsy (Wang et al., 2024; Feb 2024 news). Moreover, APOE4 has been reported to confer a slight cognitive advantage early in life, which declines with age (Lu et al., 2021; Oct 2021 news).

Non-Neurological Conditions

APOE4 was initially shown to play a role in lipid transport and cardiovascular disease (see Mahley et al., 2009; Mahley 2016). Its preference for interacting with very low-density lipoprotein (VLDL) in blood is thought to accelerate these particles’ uptake. This in turn causes a downregulation of cell surface receptors that bind ApoE which then leads to an increase in circulating cholesterol-rich LDL particles.

Large association studies of white individuals in general population cohorts revealed increases in most blood lipids—including LDL cholesterol, ApoB, and the ratio of ApoB to ApoA1 which are tied to atherosclerosis risk—sphingomyelin, and triglycerides in APOE4 carriers relative to APOE3 homozygotes (Rasmussen et al., 2019, Rasmussen et al., 2023, Compton et al., 2024). In contrast, ApoE and high-density lipoprotein (HDL) cholesterol were decreased. Interestingly, most of these differences were detected across all age groups, including children and young adults (Compton et al., 2024) but waned in older carriers, particularly after age 60. Moreover, two large studies of individuals of European ancestry indicated APOE4 is associated with age-related weight loss, independent of baseline obesity and dementia (Venkatesh et al., 2024; Kemper et al., 2024). 

Additional studies have shown associations of APOE4 with other metabolic alterations (e.g., Li et al., 2020; Ferguson et al., 2020). Also, a study of primary human hepatocytes revealed altered lipidomic signatures, suggesting disruptions of mitochondrial function and free fatty acid metabolism (Almeida et al., 2024).

APOE4 carriers have a higher risk of other medical conditions as well. For example, they are more likely to get infected by SARS-CoV-2 and die with COVID than non-carriers (Jan 2021 news; Ostendorf et al., 2022). As assessed in a COVID mouse model and in vitro experiments, potential mechanisms underlying this vulnerability include elevated viral loads, suppressed adaptive immune responses early after infection, and detrimental effects on astrocytes and neurons. Also, APOE4 carriers may be more likely than non-carriers to develop neurovascular complications associated with COVID (May 2023 conference news). They may also be more prone to accumulate chromosomal alterations with age (Leshchyk et al., 2023).

Indeed, multiple studies have found associations between APOE4 and an increased risk of death (see Abondio et al., 2019 for review). Interestingly, a study of more than 14,000 individuals from the UK and France, suggested that dementia contributed substantially to the association with all-cause mortality in APOE4 homozygotes, while other factors, particularly cardiovascular disease, elevated death risk in APOE4 heterozygotes (Régy et al., 2024).

A few studies have revealed protective effects, however, such as a better prognosis for melanoma (Ostendorf et al., 2020) and a lower risk for non-alcoholic fatty liver disease and obesity (e.g., Palmer et al., 2021, Huebbe et al., 2023). APOE4 has also been tied to a moderate enhancement in myocardial function (Topriceanu et al., 2024). Interestingly, one study suggested that, although APOE4 carriers with high levels of AD neuropathology at death had higher mortality risk than non-carriers, APOE4 carriers with low levels of AD neuropathology had a lower mortality risk than non-carriers (Pirraglia et al., 2023).

Also, it has been suggested that APOE4 may provide an evolutionary advantage in highly infectious environments, such as those experienced by early humans (e.g., van Exel et al., 2017; Garcia et al., 2021, Smith and Ashford, 2023, Trumble et al., 2023). In non-industrialized, subsistence communities, APOE4 was associated with increased fertility, better immune activation during infection, and lower levels of baseline inflammation, which may outweigh the neurological and cardiovascular risks identified in industrialized populations. Moreover, even in European populations, extreme climate conditions, which influence cholesterol demand, and an increased need for vitamin D may have fueled APOE4 selection (see Harerimana et al., 2022 for review).

Biological Effects

ApoE4 has been implicated in a remarkable number of alterations associated with AD, including gain- and loss-of-function effects (see Yamazaki et al., 2019; Belloy et al., 2019; Serrano-Pozo et al., 2021; Koutsodendris et al., 2021; Martens et al., 2022; Steele et al., 2022 for reviews), with most studies pointing to gains of function as major contributors to the allele’s toxicity (Vance et al., 2024).

APOE4 appears to exacerbate both hallmark AD pathologies, amyloid plaques (e.g., Nov 2021 news; July 2021 news; May 2019 conference news; Jul 2018 news; Jun 2018 news; Jan 2017 news) and neurofibrillary tangles (e.g., Sep 2017 news; June 2018 news; Apr 2021 news; Saroja et al., 2022; Nov 2022 news; Jan 2023 news). In addition, it has been blamed for altering lipid transport and metabolism in brain cells (e.g., Nov 2021 conference news; Mar 2021 news; Aug 2019 news; Apr 2019 conference news; Jul 2018 conference news, Apr 2023 conference news) and fueling neuroinflammation (Nov 2021 conference news; Jul 2018 conference news; Aug 2019 news; Asante et al., 2022; Parhizkar and Holtzman 2022; Kloske et al., 2023), abnormal cellular stress responses (e.g., Martens et al., 2022), neurodegeneration (e.g., May 2021 news; Apr 2021 news; Oct 2019 news), and blood-brain barrier breakdown (e.g., Jun 2020 news; May 2020 news; Sep 2022 conference news; Denkinger et al., 2024).

ApoE4 has also been reported to reduce neurogenesis (e.g., Oct 2020 news; Aug 2018 news), alter neuronal structure and function (e.g., Koutsodendris et al., 2021), disrupt endocytosis and intracellular trafficking (e.g., Martens et al., 2022; July 2021 news; Oct 2020 news), impair mitochondrial function, energy metabolism (Mahley 2023) and mitophagy (e.g., Hou et al., 2023), as well as modify DNA methylation (e.g., Panitch et al., 2024) and transcription (e.g., Theendakara et al., 2018), including enhancing the expression of APP (Jan 2017 news, Huang et al., 2017). At a tissue level, it appears to alter brain glucose metabolism (e.g., Johnson, 2020; Yassine and Finch, 2020) and cause neural network dysfunction (e.g., Koutsodendris et al., 2021).

In addition to its effects on AD pathology, ApoE4 may fuel other types of neurodegenerative damage. Indeed, ApoE interacts with multiple amyloid proteins in addtion to Aβ (for review see Loch et al., 2023). For example, a post-mortem study indicated increased ApoE accumulation in the Lewy bodies of APOE4 carriers with Lewy body dementia, and other studies suggest ApoE4 exacerbates α-synuclein pathology, increasing the seeding of aggregates that are particularly toxic to neurons  (e.g., Feb 2020 news;  Zhao et al., 2021; Jin et al., 2022). In mouse models of synucleinopathy, ApoE4 worsened neurodegeneration, inflammation, memory loss, and motor deficits.

Although it is unclear which of these myriad alterations play primary roles in the disease process, several occur during the initial stages of disease. Through multiple mechanisms, ApoE4 is thus thought to initiate a cascade of early alterations leading to later pathological changes (Koutsodendris et al., 2021; Martens et al., 2022; Steele et al., 2022).

Molecular Level Effects

How a single amino acid substitution triggers this cascade remains uncertain. The replacement of a cysteine by an arginine makes ApoE4 more basic than ApoE3. One possible consequence is reduced solubility in early endosomes which can disrupt vesicular trafficking (e.g., July 2021 news). The substitution also affects ApoE's functional regions: ApoE4 binds lipids more poorly, heparin more tightly, and is more prone to self-aggregation than ApoE3. The structural underpinnings of these differences have yet to be elucidated. Initial studies predicted an interaction between R79 and Glu273 mediated by ApoE4’s arginine in the C130 position, resulting in a tighter interaction between the N-terminal and C-terminal domains of the protein (Hatters et al., 2005, Xu et al., 2004). However, the importance of this bridge has been called into question and other models hint at increased flexibility of the bundle of helices in the N-terminal domain (see Chen et al., 2020 for review).

Of note, even under highly controlled conditions, with ApoE4 in monomeric form, the protein appears to adopt multiple configurations (Stuchell-Brereton et al., 2023). Moreover, ApoE4 is predicted to change conformation depending on its lipidation status, association with other molecules (including other ApoE proteins), post-translational modifications, and microenvironment. Insights into ApoE4’s behavior under these diverse conditions are beginning to emerge. For example, one study indicated lipid-free ApoE4 forms V-shaped dimers with the N-terminal domains coming together at an angle that likely fuels aggregation and is different from that formed by ApoE3 and ApoE2 dimers (Nemergut et al., 2023). Of particular physiological relevance, a high-resolution  structural analysis of lipidated ApoE in astrocyte-secreted lipoproteins suggested two ApoE proteins wrap around a lipid disc in an anti-parallel conformation (Feb 2024 news; Strickland et al., 2024). The resulting lipoprotein particle was smaller when formed by ApoE4 than by ApoE2 or ApoE3.  

Distinct Cell Type Effects: Glial Cells

Interestingly, the cellular source of ApoE4 appears to be important in determining its consequences (see Blumenfeld et al., 2024 for review). In glial cells, ApoE4 has been reported to disrupt lipid metabolism, altering cholesterol and cholesterol ester production and export, as well as disrupting lipid droplet number, size, and composition (e.g., Sep 2023 news, Haney et al., 2024, Aug 2019 news, March 2019 news, Nov 2021 news, Nov 2022 news, Windham and Cohen, 2023, Nov 2023 news, Windham et al., 2024, Feringa et al., 2024). It also has been shown to impair endolysosomal trafficking, alter mitochondrial metabolism, and upregulate innate immune pathways.

ApoE4-expressing microglia have distinct immune and metabolic transcription profiles associated with aging, amyloid and tau pathologies, inflammatory challenge, and brain plasticity. These are characterized by enhanced glycolysis (Lee et al., 2023), altered regulation of genes involved in extracellular matrix organization and chondroitin sulfate biosynthesis (Brase et al., 2023), and changes in the expression of genes that define homeostatic versus disease-associated states (Lee et al., 2023, Yin et al., 2023, Liu et al., 2023, Oct 2023 news). Moreover, microglial efferocytosis—the clearance of apoptotic cells and debris in the brain—has been identified as a genetic risk hub for AD, with ApoE4 affecting multiple steps in this process (Romero-Molina et al., 2022).

Several studies have reported that ApoE4 microglia have sluggish phagocytosis and heightened inflammatory responses compared with their ApoE3 counterparts (e.g., June 2018 news, Aug 2019 news, Sep 2019 news), and appear to be locked in a state of homeostasis unable to clear plaque or tangles efficiently (Sep 2022 conference news, Oct 2023 news). Dysregulation of microglial receptors may underlie some of ApoE4's effects on microglial behavior. For example, increased binding of ApoE4, compared with ApoE2 or ApoE3, to the microglial leukocyte immunoglobulin-like receptor B3 (LilrB3) may facilitate pro-inflammatory activation of microglia (Zhou et al., 2023), while decreased expression of the microglial P2RY12 receptor may slow down migration of these cells towards Aβ (Sepulveda et al., 2024). ApoE4 may also accelerate the emergence of terminally inflammatory microglia (TIM), a reactive microglia subtype that accumulates during aging and is characterized by a less inflammatory, functionally impaired state analogous to that of exhausted T cells (Millet et al., 2023).

Multiple effects on the function of astrocytes—which express high levels of ApoE—have also been reported, including dysregulation of lipid metabolism and matrisome signaling, increased inflammatory signaling, and reduced Aβ uptake (e.g., Lin et al., 2018; Qi et al., 2021; de Leeuw et al., 2022; Tcw et al., 2022; Watanabe et al., 2023). As suggested in a preprint, ApoE4 also appears to suppress astrocytic immune activation which may occur via enhanced cholesterol esterification (Feringa et al., 2024).

In addition, ApoE4 has been reported to alter glial-neuronal interactions: driving tau-mediated neurodegeneration via glia-derived ApoE4 (Shi et al., 2019; Oct 2019 news; Wang et al., 2021; Apr 2021 news, Haney et al., 2024), disrupting immune signaling associated with neuroinflammation (e.g., Aug 2019 news; Tcw et al., 2022; Serrano-Pozo et al., 2021; Parhizkar and Holtzman 2022; Chernyaeva et al., 2023), and perturbing neuron-astrocyte coupling of lipid metabolism (e.g., Qi et al., 2021; Oct 2023 conference news). Moreover, in the context of tau pathology, microglial ApoE4 appears to induce lysosomal abnormalities and ramp up synapse phagocytosis (Gratuze et al., 2022; Nov 2022 news). Astrocytic ApoE4 may also affect synapses, decreasing dendritic spine density and altering their architecture (Watanabe et al., 2023). In addition, ApoE4 may disrupt axon myelination by affecting oligodendrocyte health and differentiation (Cheng et al., 2022, Blanchard et al., 2022, Mok et al., 2022), impair microglial surveillance of the activity of neuronal networks (Victor et al., 2022), and possibly interfere with the regulation of neuronal gene expression via astrocyte-derived miRNAs (Li et al., 2021).

Distinct Cell Type Effects: Neurons

ApoE4 also appears to fuel neurodegeneration directly within neurons. Although neurons normally produce much less ApoE than glial cells, with age, certain neurons increase production. This correlates with elevated expression of antigen-presenting genes, tau pathology, and ultimately cell death. In APOE4 knockin mice, this ApoE surge occurred earlier than in controls (May 2021 news), and a preprint reported early hyperexcitability in a subpopulation of hippocampal excitatory neurons (Tabuena et al., 2024). In a tauopathy mouse model, removing ApoE4 from neurons drastically reduced neurofibrillary tangles, tau-mediated gliosis, and myelin loss (Feb 2023 news; Koutsodendris et al., 2023). Moreover, human APOE4 neurons transplanted into the hippocampi of APOE4 knockin mouse generated Aβ and phospho-tau aggregates, and elevated the levels of pro-inflammatory microglia, as reported in a preprint (Rao et al., 2023). Interestingly, tau pathology in these mice was dependent on the presence of microglia. 

Several mechanisms have been suggested to explain ApoE4’s effects in neurons. For example, ApoE4 can be aberrantly cleaved in neurons to generate toxic C-terminal fragments. These fragments can cause mitochondrial dysfunction, tau pathology, and neuronal death (Koutsodendris et al., 2021). Moreover, one study found ApoE can inhibit Aβ production by binding to γ-secretase in neurons, and ApoE4 is less capable of doing so compared with ApoE3 and ApoE2 (Hou et al., 2023). Also, a preprint suggested ApoE4 may drive tau aggregation in neurons by disrupting the function of neuroproteasomes—proteasomes localized to neuronal plasma membranes that degrade newly synthesized proteins, including tau (Paradise et al., 2023).

Distinct Cell Type Effects: Vascular Cells

Vascular cell function seems to be affected by ApoE4 as well. In pericytes, for example, ApoE4 appears to cause alterations that disrupt the blood-brain barrier (e.g., Bell et al., 2012; May 2012 news; May 2020 news; Montagne et al., 2021) and, in a 3D cell-culture model system, it promoted cerebral amyloid angiopathy (Blanchard et al., 2020; Jun 2020 news). In addition, ApoE4 is associated with changes in gene expression in endothelial cells, pericytes, and perivascular fibroblasts (Sep 2022 conference news, Sun et al., 2023). Vascular cell function may also be affected indirectly by expression of ApoE4 in astrocytes. In AD mice with ApoE4-deficient astrocytes, for example, gliosis was dampened, and cerebrovascular integrity and function were improved, although Aβ deposition shifted from the brain parenchyma to the vasculature (Xiong et al., 2023). ApoE4 may also facilitate the pathological accumulation of fibronectin 1 and gliosis in the vasculature (May 2024 news, Bhattarai et al., 2024). Moreover, observations reported in a preprint revealed that, in mice, macrophages closely apposed to neocortical microvessels, a.k.a. border associated macrophages, produce ApoE4 and react to it, releasing reactive oxygen species that result in resticted cerebral blood flow (Apr 2023 conference news, Iadecola et al., 2023).

Peripheral Effects on Brain Health

Interestingly, although ApoE produced systemically, by the liver and peripheral macrophages, is excluded from the brain, increasing evidence suggests it is tied to neurological health. For example, a study of more than 100,000 Danes found that APOE genetic variants associated with low ApoE levels in plasma, including APOE4, were more likely to be associated with an increased risk for dementia, and for AD in particular (Rasmussen et al., 2020). Also, low plasma ApoE levels were associated with CSF AD biomarkers in patients with mild cognitive impairment and AD (Giannisis et al., 2022). Heparin-bound ApoE4, however, may be increased in AD plasma together with other heparin-binding proteins tied to AD, as reported in a preprint (Guo et al., 2023). A study that found epigenetic changes in peripheral immune cells of AD patients also suggests links between the periphery and the brain involving APOE genotype (Feb 2024 news; Ramakrishnan et al., 2024). In particular, enhanced chromatin accessibility of pro-inflammatory genes in several types of peripheral immune cells was observed in AD APOE4 carriers. Notably, APOE4-affected genes included AD risk genes BIN1 and ABCA1. Moreover, a global map of peripheral immune changes in AD patients showed that APOE4 influenced a wide range of metabolic and immunological pathways across different clinical stages of AD (Olst et al., 2024).

Although some experiments in mice have failed to detect effects of peripheral ApoE in the brain (e.g., Huynh et al., 2019), several studies have revealed substantial consequences. For example, in mice transplanted with primary human hepatocytes, peripheral ApoE was found to affect cognitive behaviors, synaptic health, neuroinflammation, insulin signaling, and cerebrovascular function (Giannisis et al., 2022; Liu et al., 2022; see also Golden and Johnson 2022). Analyses of brain tissue and plasma proteome profiling of conditional mouse models expressing human APOE4 only in the liver, as well as from a human endothelial cell model, suggest these various effects stem from vascular dysfunction (Liu et al., 2022). Also of note, breeding these conditional mice with an AD mouse model exacerbated amyloid pathology. In female APOE4 carriers, blood neutrophils infiltrating into the brain may blunt microglial responses to amyloid plaque pathology (Rosenzweig et al., 2024).

Moreover, peripheral effects on carrier health could also have indirect, AD-related consequences. For example, C-reactive protein (CRP) released during peripheral inflammation may contribute to APOE4-related AD neurodegeneration (Tao et al., 2021, Royall et al., 2017). Moreover, APOE4 carriers’ elevated risk of cardiovascular disease may select for populations of older carriers enriched in metabolic traits that enabled them to survive the risk past mid-life. These traits may modify LOAD risk and/or expression (Wu et al., 2021). Also of note, APOE4 appears to influence the composition of the gut microbiome (e.g., Zajac et al., 2022) which in turn may affect the progression of at least some neurodegenerative pathologies (e.g., Seo et al., 2023, Jan 2023 news).

Therapeutic Candidates

Since APOE4 has been implicated in both gain- and loss-of-function effects, the benefits of reducing versus increasing ApoE4 levels have been subject to debate (Belloy et al., 2019). After evaluating multiple studies in humans (mostly of European and African ancestries) and animal models, the APOE4 NIA/ADSP Consortium working group concluded that the preferred therapeutic goal is to reduce ApoE4 levels (Vance et al., 2024). 

Multiple approaches to achieve this goal are being examined, ranging from directly targeting the protein, to mitigating its downstream effects (see Serrano-Pozo et al., 2021; Yang et al., 2021; Raulin et al., 2022 for reviews). Direct strategies include reducing ApoE4 levels, enhancing the protein’s lipidation, and blocking its interactions with Aβ peptides or APP. For example, an antibody that preferentially binds to aggregated, poorly lipidated ApoE, a form often adopted by ApoE4, was reported to reduce amyloid pathology and improve cerebrovascular function in mice (Feb 2021 news; May 2019 conference news; Apr 2018 news).

Approaches to target downstream effects include blocking a proton leak channel to circumvent ApoE4-mediated stalling of early endosomes (July 2021 news), identifying drugs that normalize transcriptional signatures linked to ApoE4 (Oct 2021 news), boosting lipid efflux from glial cells (Nov 2023 news) and targeting downstream signaling cascades disrupted by ApoE4 (Dec 2021 news).

Also, other researchers are attempting to boost ApoE2/ApoE3 activity, either by using gene therapy to express the benign isoforms in APOE4 carriers (e.g., LX1001, Dec 2022 conference news, Jackson et al., 2024), or by designing small molecules to mold ApoE4 into a conformation that more closely resembles those of ApoE2/ApoE3 (e.g., Wang et al., 2018, June 2018 news, Nemergut et al., 2023, ALZ-801). 

Of note, taking into account APOE4 carriership is proving important for the development and deployment of multiple AD therapies, even those that do not target ApoE. For example, recent studies have shown that the efficacy, side effects, and likely the optimal timing, of anti-Aβ immunotherapies are all shaped by the presence of APOE4 (Ossenkoppele and van der Flier, 2023; Garcia et al., 2024). Indeed, a genome-wide search for genetic risk factors associated with amyloid-related imaging abnormalities (ARIA)—an adverse event tied to these therapies—indicated APOE4 is the strongest risk factor for ARIA incidence (Loomis et al., 2024). The mechanisms underlying this risk are still unclear, but may involve reduced cerebrovascular integrity, increased CAA, and/or neuroinflammation and immune dysregulation (Foley and Wilcock, 2024). 

Research Models

Multiple APOE4 research models have been developed, including rodent models and patient-derived iPSC lines (e.g., Nov 2022 news; Schmid et al., 2021; Raman et al., 2020).  APOE4 knock-in mice, transgenic mice and rats, and mice carrying APOE4 together with AD-relevant mutations are available. In general, mice carrying human APOE4 appear to have only limited cognitive deficits, but are more vulnerable to neurodegenerative challenges, such as co-expression of familial AD mutations, than APOE3-carrying mice (Heuvelen et al., 2024).

A particularly interesting mouse model was engineered to allow a switch from expressing APOE4 to APOE2 via activation of Cre recombinase (Aug 2023 conference news). Another mouse line described in a preprint, LOAD2, models late-onset AD, including the human APOE4 gene, the TREM2 R47H variant (which in mice reduces TREM2 expression), and a humanized Aβ sequence in the APP gene (Jan 2024 news; Kotredes et al., 2024; Pandey et al., 2024). Also reported in a preprint, a 3D human brain model derived from APOE4 carrier iPSCs has been created (Stanton et al., 2023). With six brain cell types embedded in a 3D hydrogel, it is engineered to mimic immuno-glial-neurovascular interactions. 

Nomenclature Notes

APOE was first studied at the protein level and observed to have isoforms that migrated to different positions upon isoelectric focusing. The most common isoform was named ApoE3, while isoforms with one additional positive charge were named ApoE4. Subsequent studies showed that, in most cases, these faster migrating species corresponded to C130R.

Table

APOE4-Associated AD Risk Across Groups of Different Ancestries*

*Only data from reports comparing AD risk among groups of different ancestries using the same analyses tools, in the same study, were included.
^aReference E3/E3.
^bMeta-analysis of two meta-analyses (Farrer et al., 1997, Choi et al., 2019).
^cData from MedRxiv preprint.
^dMeta-analysis of multiple studies.
^eReference: E4 non-carriers.
^fDiagnosed with dementia/ADRD, not specifically AD.

OR=odds ratio, HR=hazard ratio, RR=risk ratio.
Statistically significant associations (as assessed by the authors) are in bold.

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References

News Citations

1. Dysregulated Lipid Metabolism Comes to the Fore at AD/PD 27 Apr 2023
2. ApoE4 Hastens Alzheimer’s Disease in Down’s Syndrome 16 Jul 2021
3. Similar Risk Factors Found for Young- and Late-Onset Dementia 5 Jan 2024
4. Forget Typical Alzheimer's: AI Finds Four Types. 30 Apr 2021
5. Even Without Amyloid, ApoE4 Weakens Blood-Brain Barrier, Cognition 9 May 2020
6. Shooting Themselves in the Foot? Microglia Block “Good” State with ApoE4 9 Sep 2022
7. New Look at Sex and ApoE4 Puts Women at Risk Earlier than Men 1 Sep 2017
8. Study Finds Sex Influences CSF Tau Levels in ApoE4 Carriers 11 May 2018
9. Is a Woman’s Brain More Susceptible to Tau Pathology? 8 Feb 2019
10. ApoE4 and Tau in Alzheimer’s: Worse Than We Thought? Especially in Women 1 Nov 2019
11. Receptor Decoy Raises Risk of Alzheimer’s—But Only in Women 26 Jul 2022
12. More Data on Herpes and Alzheimer’s Disease 16 Apr 2021
13. Healthy Lifestyle Hedges Dementia Risk, but Not if Genetic Risk Runs High 27 Aug 2019
14. Young ApoE4 Carriers Wander Off the ‘Grid’ — Early Predictor of Alzheimer’s? 23 Oct 2015
15. Young ApoE4 Carriers Have Reversed AD Proteomic Signature 1 Dec 2021
16. In People Who Defy ApoE, New Alzheimer’s Risk Genes Found 29 Dec 2020
17. Up, and Down—Haptoglobin Moves APOE4 Risk in Mysterious Ways 30 Sep 2022
18. Two ApoE Mutations Decrease Risk for Alzheimer's Disease 10 Jun 2022
19. Klotho Variant Cuts ApoE4’s Alzheimer Risk by a Third 17 Apr 2020
20. Klotho VS Variant Preserves Memory by Preventing Tangles 14 Aug 2020
21. The Mutation You Want: It Protects the Brain, Extends Life 31 May 2019
22. In Oldest Old, Rare Longevity Variants Suppress Common Pathogenic Ones 18 Sep 2021
23. Does a Rare Fibronectin Variant Protect Against APOE4? 16 May 2024
24. First Genome-Wide Association Study of Dementia with Lewy Bodies 15 Dec 2017
25. Brain Volume, Myelination Different in Infants Carrying ApoE4 6 Dec 2013
26. First Whole-Genome Sequencing of PSP Nets Six New Risk Loci 8 Feb 2024
27. Not All Bad? APOE4 Sharpens Memory in Older People 9 Oct 2021
28. APOE Tied to Increased Susceptibility to SARS-CoV-2 29 Jan 2021
29. Do Lipids Lubricate ApoE's Part in Alzheimer Mechanisms? 5 Nov 2021
30. Could Juicing Up Trafficking Abolish ApoE4’s Alzheimer’s Risk? 17 Jul 2021
31. On The Docket at AD/PD: The Many Crimes of ApoE4 1 May 2019
32. ApoE Has Hand in Alzheimer’s Beyond Aβ, Beyond the Brain 14 Jul 2018
33. In Human Neurons, ApoE4 Promotes Aβ Production and Tau Phosphorylation 15 Jun 2018
34. ApoE Risk Explained? Isoform-Dependent Boost in APP Expression Uncovered 20 Jan 2017
35. ApoE4 Makes All Things Tau Worse, From Beginning to End 20 Sep 2017
36. Squelching ApoE in Astrocytes of Tau-Ravaged Mice Dampens Degeneration 10 Apr 2021
37. Sans TREM2, ApoE4 Drives Microgliosis and Atrophy in Tauopathy Model 18 Nov 2022
38. Meddling Microbiome Worsens Tauopathy and Neurodegeneration 13 Jan 2023
39. Droplets of Unsaturated Fats Burden Human ApoE4 Astrocytes 12 Mar 2021
40. ApoE4 Glia Bungle Lipid Processing, Mess with the Matrisome 16 Aug 2019
41. At AD/PD Conference, New Alzheimer’s Genes Reinforce Known Pathways 19 Apr 2019
42. Does ApoE in Neurons Drive Selective Vulnerability in Alzheimer’s? 21 May 2021
43. In Tauopathy, ApoE Destroys Neurons Via Microglia 17 Oct 2019
44. Human Blood-Brain Barrier Model Blames Pericytes for CAA 15 Jun 2020
45. Alzheimer's Risk Genes Nip at Hippocampus Throughout Life 30 Oct 2020
46. Alzheimer’s Disease-Related Proteins Needed for Neurogenesis 3 Aug 2018
47. In Astrocytes, ApoE4 Bungles Endocytosis, PICALM Picks Up the Slack 28 Oct 2020
48. Toxic α-Synuclein: Egged on by ApoE4, Thwarted by ApoE2? 7 Feb 2020
49. In Lipoparticles, ApoE Double Belt Keeps the Fat In 1 Feb 2024
50. Lipid-Laden, Sluggish Microglia? Blame Aβ. 6 Sep 2023
51. Do APOE4’s Lipid Shenanigans Trigger Tauopathy? 23 Nov 2023
52. In Amyloid and Tangle Models, APOE4 Paralyzes Microglia 26 Oct 2023
53. Among AD Mutations, Only ApoE4 Seems to Hobble Microglia 14 Sep 2019
54. Cracking the Cholesterol-AD Code: Metabolites and Cell Type 21 Oct 2023
55. Secreted by Neurons, ApoE4 Makes Tangles and Degeneration Worse 24 Feb 2023
56. ApoE4 Makes Blood Vessels Leak, Could Kick Off Brain Damage 17 May 2012
57. Survey of Tau Partners Highlights Synaptic, Mitochondrial Roles 27 Jan 2022
58. Macrophages Blamed for Vascular Trouble in ApoE4 Carriers 13 Apr 2023
59. Epigenetic Shenanigans—In AD, Chromatin Opens Up in Blood Immune Cells 15 Feb 2024
60. Would ApoE Make a Better Therapeutic Target Than Aβ? 26 Feb 2021
61. Antibodies Against Microglial Receptors TREM2 and CD33 Head to Trials 10 May 2019
62. Human ApoE Antibody Nips Mouse Amyloid in the Bud 5 Apr 2018
63. Can an Old Diuretic Drug Disarm APOE4, Prevent Alzheimer’s? 15 Oct 2021
64. In Small Trial, Gene Therapy Spurs ApoE2 Production 14 Dec 2022
65. Cornucopia: LOADs of New Mouse Models Available 5 Nov 2022
66. Meet the Switching Mice: They Flip Their Glia APOE4 to APOE2 23 Aug 2023

Mutations Citations

1. Trisomy 21
2. PSEN1 E280A (Paisa)
3. APOE R269G
4. APOE R154S (Christchurch)

Therapeutics Citations

1. LX1001
2. ALZ-801

Research Models Citations

1. hAbeta/APOE4/Trem2*R47H

Paper Citations

1. Belloy ME, Napolioni V, Greicius MD. A Quarter Century of APOE and Alzheimer's Disease: Progress to Date and the Path Forward. Neuron. 2019 Mar 6;101(5):820-838. PubMed.
2. Yamazaki Y, Zhao N, Caulfield TR, Liu CC, Bu G. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol. 2019 Sep;15(9):501-518. Epub 2019 Jul 31 PubMed.
3. Serrano-Pozo A, Das S, Hyman BT. APOE and Alzheimer's disease: advances in genetics, pathophysiology, and therapeutic approaches. Lancet Neurol. 2021 Jan;20(1):68-80. PubMed.
4. Koutsodendris N, Nelson MR, Rao A, Huang Y. Apolipoprotein E and Alzheimer's Disease: Findings, Hypotheses, and Potential Mechanisms. Annu Rev Pathol. 2022 Jan 24;17:73-99. Epub 2021 Aug 30 PubMed.
5. Martens YA, Zhao N, Liu CC, Kanekiyo T, Yang AJ, Goate AM, Holtzman DM, Bu G. ApoE Cascade Hypothesis in the pathogenesis of Alzheimer's disease and related dementias. Neuron. 2022 Apr 20;110(8):1304-1317. Epub 2022 Mar 16 PubMed.
6. Weisgraber KH, Rall SC Jr, Mahley RW. Human E apoprotein heterogeneity. Cysteine-arginine interchanges in the amino acid sequence of the apo-E isoforms. J Biol Chem. 1981 Sep 10;256(17):9077-83. PubMed.
7. Zannis VI, Breslow JL. Human very low density lipoprotein apolipoprotein E isoprotein polymorphism is explained by genetic variation and posttranslational modification. Biochemistry. 1981 Feb 17;20(4):1033-41. PubMed.
8. Hanlon CS, Rubinsztein DC. Arginine residues at codons 112 and 158 in the apolipoprotein E gene correspond to the ancestral state in humans. Atherosclerosis. 1995 Jan 6;112(1):85-90. PubMed.
9. Seixas S, Trovoada MJ, Rocha J. Haplotype analysis of the apolipoprotein E and apolipoprotein C1 loci in Portugal and São Tomé e Príncipe (Gulf of Guinea): linkage disequilibrium evidence that APOE*4 is the ancestral APOE allele. Hum Biol. 1999 Dec;71(6):1001-8. PubMed.
10. Fullerton SM, Clark AG, Weiss KM, Nickerson DA, Taylor SL, Stengârd JH, Salomaa V, Vartiainen E, Perola M, Boerwinkle E, Sing CF. Apolipoprotein E variation at the sequence haplotype level: implications for the origin and maintenance of a major human polymorphism. Am J Hum Genet. 2000 Oct;67(4):881-900. Epub 2000 Sep 13 PubMed.
11. Abondio P, Sazzini M, Garagnani P, Boattini A, Monti D, Franceschi C, Luiselli D, Giuliani C. The Genetic Variability of APOE in Different Human Populations and Its Implications for Longevity. Genes (Basel). 2019 Mar 15;10(3) PubMed.
12. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993 Aug 13;261(5123):921-3. PubMed.
13. Saunders AM, Strittmatter WJ, Schmechel D, George-Hyslop PH, Pericak-Vance MA, Joo SH, Rosi BL, Gusella JF, Crapper-MacLachlan DR, Alberts MJ. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology. 1993 Aug;43(8):1467-72. PubMed.
14. Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1977-81. PubMed.
15. Poirier J, Davignon J, Bouthillier D, Kogan S, Bertrand P, Gauthier S. Apolipoprotein E polymorphism and Alzheimer's disease. Lancet. 1993 Sep 18;342(8873):697-9. PubMed.
16. Coon KD, Myers AJ, Craig DW, Webster JA, Pearson JV, Lince DH, Zismann VL, Beach TG, Leung D, Bryden L, Halperin RF, Marlowe L, Kaleem M, Walker DG, Ravid R, Heward CB, Rogers J, Papassotiropoulos A, Reiman EM, Hardy J, Stephan DA. A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer's disease. J Clin Psychiatry. 2007 Apr;68(4):613-8. PubMed.
17. Grupe A, Abraham R, Li Y, Rowland C, Hollingworth P, Morgan A, Jehu L, Segurado R, Stone D, Schadt E, Karnoub M, Nowotny P, Tacey K, Catanese J, Sninsky J, Brayne C, Rubinsztein D, Gill M, Lawlor B, Lovestone S, Holmans P, O'Donovan M, Morris JC, Thal L, Goate A, Owen MJ, Williams J. Evidence for novel susceptibility genes for late-onset Alzheimer's disease from a genome-wide association study of putative functional variants. Hum Mol Genet. 2007 Apr 15;16(8):865-73. Epub 2007 Feb 22 PubMed.
18. Reyes-Dumeyer D, Faber K, Vardarajan B, Goate A, Renton A, Chao M, Boeve B, Cruchaga C, Pericak-Vance M, Haines JL, Rosenberg R, Tsuang D, Sweet RA, Bennett DA, Wilson RS, Foroud T, Mayeux R. The National Institute on Aging Late-Onset Alzheimer's Disease Family Based Study: A resource for genetic discovery. Alzheimers Dement. 2022 Jan 3; PubMed.
19. Genin E, Hannequin D, Wallon D, Sleegers K, Hiltunen M, Combarros O, Bullido MJ, Engelborghs S, De Deyn P, Berr C, Pasquier F, Dubois B, Tognoni G, Fiévet N, Brouwers N, Bettens K, Arosio B, Coto E, Del Zompo M, Mateo I, Epelbaum J, Frank-Garcia A, Helisalmi S, Porcellini E, Pilotto A, Forti P, Ferri R, Scarpini E, Siciliano G, Solfrizzi V, Sorbi S, Spalletta G, Valdivieso F, Vepsäläinen S, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossù P, Hanon O, Piccardi P, Annoni G, Seripa D, Galimberti D, Licastro F, Soininen H, Dartigues JF, Kamboh MI, Van Broeckhoven C, Lambert JC, Amouyel P, Campion D. APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol Psychiatry. 2011 Sep;16(9):903-7. Epub 2011 May 10 PubMed.
21. Fortea J, Pegueroles J, Alcolea D, Belbin O, Dols-Icardo O, Vaqué-Alcázar L, Videla L, Gispert JD, Suárez-Calvet M, Johnson SC, Sperling R, Bejanin A, Lleó A, Montal V. APOE4 homozygozity represents a distinct genetic form of Alzheimer's disease. Nat Med. 2024 May;30(5):1284-1291. Epub 2024 May 6 PubMed. Correction.
22. Qian J, Wolters FJ, Beiser A, Haan M, Ikram MA, Karlawish J, Langbaum JB, Neuhaus JM, Reiman EM, Roberts JS, Seshadri S, Tariot PN, Woods BM, Betensky RA, Blacker D. APOE-related risk of mild cognitive impairment and dementia for prevention trials: An analysis of four cohorts. PLoS Med. 2017 Mar;14(3):e1002254. Epub 2017 Mar 21 PubMed.
23. Sando SB, Melquist S, Cannon A, Hutton ML, Sletvold O, Saltvedt I, White LR, Lydersen S, Aasly JO. APOE epsilon 4 lowers age at onset and is a high risk factor for Alzheimer's disease; a case control study from central Norway. BMC Neurol. 2008 Apr 16;8:9. PubMed.
24. de Rojas I, Moreno-Grau S, Tesi N, Grenier-Boley B, Andrade V, Jansen IE, Pedersen NL, Stringa N, Zettergren A, Hernández I, Montrreal L, Antúnez C, Antonell A, Tankard RM, Bis JC, Sims R, Bellenguez C, Quintela I, González-Perez A, Calero M, Franco-Macías E, Macías J, Blesa R, Cervera-Carles L, Menéndez-González M, Frank-García A, Royo JL, Moreno F, Huerto Vilas R, Baquero M, Diez-Fairen M, Lage C, García-Madrona S, García-González P, Alarcón-Martín E, Valero S, Sotolongo-Grau O, Ullgren A, Naj AC, Lemstra AW, Benaque A, Pérez-Cordón A, Benussi A, Rábano A, Padovani A, Squassina A, de Mendonça A, Arias Pastor A, Kok AA, Meggy A, Pastor AB, Espinosa A, Corma-Gómez A, Martín Montes A, Sanabria Á, DeStefano AL, Schneider A, Haapasalo A, Kinhult Ståhlbom A, Tybjærg-Hansen A, Hartmann AM, Spottke A, Corbatón-Anchuelo A, Rongve A, Borroni B, Arosio B, Nacmias B, Nordestgaard BG, Kunkle BW, Charbonnier C, Abdelnour C, Masullo C, Martínez Rodríguez C, Muñoz-Fernandez C, Dufouil C, Graff C, Ferreira CB, Chillotti C, Reynolds CA, Fenoglio C, Van Broeckhoven C, Clark C, Pisanu C, Satizabal CL, Holmes C, Buiza-Rueda D, Aarsland D, Rujescu D, Alcolea D, Galimberti D, Wallon D, Seripa D, Grünblatt E, Dardiotis E, Düzel E, Scarpini E, Conti E, Rubino E, Gelpi E, Rodriguez-Rodriguez E, Duron E, Boerwinkle E, Ferri E, Tagliavini F, Küçükali F, Pasquier F, Sanchez-Garcia F, Mangialasche F, Jessen F, Nicolas G, Selbæk G, Ortega G, Chêne G, Hadjigeorgiou G, Rossi G, Spalletta G, Giaccone G, Grande G, Binetti G, Papenberg G, Hampel H, Bailly H, Zetterberg H, Soininen H, Karlsson IK, Alvarez I, Appollonio I, Giegling I, Skoog I, Saltvedt I, Rainero I, Rosas Allende I, Hort J, Diehl-Schmid J, Van Dongen J, Vidal JS, Lehtisalo J, Wiltfang J, Thomassen JQ, Kornhuber J, Haines JL, Vogelgsang J, Pineda JA, Fortea J, Popp J, Deckert J, Buerger K, Morgan K, Fließbach K, Sleegers K, Molina-Porcel L, Kilander L, Weinhold L, Farrer LA, Wang LS, Kleineidam L, Farotti L, Parnetti L, Tremolizzo L, Hausner L, Benussi L, Froelich L, Ikram MA, Deniz-Naranjo MC, Tsolaki M, Rosende-Roca M, Löwenmark M, Hulsman M, Spallazzi M, Pericak-Vance MA, Esiri M, Bernal Sánchez-Arjona M, Dalmasso MC, Martínez-Larrad MT, Arcaro M, Nöthen MM, Fernández-Fuertes M, Dichgans M, Ingelsson M, Herrmann MJ, Scherer M, Vyhnalek M, Kosmidis MH, Yannakoulia M, Schmid M, Ewers M, Heneka MT, Wagner M, Scamosci M, Kivipelto M, Hiltunen M, Zulaica M, Alegret M, Fornage M, Roberto N, van Schoor NM, Seidu NM, Banaj N, Armstrong NJ, Scarmeas N, Scherbaum N, Goldhardt O, Hanon O, Peters O, Skrobot OA, Quenez O, Lerch O, Bossù P, Caffarra P, Dionigi Rossi P, Sakka P, Hoffmann P, Holmans PA, Fischer P, Riederer P, Yang Q, Marshall R, Kalaria RN, Mayeux R, Vandenberghe R, Cecchetti R, Ghidoni R, Frikke-Schmidt R, Sorbi S, Hägg S, Engelborghs S, Helisalmi S, Botne Sando S, Kern S, Archetti S, Boschi S, Fostinelli S, Gil S, Mendoza S, Mead S, Ciccone S, Djurovic S, Heilmann-Heimbach S, Riedel-Heller S, Kuulasmaa T, Del Ser T, Lebouvier T, Polak T, Ngandu T, Grimmer T, Bessi V, Escott-Price V, Giedraitis V, Deramecourt V, Maier W, Jian X, Pijnenburg YA, EADB contributors, GR@ACE study group, DEGESCO consortium, IGAP (ADGC, CHARGE, EADI, GERAD), PGC-ALZ consortia, Kehoe PG, Garcia-Ribas G, Sánchez-Juan P, Pastor P, Pérez-Tur J, Piñol-Ripoll G, Lopez de Munain A, García-Alberca JM, Bullido MJ, Álvarez V, Lleó A, Real LM, Mir P, Medina M, Scheltens P, Holstege H, Marquié M, Sáez ME, Carracedo Á, Amouyel P, Schellenberg GD, Williams J, Seshadri S, van Duijn CM, Mather KA, Sánchez-Valle R, Serrano-Ríos M, Orellana A, Tárraga L, Blennow K, Huisman M, Andreassen OA, Posthuma D, Clarimón J, Boada M, van der Flier WM, Ramirez A, Lambert JC, van der Lee SJ, Ruiz A. Common variants in Alzheimer's disease and risk stratification by polygenic risk scores. Nat Commun. 2021 Jun 7;12(1):3417. PubMed. Correction.
25. Therneau TM, Knopman DS, Lowe VJ, Botha H, Graff-Radford J, Jones DT, Vemuri P, Mielke MM, Schwarz CG, Senjem ML, Gunter JL, Petersen RC, Jack CR Jr. Relationships between β-amyloid and tau in an elderly population: An accelerated failure time model. Neuroimage. 2021 Nov 15;242:118440. Epub 2021 Jul 29 PubMed.
26. Blömeke L, Rehn F, Kraemer-Schulien V, Kutzsche J, Pils M, Bujnicki T, Lewczuk P, Kornhuber J, Freiesleben SD, Schneider LS, Preis L, Priller J, Spruth EJ, Altenstein S, Lohse A, Schneider A, Fliessbach K, Wiltfang J, Hansen N, Rostamzadeh A, Düzel E, Glanz W, Incesoy EI, Butryn M, Buerger K, Janowitz D, Ewers M, Perneczky R, Rauchmann BS, Teipel S, Kilimann I, Goerss D, Laske C, Munk MH, Sanzenbacher C, Spottke A, Roy-Kluth N, Heneka MT, Brosseron F, Wagner M, Wolfsgruber S, Kleineidam L, Stark M, Schmid M, Jessen F, Bannach O, Willbold D, Peters O. Aβ oligomers peak in early stages of Alzheimer's disease preceding tau pathology. Alzheimers Dement (Amst). 2024;16(2):e12589. Epub 2024 Apr 25 PubMed. Correction.
27. Mares J, Costa AP, Dartora WJ, Wartchow KM, Lazarian A, Bennett DA, Nuriel T, Menon V, McIntire LB. Brain and serum lipidomic profiles implicate Lands cycle acyl chain remodeling association with APOEε4 and mild cognitive impairment. Front Aging Neurosci. 2024;16:1419253. Epub 2024 Jun 11 PubMed.
28. Bejanin A, Iulita MF, Vilaplana E, Carmona-Iragui M, Benejam B, Videla L, Barroeta I, Fernandez S, Altuna M, Pegueroles J, Montal V, Valldeneu S, Giménez S, González-Ortiz S, Muñoz L, Padilla C, Aranha MR, Estellés T, Illán-Gala I, Belbin O, Camacho V, Wilson LR, Annus T, Osorio RS, Videla S, Lehmann S, Holland AJ, Zetterberg H, Blennow K, Alcolea D, Clarimon J, Zaman SH, Blesa R, Lleó A, Fortea J. Association of Apolipoprotein E ɛ4 Allele With Clinical and Multimodal Biomarker Changes of Alzheimer Disease in Adults With Down Syndrome. JAMA Neurol. 2021 Aug 1;78(8):937-947. PubMed.
29. Hendriks S, Ranson JM, Peetoom K, Lourida I, Tai XY, de Vugt M, Llewellyn DJ, Köhler S. Risk Factors for Young-Onset Dementia in the UK Biobank. JAMA Neurol. 2024 Feb 1;81(2):134-142. PubMed.
30. Hammers DB, Eloyan A, Taurone A, Thangarajah M, Beckett L, Gao S, Kirby K, Aisen P, Dage JL, Foroud T, Griffin P, Grinberg LT, Jack CR Jr, Kramer J, Koeppe R, Kukull WA, Mundada NS, La Joie R, Soleimani-Meigooni DN, Iaccarino L, Murray ME, Nudelman K, Polsinelli AJ, Rumbaugh M, Toga A, Touroutoglou A, Vemuri P, Atri A, Day GS, Duara R, Graff-Radford NR, Honig LS, Jones DT, Masdeu J, Mendez MF, Womack K, Musiek E, Onyike CU, Riddle M, Rogalski E, Salloway S, Sha SJ, Turner RS, Wingo TS, Wolk DA, Carrillo MC, Dickerson BC, Rabinovici GD, Apostolova LG, LEADS Consortium. Profiling baseline performance on the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) cohort near the midpoint of data collection. Alzheimers Dement. 2023 May 31; PubMed.
31. Langella S, Barksdale NG, Vasquez D, Aguillon D, Chen Y, Su Y, Acosta-Baena N, Acosta-Uribe J, Baena AY, Garcia-Ospina G, Giraldo-Chica M, Tirado V, Muñoz C, Ríos-Romenets S, Guzman-Martínez C, Oliveira G, Yang HS, Vila-Castelar C, Pruzin JJ, Ghisays V, Arboleda-Velasquez JF, Kosik KS, Reiman EM, Lopera F, Quiroz YT. Effect of apolipoprotein genotype and educational attainment on cognitive function in autosomal dominant Alzheimer's disease. Nat Commun. 2023 Aug 23;14(1):5120. PubMed.
32. Almkvist O, Johansson C, Laffita-Mesa J, Thordardottir S, Graff C. APOE ε4 influences cognitive decline positively in APP and negatively in PSEN1 mutation carriers with autosomal-dominant Alzheimer's disease. Eur J Neurol. 2022 Dec;29(12):3580-3589. Epub 2022 Sep 11 PubMed.
33. Jutten RJ, Sikkes SA, Van der Flier WM, Scheltens P, Visser PJ, Tijms BM, Alzheimer's Disease Neuroimaging Initiative. Finding Treatment Effects in Alzheimer Trials in the Face of Disease Progression Heterogeneity. Neurology. 2021 Jun 1;96(22):e2673-e2684. PubMed.
34. Qian J, Betensky RA, Hyman BT, Serrano-Pozo A. Association of APOE Genotype With Heterogeneity of Cognitive Decline Rate in Alzheimer Disease. Neurology. 2021 May 11;96(19):e2414-e2428. Epub 2021 Mar 26 PubMed.
35. Katzourou I, Leonenko G, Ivanov D, Meggy A, Marshall R, Sims R, Williams J, Holmans P, Escott-Price V, Alzheimer’s Disease Neuroimaging Initiative. Cognitive Decline in Alzheimer's Disease Is Not Associated with APOE. J Alzheimers Dis. 2021;84(1):141-149. PubMed.
36. Vermunt L, Sikkes SA, van den Hout A, Handels R, Bos I, van der Flier WM, Kern S, Ousset PJ, Maruff P, Skoog I, Verhey FR, Freund-Levi Y, Tsolaki M, Wallin ÅK, Olde Rikkert M, Soininen H, Spiru L, Zetterberg H, Blennow K, Scheltens P, Muniz-Terrera G, Visser PJ, Alzheimer Disease Neuroimaging Initiative, AIBL Research Group, ICTUS/DSA study groups. Duration of preclinical, prodromal, and dementia stages of Alzheimer's disease in relation to age, sex, and APOE genotype. Alzheimers Dement. 2019 Jul;15(7):888-898. Epub 2019 Jun 1 PubMed.
37. Steward A, Biel D, Dewenter A, Roemer S, Wagner F, Dehsarvi A, Rathore S, Otero Svaldi D, Higgins I, Brendel M, Dichgans M, Shcherbinin S, Ewers M, Franzmeier N. ApoE4 and Connectivity-Mediated Spreading of Tau Pathology at Lower Amyloid Levels. JAMA Neurol. 2023 Dec 1;80(12):1295-1306. PubMed.
38. Altmann A, Aksman LM, Oxtoby NP, Young A, ADNI, Alexander DC, Barkhof F, Shoai M, Hardy J, Schott JM. Towards cascading genetic risk in Alzheimer's disease. Brain. 2024 May 31; PubMed.
39. Thierry M, Ponce J, Martà-Ariza M, Askenazi M, Faustin A, Leitner D, Pires G, Kanshin E, Drummond E, Ueberheide B, Wisniewski T. The influence of APOEε4 on the pTau interactome in sporadic Alzheimer's disease. Acta Neuropathol. 2024 May 21;147(1):91. PubMed.
40. Qian J, Zhang Y, Betensky RA, Hyman BT, Serrano-Pozo A. Neuropathology-Independent Association Between APOE Genotype and Cognitive Decline Rate in the Normal Aging-Early Alzheimer Continuum. Neurol Genet. 2023 Feb;9(1):e200055. Epub 2023 Jan 20 PubMed.
41. Vogel JW, Young AL, Oxtoby NP, Smith R, Ossenkoppele R, Strandberg OT, La Joie R, Aksman LM, Grothe MJ, Iturria-Medina Y, Alzheimer’s Disease Neuroimaging Initiative, Pontecorvo MJ, Devous MD, Rabinovici GD, Alexander DC, Lyoo CH, Evans AC, Hansson O. Four distinct trajectories of tau deposition identified in Alzheimer's disease. Nat Med. 2021 May;27(5):871-881. Epub 2021 Apr 29 PubMed.
42. Frisoni GB, Altomare D, Thal DR, Ribaldi F, van der Kant R, Ossenkoppele R, Blennow K, Cummings J, van Duijn C, Nilsson PM, Dietrich PY, Scheltens P, Dubois B. The probabilistic model of Alzheimer disease: the amyloid hypothesis revised. Nat Rev Neurosci. 2022 Jan;23(1):53-66. Epub 2021 Nov 23 PubMed.
43. Dai J, Johnson EC, Dammer EB, Duong DM, Gearing M, Lah JJ, Levey AI, Wingo TS, Seyfried NT. Effects of APOE Genotype on Brain Proteomic Network and Cell Type Changes in Alzheimer's Disease. Front Mol Neurosci. 2018;11:454. Epub 2018 Dec 18 PubMed.
44. Zhao N, Ren Y, Yamazaki Y, Qiao W, Li F, Felton LM, Mahmoudiandehkordi S, Kueider-Paisley A, Sonoustoun B, Arnold M, Shue F, Zheng J, Attrebi ON, Martens YA, Li Z, Bastea L, Meneses AD, Chen K, Thompson JW, St John-Williams L, Tachibana M, Aikawa T, Oue H, Job L, Yamazaki A, Liu CC, Storz P, Asmann YW, Ertekin-Taner N, Kanekiyo T, Kaddurah-Daouk R, Bu G. Alzheimer's Risk Factors Age, APOE Genotype, and Sex Drive Distinct Molecular Pathways. Neuron. 2020 Jun 3;106(5):727-742.e6. Epub 2020 Mar 20 PubMed.
45. Konijnenberg E, Tijms BM, Gobom J, Dobricic V, Bos I, Vos S, Tsolaki M, Verhey F, Popp J, Martinez-Lage P, Vandenberghe R, Lleó A, Frölich L, Lovestone S, Streffer J, Bertram L, Blennow K, Teunissen CE, Veerhuis R, Smit AB, Scheltens P, Zetterberg H, Visser PJ. APOE ε4 genotype-dependent cerebrospinal fluid proteomic signatures in Alzheimer's disease. Alzheimers Res Ther. 2020 May 27;12(1):65. PubMed.
46. Madrid L, Moreno-Grau S, Ahmad S, González-Pérez A, de Rojas I, Xia R, Martino Adami PV, García-González P, Kleineidam L, Yang Q, Damotte V, Bis JC, Noguera-Perea F, Bellenguez C, Jian X, Marín-Muñoz J, Grenier-Boley B, Orellana A, Ikram MA, Amouyel P, Satizabal CL, Alzheimer’s Disease Neuroimaging Initiative (ADNI)*, EADI consortium, CHARGE consortium, GERAD consortium, GR@ACE/DEGESCO consortium, Real LM, Antúnez-Almagro C, DeStefano A, Cabrera-Socorro A, Sims R, Van Duijn CM, Boerwinkle E, Ramírez A, Fornage M, Lambert JC, Williams J, Seshadri S, ADAPTED consortium, Ried JS, Ruiz A, Saez ME. Multiomics integrative analysis identifies APOE allele-specific blood biomarkers associated to Alzheimer's disease etiopathogenesis. Aging (Albany NY). 2021 Apr 12;13(7):9277-9329. PubMed.
47. Chang R, Trushina E, Zhu K, Zaidi SS, Lau BM, Kueider-Paisley A, Moein S, He Q, Alamprese ML, Vagnerova B, Tang A, Vijayan R, Liu Y, Saykin AJ, Brinton RD, Kaddurah-Daouk R, Alzheimer's Disease Neuroimaging Initiative† and the Alzheimer's Disease Metabolomics Consortium. Predictive metabolic networks reveal sex- and APOE genotype-specific metabolic signatures and drivers for precision medicine in Alzheimer's disease. Alzheimers Dement. 2022 Apr 28; PubMed.
48. Das S, Li Z, Wachter A, Alla S, Noori A, Abdourahman A, Tamm JA, Woodbury ME, Talanian RV, Biber K, Karran EH, Hyman BT, Serrano-Pozo A. Distinct transcriptomic responses to Aβ plaques, neurofibrillary tangles, and APOE in Alzheimer's disease. Alzheimers Dement. 2023 Jul 17; PubMed.
49. Brase L, You SF, D'Oliveira Albanus R, Del-Aguila JL, Dai Y, Novotny BC, Soriano-Tarraga C, Dykstra T, Fernandez MV, Budde JP, Bergmann K, Morris JC, Bateman RJ, Perrin RJ, McDade E, Xiong C, Goate AM, Farlow M, Dominantly Inherited Alzheimer Network (DIAN), Sutherland GT, Kipnis J, Karch CM, Benitez BA, Harari O. Single-nucleus RNA-sequencing of autosomal dominant Alzheimer disease and risk variant carriers. Nat Commun. 2023 Apr 21;14(1):2314. PubMed.
50. Frick EA, Emilsson V, Jonmundsson T, Steindorsdottir AE, Johnson EC, Puerta R, Dammer EB, Shantaraman A, Cano A, Boada M, Valero S, Garcia-Gonzalez P, Gudmundsson EF, Gudjonsson A, Loureiro JJ, Orth AP, Seyfried NT, Levey AI, Ruiz A, Aspelund T, Jennings LL, Launer LJ, Gudmundsdottir V, Gudnason V. Serum proteomics reveals APOE dependent and independent protein signatures in Alzheimer's disease. 2023 Nov 09 10.1101/2023.11.08.23298251 (version 1) medRxiv.
51. Oveisgharan S, Yu L, de Paiva Lopes K, Tasaki S, Wang Y, Menon V, Schneider JA, Seyfried NT, Bennett DA. Proteins linking APOE ɛ4 with Alzheimer's disease. Alzheimers Dement. 2024 Jun 10; PubMed.
52. Shvetcov A, Thomson S, Cho A-N, Wilkins HM, Reed JH, Swerdlow RH, Brown DA, Alzheimer'sDiseaseNeuroimagingInitiative, Finney CA. Cerebrospinal fluid proteome profiling using machine learning shows a unique protein signature associated with APOE4 genotype. 2024 Apr 22 10.1101/2024.04.18.590160 (version 1) bioRxiv.
53. Dammer EB, Shantaraman A, Ping L, Duong DM, Gerasimov ES, Ravindran SP, Gudmundsdottir V, Frick EA, Gomez GT, Walker KA, Emilsson V, Jennings LL, Gudnason V, Western D, Cruchaga C, Lah JJ, Wingo TS, Wingo AP, Seyfried NT, Levey AI, Johnson EC. Proteomic analysis of Alzheimer's disease cerebrospinal fluid reveals alterations associated with APOE ε4 and atomoxetine treatment. Sci Transl Med. 2024 Jun 26;16(753):eadn3504. PubMed.
54. Emrani S, Arain HA, DeMarshall C, Nuriel T. APOE4 is associated with cognitive and pathological heterogeneity in patients with Alzheimer's disease: a systematic review. Alzheimers Res Ther. 2020 Nov 4;12(1):141. PubMed.
55. La Joie R, Visani AV, Lesman-Segev OH, Baker SL, Edwards L, Iaccarino L, Soleimani-Meigooni DN, Mellinger T, Janabi M, Miller ZA, Perry DC, Pham J, Strom A, Gorno-Tempini ML, Rosen HJ, Miller BL, Jagust WJ, Rabinovici GD. Association of APOE4 and Clinical Variability in Alzheimer Disease With the Pattern of Tau- and Amyloid-PET. Neurology. 2021 Feb 2;96(5):e650-e661. Epub 2020 Dec 1 PubMed.
56. Wearn A, Tremblay SA, Tardif CL, Leppert IR, Gauthier CJ, Baracchini G, Hughes C, Hewan P, Tremblay-Mercier J, Rosa-Neto P, Poirier J, Villeneuve S, Schmitz TW, Turner GR, Spreng RN, PREVENT-AD Research Group. Neuromodulatory subcortical nucleus integrity is associated with white matter microstructure, tauopathy and APOE status. Nat Commun. 2024 Jun 3;15(1):4706. PubMed.
57. Tao Q, Zhang C, Mercier G, Lunetta K, Ang TF, Akhter-Khan S, Zhang Z, Taylor A, Killiany RJ, Alosco M, Mez J, Au R, Zhang X, Farrer LA, Qiu WW, Alzheimer's Disease Neuroimaging Initiative. Identification of an APOE ε4-specific blood-based molecular pathway for Alzheimer's disease risk. Alzheimers Dement (Amst). 2023;15(4):e12490. Epub 2023 Oct 16 PubMed.
58. Montagne A, Nation DA, Sagare AP, Barisano G, Sweeney MD, Chakhoyan A, Pachicano M, Joe E, Nelson AR, D'Orazio LM, Buennagel DP, Harrington MG, Benzinger TL, Fagan AM, Ringman JM, Schneider LS, Morris JC, Reiman EM, Caselli RJ, Chui HC, Tcw J, Chen Y, Pa J, Conti PS, Law M, Toga AW, Zlokovic BV. APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. Nature. 2020 May;581(7806):71-76. Epub 2020 Apr 29 PubMed.
59. Chen Z, Schwulst SJ, Mentis AA. APOE4-mediated Alzheimer disease and "Vascular"-"Meningeal Lymphatic" components: towards a novel therapeutic era?. Mol Psychiatry. 2021 Oct;26(10):5472-5474. Epub 2021 Aug 10 PubMed. Correction.
60. Sun N, Akay LA, Murdock MH, Park Y, Galiana-Melendez F, Bubnys A, Galani K, Mathys H, Jiang X, Ng AP, Bennett DA, Tsai LH, Kellis M. Single-nucleus multiregion transcriptomic analysis of brain vasculature in Alzheimer's disease. Nat Neurosci. 2023 Jun;26(6):970-982. PubMed. Correction.
61. Cacciaglia R, Operto G, Falcón C, de Echavarri-Gómez JM, Sánchez-Benavides G, Brugulat-Serrat A, Milà-Alomà M, Blennow K, Zetterberg H, Molinuevo JL, Suárez-Calvet M, Gispert JD, ALFA study. Genotypic effects of APOE-ε4 on resting-state connectivity in cognitively intact individuals support functional brain compensation. Cereb Cortex. 2022 Jun 27; PubMed.
62. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997 Oct 22-29;278(16):1349-56. PubMed.
63. Bickeböller H, Campion D, Brice A, Amouyel P, Hannequin D, Didierjean O, Penet C, Martin C, Pérez-Tur J, Michon A, Dubois B, Ledoze F, Thomas-Anterion C, Pasquier F, Puel M, Demonet JF, Moreaud O, Babron MC, Meulien D, Guez D, Chartier-Harlin MC, Frebourg T, Agid Y, Martinez M, Clerget-Darpoux F. Apolipoprotein E and Alzheimer disease: genotype-specific risks by age and sex. Am J Hum Genet. 1997 Feb;60(2):439-46. PubMed.
64. Altmann A, Tian L, Henderson VW, Greicius MD, Alzheimer's Disease Neuroimaging Initiative Investigators. Sex modifies the APOE-related risk of developing Alzheimer disease. Ann Neurol. 2014 Apr;75(4):563-73. Epub 2014 Apr 14 PubMed.
65. Neu SC, Pa J, Kukull W, Beekly D, Kuzma A, Gangadharan P, Wang LS, Romero K, Arneric SP, Redolfi A, Orlandi D, Frisoni GB, Au R, Devine S, Auerbach S, Espinosa A, Boada M, Ruiz A, Johnson SC, Koscik R, Wang JJ, Hsu WC, Chen YL, Toga AW. Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-analysis. JAMA Neurol. 2017 Oct 1;74(10):1178-1189. PubMed.
66. Nemes S, Logan PE, Manchella MK, Mundada NS, La Joie R, Polsinelli AJ, Hammers DB, Koeppe RA, Foroud TM, Nudelman KN, Eloyan A, Iaccarino L, Dorsant-Ardón V, Taurone A, Thangarajah M, Dage JL, Aisen P, Grinberg LT, Jack CR Jr, Kramer J, Kukull WA, Murray ME, Rumbaugh M, Soleimani-Meigooni DN, Toga A, Touroutoglou A, Vemuri P, Atri A, Day GS, Duara R, Graff-Radford NR, Honig LS, Jones DT, Masdeu J, Mendez MF, Musiek E, Onyike CU, Riddle M, Rogalski E, Salloway S, Sha SJ, Turner RS, Wingo TS, Womack KB, Wolk DA, Rabinovici GD, Carrillo MC, Dickerson BC, Apostolova LG, LEADS Consortium. Sex and APOE ε4 carrier effects on atrophy, amyloid PET, and tau PET burden in early-onset Alzheimer's disease. Alzheimers Dement. 2023 Nov;19 Suppl 9:S49-S63. Epub 2023 Jul 26 PubMed.
67. Belloy ME, Andrews SJ, Le Guen Y, Cuccaro M, Farrer LA, Napolioni V, Greicius MD. APOE Genotype and Alzheimer Disease Risk Across Age, Sex, and Population Ancestry. JAMA Neurol. 2023 Dec 1;80(12):1284-1294. PubMed.
68. Rohde SK, Fierro-Hernandez P, Rozemuller AJ, NetherlandsBrainBank, Lorenz LM, Zhang M, Graat M, vanderHoorn M, Daatselaar D, Hulsman M, Scheltens P, Sikkes SA, Hoozemans JJ, Holstege H. Resistance to cortical amyloid-beta associates with cognitive health in centenarians. 2023 Dec 29 10.1101/2023.12.28.23300604 (version 1) medRxiv.
69. Hohman TJ, Dumitrescu L, Barnes LL, Thambisetty M, Beecham G, Kunkle B, Gifford KA, Bush WS, Chibnik LB, Mukherjee S, De Jager PL, Kukull W, Crane PK, Resnick SM, Keene CD, Montine TJ, Schellenberg GD, Haines JL, Zetterberg H, Blennow K, Larson EB, Johnson SC, Albert M, Bennett DA, Schneider JA, Jefferson AL, Alzheimer’s Disease Genetics Consortium and the Alzheimer’s Disease Neuroimaging Initiative. Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau. JAMA Neurol. 2018 Aug 1;75(8):989-998. PubMed.
70. Babapour Mofrad R, Tijms BM, Scheltens P, Barkhof F, van der Flier WM, Sikkes SA, Teunissen CE. Sex differences in CSF biomarkers vary by Alzheimer disease stage and APOE ε4 genotype. Neurology. 2020 Oct 27;95(17):e2378-e2388. Epub 2020 Aug 11 PubMed.
71. Savignac C, Villeneuve S, Badhwar A, Saltoun K, Shafighi K, Zajner C, Sharma V, Gagliano Taliun SA, Farhan S, Poirier J, Bzdok D. APOE alleles are associated with sex-specific structural differences in brain regions affected in Alzheimer's disease and related dementia. PLoS Biol. 2022 Dec;20(12):e3001863. Epub 2022 Dec 13 PubMed.
72. Xiong J, Kang SS, Wang M, Wang Z, Xia Y, Liao J, Liu X, Yu SP, Zhang Z, Ryu V, Yuen T, Zaidi M, Ye K. FSH and ApoE4 contribute to Alzheimer's disease-like pathogenesis via C/EBPβ/δ-secretase in female mice. Nat Commun. 2023 Oct 18;14(1):6577. PubMed.
73. Jiang Y, Zhou X, Wong HY, Ouyang L, FCF Ip, Chau VMN, Lau SF, Wu W, Wong DYK, Seo H, Fu WY, Lai NCH, Chen Y, Chen Y, Tong EPS, Alzheimer’s Disease Neuroimaging Initiative, Mok VCT, Kwok TCY, Mok KY, Shoai M, Lehallier B, Losada PM, O’Brien E, Porter T, Laws SM, Hardy J, Wyss-Coray T, Masters CL, Fu AKY, Ip NY. An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-ε4 in female patients with Alzheimer’s disease. Nat Aging (2022). Nature Aging
74. Panitch R, Sahelijo N, Hu J, Nho K, Bennett DA, Lunetta KL, Au R, Stein TD, Farrer LA, Jun GR. APOE genotype-specific methylation patterns are linked to Alzheimer disease pathology and estrogen response. Transl Psychiatry. 2024 Feb 29;14(1):129. PubMed.
75. Samuelsson J, Najar J, Wallengren O, Kern S, Wetterberg H, Mellqvist Fässberg M, Zetterberg H, Blennow K, Lissner L, Rothenberg E, Skoog I, Zettergren A. Interactions between dietary patterns and genetic factors in relation to incident dementia among 70-year-olds. Eur J Nutr. 2022 Mar;61(2):871-884. Epub 2021 Oct 10 PubMed.
76. Jia J, Zhao T, Liu Z, Liang Y, Li F, Li Y, Liu W, Li F, Shi S, Zhou C, Yang H, Liao Z, Li Y, Zhao H, Zhang J, Zhang K, Kan M, Yang S, Li H, Liu Z, Ma R, Lv J, Wang Y, Yan X, Liang F, Yuan X, Zhang J, Gauthier S, Cummings J. Association between healthy lifestyle and memory decline in older adults: 10 year, population based, prospective cohort study. BMJ. 2023 Jan 25;380:e072691. PubMed.
78. Rajabli F, Seixas AA, Akgun B, Adams LD, Inciute J, Hamilton KL, Whithead PG, Konidari I, Gu T, Arvizu J, Golightly CG, Starks TD, Laux R, Byrd GS, Haines JL, Beecham GW, Griswold AJ, Vance JM, Cuccaro ML, Pericak-Vance MA. African Ancestry Individuals with Higher Educational Attainment Are Resilient to Alzheimer's Disease Measured by pTau181. J Alzheimers Dis. 2024;98(1):221-229. PubMed.
80. Kim YW, Al-Ramahi I, Koire A, Wilson SJ, Konecki DM, Mota S, Soleimani S, Botas J, Lichtarge O. Harnessing the paradoxical phenotypes of APOE ɛ2 and APOE ɛ4 to identify genetic modifiers in Alzheimer's disease. Alzheimers Dement. 2021 May;17(5):831-846. Epub 2020 Dec 7 PubMed.
81. Ebenau JL, van der Lee SJ, Hulsman M, Tesi N, Jansen IE, Verberk IM, van Leeuwenstijn M, Teunissen CE, Barkhof F, Prins ND, Scheltens P, Holstege H, van Berckel BN, van der Flier WM. Risk of dementia in APOE ε4 carriers is mitigated by a polygenic risk score. Alzheimers Dement (Amst). 2021;13(1):e12229. Epub 2021 Sep 14 PubMed.
82. Huq AJ, Fulton-Howard B, Riaz M, Laws S, Sebra R, Ryan J, Alzheimer's Disease Genetics Consortium, Renton AE, Goate AM, Masters CL, Storey E, Shah RC, Murray A, McNeil J, Winship I, James PA, Lacaze P. Polygenic score modifies risk for Alzheimer's disease in APOE ε4 homozygotes at phenotypic extremes. Alzheimers Dement (Amst). 2021;13(1):e12226. Epub 2021 Aug 5 PubMed.
83. Nazarian A, Loika Y, He L, Culminskaya I, Kulminski AM. Genome-wide analysis identified abundant genetic modulators of contributions of the apolipoprotein E alleles to Alzheimer's disease risk. Alzheimers Dement. 2022 Nov;18(11):2067-2078. Epub 2022 Jan 3 PubMed.
84. Nazarian A, Philipp I, Culminskaya I, He L, Kulminski AM. Inter- and intra-chromosomal modulators of the APOE ɛ2 and ɛ4 effects on the Alzheimer's disease risk. Geroscience. 2022 Jul 9; PubMed.
85. Le Guen Y, Belloy ME, Grenier-Boley B, de Rojas I, Castillo-Morales A, Jansen I, Nicolas A, Bellenguez C, Dalmasso C, Küçükali F, Eger SJ, Rasmussen KL, Thomassen JQ, Deleuze JF, He Z, Napolioni V, Amouyel P, Jessen F, Kehoe PG, van Duijn C, Tsolaki M, Sánchez-Juan P, Sleegers K, Ingelsson M, Rossi G, Hiltunen M, Sims R, van der Flier WM, Ramirez A, Andreassen OA, Frikke-Schmidt R, Williams J, Ruiz A, Lambert JC, Greicius MD, Members of the EADB, GR@ACE, DEGESCO, DemGene, GERAD, and EADI Groups, Arosio B, Benussi L, Boland A, Borroni B, Caffarra P, Daian D, Daniele A, Debette S, Dufouil C, Düzel E, Galimberti D, Giedraitis V, Grimmer T, Graff C, Grünblatt E, Hanon O, Hausner L, Heilmann-Heimbach S, Holstege H, Hort J, Jürgen D, Kuulasmaa T, van der Lugt A, Masullo C, Mecocci P, Mehrabian S, de Mendonça A, Moebus S, Nacmias B, Nicolas G, Olaso R, Papenberg G, Parnetti L, Pasquier F, Peters O, Pijnenburg YA, Popp J, Rainero I, Ramakers I, Riedel-Heller S, Scarmeas N, Scheltens P, Scherbaum N, Schneider A, Seripa D, Soininen H, Solfrizzi V, Spalletta G, Squassina A, van Swieten J, Tegos TJ, Tremolizzo L, Verhey F, Vyhnalek M, Wiltfang J, Boada M, García-González P, Puerta R, Real LM, Álvarez V, Bullido MJ, Clarimon J, García-Alberca JM, Mir P, Moreno F, Pastor P, Piñol-Ripoll G, Molina-Porcel L, Pérez-Tur J, Rodríguez-Rodríguez E, Royo JL, Sánchez-Valle R, Dichgans M, Rujescu D. Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease. JAMA Neurol. 2022 Jul 1;79(7):652-663. PubMed.
86. Nelson MR, Liu P, Agrawal A, Yip O, Blumenfeld J, Traglia M, Kim MJ, Koutsodendris N, Rao A, Grone B, Hao Y, Yoon SY, Xu Q, De Leon S, Choenyi T, Thomas R, Lopera F, Quiroz YT, Arboleda-Velasquez JF, Reiman EM, Mahley RW, Huang Y. The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. Nat Neurosci. 2023 Dec;26(12):2104-2121. Epub 2023 Nov 13 PubMed.
87. Erickson CM, Schultz SA, Oh JM, Darst BF, Ma Y, Norton D, Betthauser T, Gallagher CL, Carlsson CM, Bendlin BB, Asthana S, Hermann BP, Sager MA, Blennow K, Zetterberg H, Engelman CD, Christian BT, Johnson SC, Dubal DB, Okonkwo OC. KLOTHO heterozygosity attenuates APOE4-related amyloid burden in preclinical AD. Neurology. 2019 Apr 16;92(16):e1878-e1889. Epub 2019 Mar 13 PubMed.
88. Belloy ME, Napolioni V, Han SS, Le Guen Y, Greicius MD, Alzheimer’s Disease Neuroimaging Initiative. Association of Klotho-VS Heterozygosity With Risk of Alzheimer Disease in Individuals Who Carry APOE4. JAMA Neurol. 2020 Jul 1;77(7):849-862. PubMed.
89. Neitzel J, Franzmeier N, Rubinski A, Dichgans M, Brendel M, Alzheimer’s Disease Neuroimaging Initiative (ADNI), Malik R, Ewers M. KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer's disease. Nat Commun. 2021 Jun 22;12(1):3825. PubMed.
90. Belloy ME, Eger SJ, Le Guen Y, Napolioni V, Deters KD, Yang HS, Scelsi MA, Porter T, James SN, Wong A, Schott JM, Sperling RA, Laws SM, Mormino EC, He Z, Han SS, Altmann A, Greicius MD, A4 Study Team, Insight 46 Study Team, Australian Imaging Biomarkers and Lifestyle (AIBL) Study, Alzheimer's Disease Neuroimaging Initiative. KL∗VS heterozygosity reduces brain amyloid in asymptomatic at-risk APOE∗4 carriers. Neurobiol Aging. 2021 May;101:123-129. Epub 2021 Jan 23 PubMed.
91. Driscoll I, Ma Y, Gallagher CL, Johnson SC, Asthana S, Hermann BP, Sager MA, Blennow K, Zetterberg H, Carlsson CM, Engelman CD, Dubal DB, Okonkwo OC. Age-Related Tau Burden and Cognitive Deficits Are Attenuated in KLOTHO KL-VS Heterozygotes. J Alzheimers Dis. 2021;79(3):1297-1305. PubMed.
92. Ali M, Sung YJ, Wang F, Fernández MV, Morris JC, Fagan AM, Blennow K, Zetterberg H, Heslegrave A, Johansson PM, Svensson J, Nellgård B, Lleó A, Alcolea D, Clarimon J, Rami L, Molinuevo JL, Suárez-Calvet M, Morenas-Rodríguez E, Kleinberger G, Haass C, Ewers M, Levin J, Farlow MR, Perrin RJ, Alzheimer’s Disease Neuroimaging Initiative (ADNI), Dominantly Inherited Alzheimer Network (DIAN), Cruchaga C. Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk. PLoS One. 2022;17(5):e0267298. Epub 2022 May 26 PubMed.
93. Grøntvedt GR, Sando SB, Lauridsen C, Bråthen G, White LR, Salvesen Ø, Aarsland D, Hessen E, Fladby T, Waterloo K, Scheffler K. Association of Klotho Protein Levels and KL-VS Heterozygosity With Alzheimer Disease and Amyloid and Tau Burden. JAMA Netw Open. 2022 Nov 1;5(11):e2243232. PubMed.
94. Chen XR, Shao Y, Sadowski MJ, On Behalf Of The Alzheimer's Disease Neuroimaging Initiative. Interaction between KLOTHO-VS Heterozygosity and APOE ε4 Allele Predicts Rate of Cognitive Decline in Late-Onset Alzheimer's Disease. Genes (Basel). 2023 Apr 15;14(4) PubMed.
95. van der Lee SJ, Conway OJ, Jansen I, Carrasquillo MM, Kleineidam L, van den Akker E, Hernández I, van Eijk KR, Stringa N, Chen JA, Zettergren A, Andlauer TF, Diez-Fairen M, Simon-Sanchez J, Lleó A, Zetterberg H, Nygaard M, Blauwendraat C, Savage JE, Mengel-From J, Moreno-Grau S, Wagner M, Fortea J, Keogh MJ, Blennow K, Skoog I, Friese MA, Pletnikova O, Zulaica M, Lage C, de Rojas I, Riedel-Heller S, Illán-Gala I, Wei W, Jeune B, Orellana A, Then Bergh F, Wang X, Hulsman M, Beker N, Tesi N, Morris CM, Indakoetxea B, Collij LE, Scherer M, Morenas-Rodríguez E, Ironside JW, van Berckel BN, Alcolea D, Wiendl H, Strickland SL, Pastor P, Rodríguez Rodríguez E, DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA biobank), EADB (Alzheimer Disease European DNA biobank), IFGC (International FTD-Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), RiMod-FTD (Risk and Modifying factors in Fronto-Temporal Dementia), Netherlands Brain Bank (NBB), Boeve BF, Petersen RC, Ferman TJ, van Gerpen JA, Reinders MJ, Uitti RJ, Tárraga L, Maier W, Dols-Icardo O, Kawalia A, Dalmasso MC, Boada M, Zettl UK, van Schoor NM, Beekman M, Allen M, Masliah E, de Munain AL, Pantelyat A, Wszolek ZK, Ross OA, Dickson DW, Graff-Radford NR, Knopman D, Rademakers R, Lemstra AW, Pijnenburg YA, Scheltens P, Gasser T, Chinnery PF, Hemmer B, Huisman MA, Troncoso J, Moreno F, Nohr EA, Sørensen TI, Heutink P, Sánchez-Juan P, Posthuma D, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, Clarimón J, Christensen K, Ertekin-Taner N, Scholz SW, Ramirez A, Ruiz A, Slagboom E, van der Flier WM, Holstege H. A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity. Acta Neuropathol. 2019 Aug;138(2):237-250. Epub 2019 May 27 PubMed.
96. Lin JR, Sin-Chan P, Napolioni V, Zhang ZD. Rare genetic coding variants associated with human longevity and protection against age-related diseases. Nature Aging, 1, 2021, pp.783–94. Nat Aging.
97. Bai H, Naj AC, Benchek P, Dumitrescu L, Hohman T, Hamilton-Nelson K, Kallianpur AR, Griswold AJ, Vardarajan B, Martin ER, Beecham GW, Below JE, Schellenberg G, Mayeux R, Farrer L, Pericak-Vance MA, Haines JL, Bush WS, Alzheimer's Disease Genetics Consortium. A haptoglobin (HP) structural variant alters the effect of APOE alleles on Alzheimer's disease. Alzheimers Dement. 2023 Apr 12; PubMed.
98. Miller B, Kim SJ, Cao K, Mehta HH, Thumaty N, Kumagai H, Iida T, McGill C, Pike CJ, Nurmakova K, Levine ZA, Sullivan PM, Yen K, Ertekin-Taner N, Atzmon G, Barzilai N, Cohen P. Humanin variant P3S is associated with longevity in APOE4 carriers and resists APOE4-induced brain pathology. Aging Cell. 2024 Mar 22;:e14153. PubMed.
99. Bhattarai P, Gunasekaran TI, Belloy ME, Reyes-Dumeyer D, Jülich D, Tayran H, Yilmaz E, Flaherty D, Turgutalp B, Sukumar G, Alba C, McGrath EM, Hupalo DN, Bacikova D, Le Guen Y, Lantigua R, Medrano M, Rivera D, Recio P, Nuriel T, Ertekin-Taner N, Teich AF, Dickson DW, Holley S, Greicius M, Dalgard CL, Zody M, Mayeux R, Kizil C, Vardarajan BN. Rare genetic variation in fibronectin 1 (FN1) protects against APOEε4 in Alzheimer's disease. Acta Neuropathol. 2024 Apr 10;147(1):70. PubMed.
100. Branciamore S, Gogoshin G, Rodin AS, Myers AJ. Changes in expression of VGF, SPECC1L, HLA-DRA and RANBP3L act with APOE E4 to alter risk for late onset Alzheimer's disease. Sci Rep. 2024 Jun 28;14(1):14954. PubMed.
101. Schramm C, Charbonnier C, Zaréa A, Lacour M, Wallon D, CNRMAJ collaborators, Boland A, Deleuze JF, Olaso R, ADES consortium, Alarcon F, Campion D, Nuel G, Nicolas G. Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes. Genome Med. 2022 Jun 28;14(1):69. PubMed. Correction.
102. Maestre G, Ottman R, Stern Y, Gurland B, Chun M, Tang MX, Shelanski M, Tycko B, Mayeux R. Apolipoprotein E and Alzheimer's disease: ethnic variation in genotypic risks. Ann Neurol. 1995 Feb;37(2):254-9. PubMed.
103. Tang MX, Maestre G, Tsai WY, Liu XH, Feng L, Chung WY, Chun M, Schofield P, Stern Y, Tycko B, Mayeux R. Relative risk of Alzheimer disease and age-at-onset distributions, based on APOE genotypes among elderly African Americans, Caucasians, and Hispanics in New York City. Am J Hum Genet. 1996 Mar;58(3):574-84. PubMed.
104. Harerimana NV, Goate AM, Bowles KR. The influence of 17q21.31 and APOE genetic ancestry on neurodegenerative disease risk. Front Aging Neurosci. 2022;14:1021918. Epub 2022 Oct 20 PubMed.
105. Rajabli F, Benchek P, Tosto G, Kushch N, Sha J, Bazemore K, Zhu C, Lee W-P, Haut J, Hamilton-Nelson KL, Wheeler NR, Zhao Y, Farrell JJ, Grunin MA, Leung YY, Kuksa PP, Li D, LuciodaFonseca E, Mez JB, Palmer EL, Pillai J, Sherva RM, Song YE, Zhang X, Iqbal T, Pathak O, Valladares O, Kuzma AB, Abner E, Adams PM, Aguirre A, Albert MS, Albin RL, Allen M, Alvarez L, Apostolova LG, Arnold SE, Asthana S, Atwood CS, Ayres G, Baldwin CT, Barber RC, Barnes LL, Barral S, Beach. Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies LRRC4C, LHX5-AS1 and nominates ancestry-specific loci PTPRK, GRB14, and KIAA0825 as novel risk loci for Alzheimer disease: the Alzheimer Disease Genetics Consortium. 2023 Jul 08 10.1101/2023.07.06.23292311 (version 1) medRxiv.
106. Choi KY, Lee JJ, Gunasekaran TI, Kang S, Lee W, Jeong J, Lim HJ, Zhang X, Zhu C, Won SY, Choi YY, Seo EH, Lee SC, Gim J, Chung JY, Chong A, Byun MS, Seo S, Ko PW, Han JW, McLean C, Farrell J, Lunetta KL, Miyashita A, Hara N, Won S, Choi SM, Ha JM, Jeong JH, Kuwano R, Song MK, An SS, Lee YM, Park KW, Lee HW, Choi SH, Rhee S, Song WK, Lee JS, Mayeux R, Haines JL, Pericak-Vance MA, Choo IL, Nho K, Kim KW, Lee DY, Kim S, Kim BC, Kim H, Jun GR, Schellenberg GD, Ikeuchi T, Farrer LA, Lee KH, Neuroimaging Initative AD. APOE Promoter Polymorphism-219T/G is an Effect Modifier of the Influence of APOE ε4 on Alzheimer's Disease Risk in a Multiracial Sample. J Clin Med. 2019 Aug 16;8(8) PubMed.
107. Ali M, Archer DB, Gorijala P, Western D, Timsina J, Fernández MV, Wang TC, Satizabal CL, Yang Q, Beiser AS, Wang R, Chen G, Gordon B, Benzinger TL, Xiong C, Morris JC, Bateman RJ, Karch CM, McDade E, Goate A, Seshadri S, Mayeux RP, Sperling RA, Buckley RF, Johnson KA, Won HH, Jung SH, Kim HR, Seo SW, Kim HJ, Mormino E, Laws SM, Fan KH, Kamboh MI, Vemuri P, Ramanan VK, Yang HS, Wenzel A, Rajula HS, Mishra A, Dufouil C, Debette S, Lopez OL, DeKosky ST, Tao F, Nagle MW, Knight Alzheimer Disease Research Center (Knight ADRC), Dominantly Inherited Alzheimer Network (DIAN), Alzheimer’s Disease Neuroimaging Initiative (ADNI), ADNI-DOD, A4 Study Team, Australian Imaging Biomarkers, Lifestyle (AIBL) Study, Hohman TJ, Sung YJ, Dumitrescu L, Cruchaga C. Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease. Acta Neuropathol Commun. 2023 Apr 26;11(1):68. PubMed.
108. Rajabli F, Feliciano BE, Celis K, Hamilton-Nelson KL, Whitehead PL, Adams LD, Bussies PL, Manrique CP, Rodriguez A, Rodriguez V, Starks T, Byfield GE, Sierra Lopez CB, McCauley JL, Acosta H, Chinea A, Kunkle BW, Reitz C, Farrer LA, Schellenberg GD, Vardarajan BN, Vance JM, Cuccaro ML, Martin ER, Haines JL, Byrd GS, Beecham GW, Pericak-Vance MA. Ancestral origin of ApoE ε4 Alzheimer disease risk in Puerto Rican and African American populations. PLoS Genet. 2018 Dec;14(12):e1007791. Epub 2018 Dec 5 PubMed.
109. Babenko VN, Afonnikov DA, Ignatieva EV, Klimov AV, Gusev FE, Rogaev EI. Haplotype analysis of APOE intragenic SNPs. BMC Neurosci. 2018 Apr 19;19(Suppl 1):16. PubMed.
110. Rajabli F, Beecham GW, Hendrie HC, Baiyewu O, Ogunniyi A, Gao S, Kushch NA, Lipkin-Vasquez M, Hamilton-Nelson KL, Young JI, Dykxhoorn DM, Nuytemans K, Kunkle BW, Wang L, Jin F, Liu X, Feliciano-Astacio BE, Alzheimer’s Disease Sequencing Project, Alzheimer’s Disease Genetic Consortium, Schellenberg GD, Dalgard CL, Griswold AJ, Byrd GS, Reitz C, Cuccaro ML, Haines JL, Pericak-Vance MA, Vance JM. A locus at 19q13.31 significantly reduces the ApoE ε4 risk for Alzheimer's Disease in African Ancestry. PLoS Genet. 2022 Jul;18(7):e1009977. Epub 2022 Jul 5 PubMed.
111. Zhang A, Zhao Q, Xu D, Jiang S. Brain APOE expression quantitative trait loci-based association study identified one susceptibility locus for Alzheimer's disease by interacting with APOE ε4. Sci Rep. 2018 May 23;8(1):8068. PubMed.
112. Nuytemans K, Lipkin Vasquez M, Wang L, Van Booven D, Griswold AJ, Rajabli F, Celis K, Oron O, Hofmann N, Rolati S, Garcia-Serje C, Zhang S, Jin F, Argenziano M, Grant SF, Chesi A, Brown CD, Young JI, Dykxhoorn DM, Pericak-Vance MA, Vance JM. Identifying differential regulatory control of APOE ɛ4 on African versus European haplotypes as potential therapeutic targets. Alzheimers Dement. 2022 Jan 3; PubMed.
113. Granot-Hershkovitz E, Xia R, Yang Y, Spitzer B, Tarraf W, Vásquez PM, Lipton RB, Daviglus M, Argos M, Cai J, Kaplan R, Fornage M, DeCarli C, Gonzalez HM, Sofer T. Interaction analysis of ancestry-enriched variants with APOE-ɛ4 on MCI in the Study of Latinos-Investigation of Neurocognitive Aging. Sci Rep. 2023 Mar 29;13(1):5114. PubMed.
114. Griswold AJ, Celis K, Bussies PL, Rajabli F, Whitehead PL, Hamilton-Nelson KL, Beecham GW, Dykxhoorn DM, Nuytemans K, Wang L, Gardner OK, Dorfsman DA, Bigio EH, Mesulam MM, Weintraub S, Geula C, Gearing M, McGrath-Martinez E, Dalgard CL, Scott WK, Haines JL, Pericak-Vance MA, Young JI, Vance JM. Increased APOE ε4 expression is associated with the difference in Alzheimer's disease risk from diverse ancestral backgrounds. Alzheimers Dement. 2021 Jul;17(7):1179-1188. Epub 2021 Feb 1 PubMed.
115. Andrews SJ, Belloy ME, Renton AE, Fulton-Howard B, Brenowitz WD, Yaffe K. Modifiable risk factors, APOE and risk of Alzheimer disease: one size does not fit all. 2024 Apr 29 10.1101/2024.04.27.24306486 (version 1) medRxiv.
116. Blue EE, Horimoto AR, Mukherjee S, Wijsman EM, Thornton TA. Local ancestry at APOE modifies Alzheimer's disease risk in Caribbean Hispanics. Alzheimers Dement. 2019 Dec;15(12):1524-1532. Epub 2019 Oct 9 PubMed.
117. Marca-Ysabel MV, Rajabli F, Cornejo-Olivas M, Whitehead PG, Hofmann NK, Illanes Manrique MZ, Veliz Otani DM, Milla Neyra AK, Castro Suarez S, Meza Vega M, Adams LD, Mena PR, Rosario I, Cuccaro ML, Vance JM, Beecham GW, Custodio N, Montesinos R, Mazzetti Soler PE, Pericak-Vance MA. Dissecting the role of Amerindian genetic ancestry and the ApoE ε4 allele on Alzheimer disease in an admixed Peruvian population. Neurobiol Aging. 2021 May;101:298.e11-298.e15. Epub 2020 Dec 10 PubMed.
118. Knopman DS, Mosley TH, Catellier DJ, Coker LH, Atherosclerosis Risk in Communities Study Brain MRI Study. Fourteen-year longitudinal study of vascular risk factors, APOE genotype, and cognition: the ARIC MRI Study. Alzheimers Dement. 2009 May;5(3):207-14. Epub 2009 Apr 11 PubMed.
119. Sawyer K, Sachs-Ericsson N, Preacher KJ, Blazer DG. Racial differences in the influence of the APOE epsilon 4 allele on cognitive decline in a sample of community-dwelling older adults. Gerontology. 2009;55(1):32-40. Epub 2008 Jun 5 PubMed.
120. Mezlini AM, Magdamo C, Merrill E, Chibnik LB, Blacker DL, Hyman BT, Das S. Characterizing Clinical and Neuropathological Traits of APOE Haplotypes in African Americans and Europeans. J Alzheimers Dis. 2020;78(1):467-477. PubMed.
121. Curtis D, Alzheimer's Disease Neuroimaging Initiative. Analysis of whole genome sequenced cases and controls shows that the association of variants in TOMM40, BCAM, NECTIN2 and APOC1 with late onset Alzheimer's disease is driven by linkage disequilibrium with APOE ε2/ε3/ε4 alleles. J Neurogenet. 2021 Mar-Jun;35(2):59-66. Epub 2021 May 10 PubMed.
122. Mukadam N, Giannakopoulou O, Bass N, Kuchenbaecker K, McQuillin A. Genetic risk scores and dementia risk across different ethnic groups in UK Biobank. PLoS One. 2022;17(12):e0277378. Epub 2022 Dec 7 PubMed.
123. Belloy ME, Eger SJ, Le Guen Y, Damotte V, Ahmad S, Ikram MA, Ramirez A, Tsolaki AC, Rossi G, Jansen IE, de Rojas I, Parveen K, Sleegers K, Ingelsson M, Hiltunen M, Amin N, Andreassen O, Sánchez-Juan P, Kehoe P, Amouyel P, Sims R, Frikke-Schmidt R, van der Flier WM, Lambert JC, European Alzheimer & Dementia BioBank (EADB), He Z, Han SS, Napolioni V, Greicius MD. Challenges at the APOE locus: a robust quality control approach for accurate APOE genotyping. Alzheimers Res Ther. 2022 Feb 4;14(1):22. PubMed.
124. Kamboh MI. Apolipoprotein E polymorphism and susceptibility to Alzheimer's disease. Hum Biol. 1995 Apr;67(2):195-215. PubMed.
125. Wang YY, Ge YJ, Tan CC, Cao XP, Tan L, Xu W. The Proportion of APOE4 Carriers Among Non-Demented Individuals: A Pooled Analysis of 389,000 Community-Dwellers. J Alzheimers Dis. 2021;81(3):1331-1339. PubMed.
126. Premkumar DR, Cohen DL, Hedera P, Friedland RP, Kalaria RN. Apolipoprotein E-epsilon4 alleles in cerebral amyloid angiopathy and cerebrovascular pathology associated with Alzheimer's disease. Am J Pathol. 1996 Jun;148(6):2083-95. PubMed.
127. Rannikmäe K, Kalaria RN, Greenberg SM, Chui HC, Schmitt FA, Samarasekera N, Al-Shahi Salman R, Sudlow CL. APOE associations with severe CAA-associated vasculopathic changes: collaborative meta-analysis. J Neurol Neurosurg Psychiatry. 2014 Mar;85(3):300-5. Epub 2013 Oct 25 PubMed.
128. Reiman EM, Arboleda-Velasquez JF, Quiroz YT, Huentelman MJ, Beach TG, Caselli RJ, Chen Y, Su Y, Myers AJ, Hardy J, Paul Vonsattel J, Younkin SG, Bennett DA, De Jager PL, Larson EB, Crane PK, Keene CD, Kamboh MI, Kofler JK, Duque L, Gilbert JR, Gwirtsman HE, Buxbaum JD, Dickson DW, Frosch MP, Ghetti BF, Lunetta KL, Wang LS, Hyman BT, Kukull WA, Foroud T, Haines JL, Mayeux RP, Pericak-Vance MA, Schneider JA, Trojanowski JQ, Farrer LA, Schellenberg GD, Beecham GW, Montine TJ, Jun GR, Alzheimer’s Disease Genetics Consortium. Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study. Nat Commun. 2020 Feb 3;11(1):667. PubMed.
129. Grangeon L, Quesney G, Verdalle-Cazes M, Coulette S, Renard D, Wacongne A, Allou T, Olivier N, Boukriche Y, Blanchet-Fourcade G, Labauge P, Arquizan C, Canaple S, Godefroy O, Martinaud O, Verdure P, Quillard-Muraine M, Pariente J, Magnin E, Nicolas G, Charbonnier C, Maltête D, Formaglio M, Raposo N, Ayrignac X, Wallon D. Different clinical outcomes between cerebral amyloid angiopathy-related inflammation and non-inflammatory form. J Neurol. 2022 Sep;269(9):4972-4984. Epub 2022 Jun 26 PubMed.
130. DeMichele-Sweet MA, Klei L, Creese B, Harwood JC, Weamer EA, McClain L, Sims R, Hernandez I, Moreno-Grau S, Tárraga L, Boada M, Alarcón-Martín E, Valero S, NIA-LOAD Family Based Study Consortium, Alzheimer’s Disease Genetics Consortium (ADGC), Liu Y, Hooli B, Aarsland D, Selbaek G, Bergh S, Rongve A, Saltvedt I, Skjellegrind HK, Engdahl B, Stordal E, Andreassen OA, Djurovic S, Athanasiu L, Seripa D, Borroni B, Albani D, Forloni G, Mecocci P, Serretti A, De Ronchi D, Politis A, Williams J, Mayeux R, Foroud T, Ruiz A, Ballard C, Holmans P, Lopez OL, Kamboh MI, Devlin B, Sweet RA. Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease. Mol Psychiatry. 2021 Oct;26(10):5797-5811. Epub 2021 Jun 10 PubMed.
131. Rasmussen KL, Luo J, Nordestgaard BG, Tybjærg-Hansen A, Frikke-Schmidt R. APOE and vascular disease: Sequencing and genotyping in general population cohorts. Atherosclerosis. 2023 Nov;385:117218. Epub 2023 Aug 9 PubMed.
132. Yang HS, Yu L, White CC, Chibnik LB, Chhatwal JP, Sperling RA, Bennett DA, Schneider JA, De Jager PL. Evaluation of TDP-43 proteinopathy and hippocampal sclerosis in relation to APOE ε4 haplotype status: a community-based cohort study. Lancet Neurol. 2018 Sep;17(9):773-781. Epub 2018 Aug 6 PubMed.
133. Dugan AJ, Nelson PT, Katsumata Y, Shade LM, Boehme KL, Teylan MA, Cykowski MD, Mukherjee S, Kauwe JS, Hohman TJ, Schneider JA, Alzheimer’s Disease Genetics Consortium, Fardo DW. Analysis of genes (TMEM106B, GRN, ABCC9, KCNMB2, and APOE) implicated in risk for LATE-NC and hippocampal sclerosis provides pathogenetic insights: a retrospective genetic association study. Acta Neuropathol Commun. 2021 Sep 15;9(1):152. PubMed.
134. Atherton K, Han X, Chung J, Cherry JD, Baucom Z, Saltiel N, Nair E, Abdolmohammadi B, Uretsky M, Khan MM, Shea C, Durape S, Martin BM, Palmisano JN, Farrell K, Nowinski CJ, Alvarez VE, Dwyer B, Daneshvar DH, Katz DI, Goldstein LE, Cantu RC, Kowall NW, Alosco ML, Huber BR, Tripodis Y, Crary JF, Farrer L, Stern RA, Stein TD, McKee AC, Mez J. Association of APOE Genotypes and Chronic Traumatic Encephalopathy. JAMA Neurol. 2022 Aug 1;79(8):787-796. PubMed.
136. Walker JM, Richardson TE. Cognitive resistance to and resilience against multiple comorbid neurodegenerative pathologies and the impact of APOE status. J Neuropathol Exp Neurol. 2023 Jan 20;82(2):110-119. PubMed.
137. Maldonado-Díaz C, Hiya S, Yokoda RT, Farrell K, Marx GA, Kauffman J, Daoud EV, Gonzales MM, Parker AS, Canbeldek L, Kulumani Mahadevan LS, Crary JF, White CL 3rd, Walker JM, Richardson TE. Disentangling and quantifying the relative cognitive impact of concurrent mixed neurodegenerative pathologies. Acta Neuropathol. 2024 Mar 23;147(1):58. PubMed.
138. Paul KC, Rausch R, Creek MM, Sinsheimer JS, Bronstein JM, Bordelon Y, Ritz B. APOE, MAPT, and COMT and Parkinson's Disease Susceptibility and Cognitive Symptom Progression. J Parkinsons Dis. 2016 Apr 2;6(2):349-59. PubMed.
139. Tan MM, Lawton MA, Jabbari E, Reynolds RH, Iwaki H, Blauwendraat C, Kanavou S, Pollard MI, Hubbard L, Malek N, Grosset KA, Marrinan SL, Bajaj N, Barker RA, Burn DJ, Bresner C, Foltynie T, Wood NW, Williams-Gray CH, Hardy J, Nalls MA, Singleton AB, Williams NM, Ben-Shlomo Y, Hu MT, Grosset DG, Shoai M, Morris HR. Genome-Wide Association Studies of Cognitive and Motor Progression in Parkinson's Disease. Mov Disord. 2021 Feb;36(2):424-433. Epub 2020 Oct 28 PubMed.
140. Liu G, Peng J, Liao Z, Locascio JJ, Corvol JC, Zhu F, Dong X, Maple-Grødem J, Campbell MC, Elbaz A, Lesage S, Brice A, Mangone G, Growdon JH, Hung AY, Schwarzschild MA, Hayes MT, Wills AM, Herrington TM, Ravina B, Shoulson I, Taba P, Kõks S, Beach TG, Cormier-Dequaire F, Alves G, Tysnes OB, Perlmutter JS, Heutink P, Amr SS, van Hilten JJ, Kasten M, Mollenhauer B, Trenkwalder C, Klein C, Barker RA, Williams-Gray CH, Marinus J, International Genetics of Parkinson Disease Progression (IGPP) Consortium, Scherzer CR. Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson's disease. Nat Genet. 2021 Jun;53(6):787-793. Epub 2021 May 6 PubMed.
141. Pu JL, Jin CY, Wang ZX, Fang Y, Li YL, Xue NJ, Zheng R, Lin ZH, Yan YQ, Si XL, Chen Y, Liu Y, Song Z, Yan YP, Tian J, Yin XZ, Zhang BR. Apolipoprotein E Genotype Contributes to Motor Progression in Parkinson's Disease. Mov Disord. 2022 Jan;37(1):196-200. Epub 2021 Oct 6 PubMed.
142. Wu LY, Real R, Martinez A, Chia R, Lawton M, Shoai M, Bresner C, Hubbard L, Blauwendraat C, Singleton A, Ryten M, Scholz SW, Traynor B, Williams N, Hu M, Ben-Shlomo Y, Grosset D, Hardy J, Morris H. Investigation of the genetic aetiology of Lewy body diseases with and without dementia. 2023 Oct 27 10.1101/2023.10.17.23297157 (version 2) medRxiv.
143. Hardy J, Crook R, Prihar G, Roberts G, Raghavan R, Perry R. Senile dementia of the Lewy body type has an apolipoprotein E epsilon 4 allele frequency intermediate between controls and Alzheimer's disease. Neurosci Lett. 1994 Nov 21;182(1):1-2. PubMed.
144. Tsuang D, Leverenz JB, Lopez OL, Hamilton RL, Bennett DA, Schneider JA, Buchman AS, Larson EB, Crane PK, Kaye JA, Kramer P, Woltjer R, Trojanowski JQ, Weintraub D, Chen-Plotkin AS, Irwin DJ, Rick J, Schellenberg GD, Watson GS, Kukull W, Nelson PT, Jicha GA, Neltner JH, Galasko D, Masliah E, Quinn JF, Chung KA, Yearout D, Mata IF, Wan JY, Edwards KL, Montine TJ, Zabetian CP. APOE ε4 increases risk for dementia in pure synucleinopathies. JAMA Neurol. 2013 Feb;70(2):223-8. PubMed.
145. Guerreiro R, Ross OA, Kun-Rodrigues C, Hernandez DG, Orme T, Eicher JD, Shepherd CE, Parkkinen L, Darwent L, Heckman MG, Scholz SW, Troncoso JC, Pletnikova O, Ansorge O, Clarimon J, Lleo A, Morenas-Rodriguez E, Clark L, Honig LS, Marder K, Lemstra A, Rogaeva E, St George-Hyslop P, Londos E, Zetterberg H, Barber I, Braae A, Brown K, Morgan K, Troakes C, Al-Sarraj S, Lashley T, Holton J, Compta Y, Van Deerlin V, Serrano GE, Beach TG, Lesage S, Galasko D, Masliah E, Santana I, Pastor P, Diez-Fairen M, Aguilar M, Tienari PJ, Myllykangas L, Oinas M, Revesz T, Lees A, Boeve BF, Petersen RC, Ferman TJ, Escott-Price V, Graff-Radford N, Cairns NJ, Morris JC, Pickering-Brown S, Mann D, Halliday GM, Hardy J, Trojanowski JQ, Dickson DW, Singleton A, Stone DJ, Bras J. Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. Lancet Neurol. 2018 Jan;17(1):64-74. Epub 2017 Dec 16 PubMed.
146. Kaivola K, Shah Z, Chia R, International LBD Genomics Consortium, Scholz SW. Genetic evaluation of dementia with Lewy bodies implicates distinct disease subgroups. Brain. 2022 Jun 3;145(5):1757-1762. PubMed.
147. Wu LY, Real R, Martinez-Carrasco A, Chia R, Lawton MA, Shoai M, Bresner C, Blauwendraat C, Singleton AB, Ryten M, International Lewy Body Dementia Genomics Consortium, Scholz SW, Traynor BJ, Williams NM, Hu MT, Ben-Shlomo Y, Grosset DG, Hardy J, Morris HR. Investigation of the genetic aetiology of Lewy body diseases with and without dementia. Brain Commun. 2024;6(4):fcae190. Epub 2024 May 31 PubMed.
148. Talyansky S, Le Guen Y, Kasireddy N, Belloy ME, Greicius MD. APOE-ε4 and BIN1 increase risk of Alzheimer's disease pathology but not specifically of Lewy body pathology. Acta Neuropathol Commun. 2023 Sep 12;11(1):149. PubMed.
149. Govone F, Vacca A, Rubino E, Gai A, Boschi S, Gentile S, Orsi L, Pinessi L, Rainero I. Lack of association between APOE gene polymorphisms and amyotrophic lateral sclerosis: a comprehensive meta-analysis. Amyotroph Lateral Scler Frontotemporal Degener. 2014 Dec;15(7-8):551-6. Epub 2014 Jun 11 PubMed.
150. Ouidir M, Chatterjee S, Wu J, Tekola-Ayele F. Genomic study of maternal lipid traits in early pregnancy concurs with four known adult lipid loci. J Clin Lipidol. 2022 Nov 17; PubMed.
151. Raj T, Chibnik LB, McCabe C, Wong A, Replogle JM, Yu L, Gao S, Unverzagt FW, Stranger B, Murrell J, Barnes L, Hendrie HC, Foroud T, Krichevsky A, Bennett DA, Hall KS, Evans DA, De Jager PL. Genetic architecture of age-related cognitive decline in African Americans. Neurol Genet. 2017 Feb;3(1):e125. Epub 2016 Dec 21 PubMed.
152. Corley J, Conte F, Harris SE, Taylor AM, Redmond P, Russ TC, Deary IJ, Cox SR. Predictors of longitudinal cognitive ageing from age 70 to 82 including APOE e4 status, early-life and lifestyle factors: the Lothian Birth Cohort 1936. Mol Psychiatry. 2023 Mar;28(3):1256-1271. Epub 2022 Dec 8 PubMed.
153. Tomassen J, den Braber A, van der Lee SJ, Reus LM, Konijnenberg E, Carter SF, Yaqub M, van Berckel BN, Collij LE, Boomsma DI, de Geus EJ, Scheltens P, Herholz K, Tijms BM, Visser PJ. Amyloid-β and APOE genotype predict memory decline in cognitively unimpaired older individuals independently of Alzheimer's disease polygenic risk score. BMC Neurol. 2022 Dec 15;22(1):484. PubMed.
154. Rietman ML, Onland-Moret NC, Nooyens AC, Ibi D, van Dijk KW, Samson LD, Pennings JL, Schipper M, Wong A, Spijkerman AM, Dollé ME, Verschuren WM. The APOE locus is linked to decline in general cognitive function: 20-years follow-up in the Doetinchem Cohort Study. Transl Psychiatry. 2022 Nov 29;12(1):496. PubMed.
155. Kang M, Ang TF, Devine SA, Sherva R, Mukherjee S, Trittschuh EH, Gibbons LE, Scollard P, Lee M, Choi SE, Klinedinst B, Nakano C, Dumitrescu LC, Durant A, Hohman TJ, Cuccaro ML, Saykin AJ, Kukull WA, Bennett DA, Wang LS, Mayeux RP, Haines JL, Pericak-Vance MA, Schellenberg GD, Crane PK, Au R, Lunetta KL, Mez JB, Farrer LA. A genome-wide search for pleiotropy in more than 100,000 harmonized longitudinal cognitive domain scores. Mol Neurodegener. 2023 Jun 22;18(1):40. PubMed.
156. Pettigrew C, Nazarovs J, Soldan A, Singh V, Wang J, Hohman T, Dumitrescu L, Libby J, Kunkle B, Gross AL, Johnson S, Lu Q, Engelman C, Masters CL, Maruff P, Laws SM, Morris JC, Hassenstab J, Cruchaga C, Resnick SM, Kitner-Triolo MH, An Y, Albert M. Alzheimer's disease genetic risk and cognitive reserve in relationship to long-term cognitive trajectories among cognitively normal individuals. Alzheimers Res Ther. 2023 Mar 28;15(1):66. PubMed.
157. Walters S, Contreras AG, Eissman JM, Mukherjee S, Lee ML, Choi SE, Scollard P, Trittschuh EH, Mez JB, Bush WS, Kunkle BW, Naj AC, Peterson A, Gifford KA, Cuccaro ML, Cruchaga C, Pericak-Vance MA, Farrer LA, Wang LS, Haines JL, Jefferson AL, Kukull WA, Keene CD, Saykin AJ, Thompson PM, Martin ER, Bennett DA, Barnes LL, Schneider JA, Crane PK, Hohman TJ, Dumitrescu L, Alzheimer’s Disease Neuroimaging Initiative, Alzheimer’s Disease Genetics Consortium, and Alzheimer’s Disease Sequencing Project. Associations of Sex, Race, and Apolipoprotein E Alleles With Multiple Domains of Cognition Among Older Adults. JAMA Neurol. 2023 Sep 1;80(9):929-939. PubMed.
158. Dilliott AA, Sunderland KM, McLaughlin PM, Roberts AC, Evans EC, Abrahao A, Binns MA, Black SE, Borrie M, Casaubon LK, Dowlatshahi D, Finger E, Fischer CE, Frank A, Freedman M, Grimes D, Hassan A, Jog M, Kumar S, Kwan D, Lang AE, Mandzia J, Marras C, Masellis M, McIntyre AD, Pasternak S, Pollock BG, Rajji TK, Robinson JF, Rogaeva E, Sahlas DJ, Saposnik G, Sato C, Seitz D, Shoesmith C, Steeves T, Strother SC, Swartz RH, Tan B, Tang-Wai D, Tartaglia MC, Troyer AK, Turnbull J, Zinman L, ONDRI Investigators, Hegele RA. Association of apolipoprotein E variation with cognitive impairment across multiple neurodegenerative diagnoses. Neurobiol Aging. 2021 Sep;105:378.e1-378.e9. Epub 2021 Apr 24 PubMed.
159. Davies G, Lam M, Harris SE, Trampush JW, Luciano M, Hill WD, Hagenaars SP, Ritchie SJ, Marioni RE, Fawns-Ritchie C, Liewald DC, Okely JA, Ahola-Olli AV, Barnes CL, Bertram L, Bis JC, Burdick KE, Christoforou A, DeRosse P, Djurovic S, Espeseth T, Giakoumaki S, Giddaluru S, Gustavson DE, Hayward C, Hofer E, Ikram MA, Karlsson R, Knowles E, Lahti J, Leber M, Li S, Mather KA, Melle I, Morris D, Oldmeadow C, Palviainen T, Payton A, Pazoki R, Petrovic K, Reynolds CA, Sargurupremraj M, Scholz M, Smith JA, Smith AV, Terzikhan N, Thalamuthu A, Trompet S, van der Lee SJ, Ware EB, Windham BG, Wright MJ, Yang J, Yu J, Ames D, Amin N, Amouyel P, Andreassen OA, Armstrong NJ, Assareh AA, Attia JR, Attix D, Avramopoulos D, Bennett DA, Böhmer AC, Boyle PA, Brodaty H, Campbell H, Cannon TD, Cirulli ET, Congdon E, Conley ED, Corley J, Cox SR, Dale AM, Dehghan A, Dick D, Dickinson D, Eriksson JG, Evangelou E, Faul JD, Ford I, Freimer NA, Gao H, Giegling I, Gillespie NA, Gordon SD, Gottesman RF, Griswold ME, Gudnason V, Harris TB, Hartmann AM, Hatzimanolis A, Heiss G, Holliday EG, Joshi PK, Kähönen M, Kardia SL, Karlsson I, Kleineidam L, Knopman DS, Kochan NA, Konte B, Kwok JB, Le Hellard S, Lee T, Lehtimäki T, Li SC, Lill CM, Liu T, Koini M, London E, Longstreth WT Jr, Lopez OL, Loukola A, Luck T, Lundervold AJ, Lundquist A, Lyytikäinen LP, Martin NG, Montgomery GW, Murray AD, Need AC, Noordam R, Nyberg L, Ollier W, Papenberg G, Pattie A, Polasek O, Poldrack RA, Psaty BM, Reppermund S, Riedel-Heller SG, Rose RJ, Rotter JI, Roussos P, Rovio SP, Saba Y, Sabb FW, Sachdev PS, Satizabal CL, Schmid M, Scott RJ, Scult MA, Simino J, Slagboom PE, Smyrnis N, Soumaré A, Stefanis NC, Stott DJ, Straub RE, Sundet K, Taylor AM, Taylor KD, Tzoulaki I, Tzourio C, Uitterlinden A, Vitart V, Voineskos AN, Kaprio J, Wagner M, Wagner H, Weinhold L, Wen KH, Widen E, Yang Q, Zhao W, Adams HH, Arking DE, Bilder RM, Bitsios P, Boerwinkle E, Chiba-Falek O, Corvin A, De Jager PL, Debette S, Donohoe G, Elliott P, Fitzpatrick AL, Gill M, Glahn DC, Hägg S, Hansell NK, Hariri AR, Ikram MK, Jukema JW, Vuoksimaa E, Keller MC, Kremen WS, Launer L, Lindenberger U, Palotie A, Pedersen NL, Pendleton N, Porteous DJ, Räikkönen K, Raitakari OT, Ramirez A, Reinvang I, Rudan I, Dan Rujescu, Schmidt R, Schmidt H, Schofield PW, Schofield PR, Starr JM, Steen VM, Trollor JN, Turner ST, Van Duijn CM, Villringer A, Weinberger DR, Weir DR, Wilson JF, Malhotra A, McIntosh AM, Gale CR, Seshadri S, Mosley TH Jr, Bressler J, Lencz T, Deary IJ. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. Nat Commun. 2018 May 29;9(1):2098. PubMed.
160. Rahman MS, Harrison E, Biggs H, Seikus C, Elliott P, Breen G, Kingston N, Bradley JR, Hill SM, Tom BD, Chinnery PF. Dynamics of cognitive variability with age and its genetic underpinning in NIHR BioResource Genes and Cognition cohort participants. Nat Med. 2024 Jun;30(6):1739-1748. Epub 2024 May 14 PubMed.
161. Daly J, De Luca F, Berens SC, Field AP, Rusted JM, Bird CM. The effect of apolipoprotein E genotype on spatial processing in humans: A meta-analysis and systematic review. Cortex. 2024 May 31;177:268-284. PubMed.
163. Himali JJ, Baril AA, Cavuoto MG, Yiallourou S, Wiedner CD, Himali D, DeCarli C, Redline S, Beiser AS, Seshadri S, Pase MP. Association Between Slow-Wave Sleep Loss and Incident Dementia. JAMA Neurol. 2023 Dec 1;80(12):1326-1333. PubMed.
164. Cooper JG, Ghodsi M, Stukas S, Leach S, Brooks-Wilson A, Wellington CL. APOE ε4 carrier status modifies plasma p-tau181 concentrations in cognitively healthy super-seniors. Alzheimers Dement. 2024 Jun;20(6):4373-4380. Epub 2024 May 16 PubMed.
165. Kucikova L, Zeng J, Muñoz-Neira C, Muniz-Terrera G, Huang W, Gregory S, Ritchie C, O'Brien J, Su L. Genetic risk factors of Alzheimer's Disease disrupt resting-state functional connectivity in cognitively intact young individuals. J Neurol. 2023 Oct;270(10):4949-4958. Epub 2023 Jun 26 PubMed.
166. Chaloemtoem A, Thornton V, Chang Y, Anokhin AP, Belloy ME, Bijsterbosch JD, Gordon BA, Hartz SM, Bierut LJ. Hippocampal volumes in UK Biobank are associated with APOE only in older adults. 2024 Jun 05 10.1101/2024.06.05.24307704 (version 1) medRxiv.
167. Heise V, Offer A, Whiteley W, Mackay CE, Armitage JM, Parish S. A comprehensive analysis of APOE genotype effects on human brain structure in the UK Biobank. Transl Psychiatry. 2024 Mar 12;14(1):143. PubMed.
168. Tato-Fernández C, Ekblad LL, Pietilä E, Saunavaara V, Helin S, Parkkola R, Zetterberg H, Blennow K, Rinne JO, Snellman A. Cognitively healthy APOE4/4 carriers show white matter impairment associated with serum NfL and amyloid-PET. Neurobiol Dis. 2024 Mar;192:106439. Epub 2024 Feb 15 PubMed.
169. Fritsche LG, Igl W, Bailey JN, Grassmann F, Sengupta S, Bragg-Gresham JL, Burdon KP, Hebbring SJ, Wen C, Gorski M, Kim IK, Cho D, Zack D, Souied E, Scholl HP, Bala E, Lee KE, Hunter DJ, Sardell RJ, Mitchell P, Merriam JE, Cipriani V, Hoffman JD, Schick T, Lechanteur YT, Guymer RH, Johnson MP, Jiang Y, Stanton CM, Buitendijk GH, Zhan X, Kwong AM, Boleda A, Brooks M, Gieser L, Ratnapriya R, Branham KE, Foerster JR, Heckenlively JR, Othman MI, Vote BJ, Liang HH, Souzeau E, McAllister IL, Isaacs T, Hall J, Lake S, Mackey DA, Constable IJ, Craig JE, Kitchner TE, Yang Z, Su Z, Luo H, Chen D, Ouyang H, Flagg K, Lin D, Mao G, Ferreyra H, Stark K, von Strachwitz CN, Wolf A, Brandl C, Rudolph G, Olden M, Morrison MA, Morgan DJ, Schu M, Ahn J, Silvestri G, Tsironi EE, Park KH, Farrer LA, Orlin A, Brucker A, Li M, Curcio CA, Mohand-Saïd S, Sahel JA, Audo I, Benchaboune M, Cree AJ, Rennie CA, Goverdhan SV, Grunin M, Hagbi-Levi S, Campochiaro P, Katsanis N, Holz FG, Blond F, Blanché H, Deleuze JF, Igo RP Jr, Truitt B, Peachey NS, Meuer SM, Myers CE, Moore EL, Klein R, Hauser MA, Postel EA, Courtenay MD, Schwartz SG, Kovach JL, Scott WK, Liew G, Tan AG, Gopinath B, Merriam JC, Smith RT, Khan JC, Shahid H, Moore AT, McGrath JA, Laux R, Brantley MA Jr, Agarwal A, Ersoy L, Caramoy A, Langmann T, Saksens NT, de Jong EK, Hoyng CB, Cain MS, Richardson AJ, Martin TM, Blangero J, Weeks DE, Dhillon B, van Duijn CM, Doheny KF, Romm J, Klaver CC, Hayward C, Gorin MB, Klein ML, Baird PN, den Hollander AI, Fauser S, Yates JR, Allikmets R, Wang JJ, Schaumberg DA, Klein BE, Hagstrom SA, Chowers I, Lotery AJ, Léveillard T, Zhang K, Brilliant MH, Hewitt AW, Swaroop A, Chew EY, Pericak-Vance MA, DeAngelis M, Stambolian D, Haines JL, Iyengar SK, Weber BH, Abecasis GR, Heid IM. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat Genet. 2016 Feb;48(2):134-43. Epub 2015 Dec 21 PubMed.
170. Rasmussen KL, Tybjærg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. Associations of Alzheimer Disease-Protective APOE Variants With Age-Related Macular Degeneration. JAMA Ophthalmol. 2023 Jan 1;141(1):13-21. PubMed.
171. Wang H, Chang TS, Dombroski BA, Cheng P-L, Patil V, Valiente-Banuet L, Farrell K, McLean C, Molina-Porcel L, Rajput A, PaulDeDeyn P, LeBastard N, Gearing M, DonkerKaat L, VanSwieten JC, Dopper E, Ghetti BF, Newell KL, Troakes C, GdeYebenes J, Rabano-Gutierrez A, Meller T, Oertel WH, Respondek G, Stamelou M, Arzberger T, Roeber S, Muller U, Hopfner F, Hopfner F, Pastor P, Brice A, Durr A, LeBer I, Beach TG, Serrano GE, Hazrati L-N, Litvan I, Rademakers R, Ross OA, Galasko D, Boxer AL. Whole-Genome Sequencing Analysis Reveals New Susceptibility Loci and Structural Variants Associated with Progressive Supranuclear Palsy. 2024 Jan 30 10.1101/2023.12.28.23300612 (version 2) medRxiv.
172. Lu K, Nicholas JM, Pertzov Y, Grogan J, Husain M, Pavisic IM, James SN, Parker TD, Lane CA, Keshavan A, Keuss SE, Buchanan SM, Murray-Smith H, Cash DM, Malone IB, Sudre CH, Coath W, Wong A, Henley SM, Fox NC, Richards M, Schott JM, Crutch SJ. Dissociable effects of APOE-ε4 and β-amyloid pathology on visual working memory. Nat Aging. 2021 Nov;1(11):1002-1009. Epub 2021 Oct 7 PubMed.
173. Mahley RW, Weisgraber KH, Huang Y. Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer's disease to AIDS. J Lipid Res. 2009 Apr;50 Suppl(Suppl):S183-8. Epub 2008 Dec 22 PubMed.
174. Mahley RW. Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders. J Mol Med (Berl). 2016 Jul;94(7):739-46. Epub 2016 Jun 9 PubMed.
175. Rasmussen KL, Tybjærg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. Plasma levels of apolipoprotein E, APOE genotype, and all-cause and cause-specific mortality in 105 949 individuals from a white general population cohort. Eur Heart J. 2019 Sep 1;40(33):2813-2824. PubMed.
176. Compton H, Smith ML, Bull C, Korologou-Linden R, Ben-Shlomo Y, Bell JA, Williams DM, Anderson EL. Life course plasma metabolomic signatures of genetic liability to Alzheimer's disease. Sci Rep. 2024 Feb 16;14(1):3896. PubMed.
177. Venkatesh SS, Ganjgahi H, Palmer DS, Coley K, Linchangco GV Jr, Hui Q, Wilson P, Ho YL, Cho K, Arumäe K, Million Veteran Program, Estonian Biobank Research Team, Wittemans LB, Nellåker C, Vainik U, Sun YV, Holmes C, Lindgren CM, Nicholson G. Characterising the genetic architecture of changes in adiposity during adulthood using electronic health records. Nat Commun. 2024 Jul 10;15(1):5801. PubMed.
178. Kemper KE, Sidorenko J, Wang H, Hayes BJ, Wray NR, Yengo L, Keller MC, Goddard M, Visscher PM. Genetic influence on within-person longitudinal change in anthropometric traits in the UK Biobank. Nat Commun. 2024 May 6;15(1):3776. PubMed.
179. Li QS, Tian C, 23andMe Research Team, Hinds D, Seabrook GR. The association of clinical phenotypes to known AD/FTD genetic risk loci and their inter-relationship. PLoS One. 2020;15(11):e0241552. Epub 2020 Nov 5 PubMed.
180. Ferguson AC, Tank R, Lyall LM, Ward J, Celis-Morales C, Strawbridge R, Ho F, Whelan CD, Gill J, Welsh P, Anderson JJ, Mark PB, Mackay DF, Smith DJ, Pell JP, Cavanagh J, Sattar N, Lyall DM. Alzheimer's Disease Susceptibility Gene Apolipoprotein E (APOE) and Blood Biomarkers in UK Biobank (N = 395,769). J Alzheimers Dis. 2020;76(4):1541-1551. PubMed.
181. Almeida FC, Patra K, Giannisis A, Niesnerova A, Nandakumar R, Ellis E, Oliveira TG, Nielsen HM. APOE genotype dictates lipidomic signatures in primary human hepatocytes. J Lipid Res. 2024 Feb;65(2):100498. Epub 2024 Jan 11 PubMed.
182. Ostendorf BN, Patel MA, Bilanovic J, Hoffmann HH, Carrasco SE, Rice CM, Tavazoie SF. Common human genetic variants of APOE impact murine COVID-19 mortality. Nature. 2022 Nov;611(7935):346-351. Epub 2022 Sep 21 PubMed.
183. Leshchyk A, Xiang Q, Andersen SL, Gurinovich A, Song Z, Lee JH, Christensen K, Yashin A, Wojczynski M, Schwander K, Perls TT, Monti S, Sebastiani P. Mosaic Chromosomal Alterations and Human Longevity. J Gerontol A Biol Sci Med Sci. 2023 Aug 27;78(9):1561-1568. PubMed.
184. Régy M, Dugravot A, Sabia S, Helmer C, Tzourio C, Hanseeuw B, Singh-Manoux A, Dumurgier J. The role of dementia in the association between APOE4 and all-cause mortality: pooled analyses of two population-based cohort studies. Lancet Healthy Longev. 2024 Jun;5(6):e422-e430. PubMed.
185. Ostendorf BN, Bilanovic J, Adaku N, Tafreshian KN, Tavora B, Vaughan RD, Tavazoie SF. Common germline variants of the human APOE gene modulate melanoma progression and survival. Nat Med. 2020 Jul;26(7):1048-1053. Epub 2020 May 25 PubMed.
186. Palmer ND, Kahali B, Kuppa A, Chen Y, Du X, Feitosa MF, Bielak LF, O'Connell JR, Musani SK, Guo X, Smith AV, Ryan KA, Eirksdottir G, Allison MA, Bowden DW, Budoff MJ, Carr JJ, Chen YI, Taylor KD, Correa A, Crudup BF, Halligan B, Yang J, Kardia SL, Launer LJ, Fu YP, Mosley TH, Norris JM, Terry JG, O'Donnell CJ, Rotter JI, Wagenknecht LE, Gudnason V, Province MA, Peyser PA, Speliotes EK. Allele-specific variation at APOE increases nonalcoholic fatty liver disease and obesity but decreases risk of Alzheimer's disease and myocardial infarction. Hum Mol Genet. 2021 Jul 9;30(15):1443-1456. PubMed.
187. Huebbe P, Bilke S, Rueter J, Schloesser A, Campbel G, Glüer CC, Lucius R, Röcken C, Tholey A, Rimbach G. Human APOE4 Protects High-Fat and High-Sucrose Diet Fed Targeted Replacement Mice against Fatty Liver Disease Compared to APOE3. Aging Dis. 2023 Jun 12; PubMed.
188. Topriceanu CC, Shah M, Webber M, Chan F, Shiwani H, Richards M, Schott J, Chaturvedi N, Moon JC, Hughes AD, Hingorani AD, O'Regan DP, Captur G. APOE ε4 carriage associates with improved myocardial performance from adolescence to older age. BMC Cardiovasc Disord. 2024 Mar 21;24(1):172. PubMed.
189. Pirraglia E, Glodzik L, Shao Y. Lower mortality risk in APOE4 carriers with normal cognitive ageing. Sci Rep. 2023 Sep 12;13(1):15089. PubMed.
190. van Exel E, Koopman JJ, Bodegom DV, Meij JJ, Knijff P, Ziem JB, Finch CE, Westendorp RG. Effect of APOE ε4 allele on survival and fertility in an adverse environment. PLoS One. 2017;12(7):e0179497. Epub 2017 Jul 6 PubMed.
191. Garcia AR, Finch C, Gatz M, Kraft T, Eid Rodriguez D, Cummings D, Charifson M, Buetow K, Beheim BA, Allayee H, Thomas GS, Stieglitz J, Gurven MD, Kaplan H, Trumble BC. APOE4 is associated with elevated blood lipids and lower levels of innate immune biomarkers in a tropical Amerindian subsistence population. Elife. 2021 Sep 29;10 PubMed.
192. Smith CJ, Ashford JW. Apolipoprotein ɛ4-Associated Protection Against Pediatric Enteric Infections Is a Survival Advantage in Pre-Industrial Populations. J Alzheimers Dis. 2023;93(3):907-918. PubMed.
193. Trumble BC, Charifson M, Kraft T, Garcia AR, Cummings DK, Hooper P, Lea AJ, Eid Rodriguez D, Koebele SV, Buetow K, Beheim B, Minocher R, Gutierrez M, Thomas GS, Gatz M, Stieglitz J, Finch CE, Kaplan H, Gurven M. Apolipoprotein-ε4 is associated with higher fecundity in a natural fertility population. Sci Adv. 2023 Aug 9;9(32):eade9797. PubMed.
194. Steele OG, Stuart AC, Minkley L, Shaw K, Bonnar O, Anderle S, Penn AC, Rusted J, Serpell L, Hall C, King S. A multi-hit hypothesis for an APOE4-dependent pathophysiological state. Eur J Neurosci. 2022 May 5; PubMed.
195. Vance JM, Farrer LA, Huang Y, Cruchaga C, Hyman BT, Pericak-Vance MA, Goate AM, Greicius MD, Griswold AJ, Haines JL, Tcw J, Schellenberg GD, Tsai LH, Herz J, Holtzman DM. Report of the APOE4 National Institute on Aging/Alzheimer Disease Sequencing Project Consortium Working Group: Reducing APOE4 in Carriers is a Therapeutic Goal for Alzheimer's Disease. Ann Neurol. 2024 Apr;95(4):625-634. Epub 2024 Jan 5 PubMed.
196. Saroja SR, Gorbachev K, Julia T, Goate AM, Pereira AC. Astrocyte-secreted glypican-4 drives APOE4-dependent tau hyperphosphorylation. Proc Natl Acad Sci U S A. 2022 Aug 23;119(34):e2108870119. Epub 2022 Aug 15 PubMed.
197. Asante I, Louie S, Yassine HN. Uncovering mechanisms of brain inflammation in Alzheimer's disease with APOE4: Application of single cell-type lipidomics. Ann N Y Acad Sci. 2022 Dec;1518(1):84-105. Epub 2022 Oct 6 PubMed.
198. Parhizkar S, Holtzman DM. APOE mediated neuroinflammation and neurodegeneration in Alzheimer's disease. Semin Immunol. 2022 Jan;59:101594. Epub 2022 Feb 26 PubMed.
199. Kloske CM, Barnum CJ, Batista AF, Bradshaw EM, Brickman AM, Bu G, Dennison J, Gearon MD, Goate AM, Haass C, Heneka MT, Hu WT, Huggins LK, Jones NS, Koldamova R, Lemere CA, Liddelow SA, Marcora E, Marsh SE, Nielsen HM, Petersen KK, Petersen M, Piña-Escudero SD, Qiu WQ, Quiroz YT, Reiman E, Sexton C, Tansey MG, Tcw J, Teunissen CE, Tijms BM, van der Kant R, Wallings R, Weninger SC, Wharton W, Wilcock DM, Wishard TJ, Worley SL, Zetterberg H, Carrillo MC. APOE and immunity: Research highlights. Alzheimers Dement. 2023 Jun;19(6):2677-2696. Epub 2023 Mar 28 PubMed.
200. Denkinger M, Baker S, Inglis B, Kobayashi S, Juarez A, Mason S, Jagust W. Associations between regional blood-brain barrier permeability, aging, and Alzheimer's disease biomarkers in cognitively normal older adults. PLoS One. 2024;19(6):e0299764. Epub 2024 Jun 5 PubMed.
201. Mahley RW. Apolipoprotein E4 targets mitochondria and the mitochondria-associated membrane complex in neuropathology, including Alzheimer's disease. Curr Opin Neurobiol. 2023 Apr;79:102684. Epub 2023 Feb 6 PubMed.
202. Hou X, Heckman MG, Fiesel FC, Koga S, Soto-Beasley AI, Watzlawik JO, Zhao J, Valentino RR, Johnson PW, White LJ, Quicksall ZS, Reddy JS, Bras J, Guerreiro R, Zhao N, Bu G, Dickson DW, Ross OA, Springer W. Genome-wide association study identifies APOE and ZMIZ1 variants as mitophagy modifiers in Lewy body disease. 2023 Oct 16 10.1101/2023.10.16.23297100 (version 1) medRxiv.
203. Theendakara V, Peters-Libeu CA, Bredesen DE, Rao RV. Transcriptional Effects of ApoE4: Relevance to Alzheimer's Disease. Mol Neurobiol. 2018 Jun;55(6):5243-5254. Epub 2017 Sep 6 PubMed.
204. Johnson LA. APOE and metabolic dysfunction in Alzheimer's disease. Int Rev Neurobiol. 2020;154:131-151. Epub 2020 Jul 11 PubMed.
205. Yassine HN, Finch CE. APOE Alleles and Diet in Brain Aging and Alzheimer's Disease. Front Aging Neurosci. 2020;12:150. Epub 2020 Jun 10 PubMed.
206. Loch RA, Wang H, Perálvarez-Marín A, Berger P, Nielsen H, Chroni A, Luo J. Cross interactions between Apolipoprotein E and amyloid proteins in neurodegenerative diseases. Comput Struct Biotechnol J. 2023;21:1189-1204. Epub 2023 Jan 20 PubMed.
207. Zhao J, Lu W, Ren Y, Fu Y, Martens YA, Shue F, Davis MD, Wang X, Chen K, Li F, Liu CC, Graff-Radford NR, Wszolek ZK, Younkin SG, Brafman DA, Ertekin-Taner N, Asmann YW, Dickson DW, Xu Z, Pan M, Han X, Kanekiyo T, Bu G. Apolipoprotein E regulates lipid metabolism and α-synuclein pathology in human iPSC-derived cerebral organoids. Acta Neuropathol. 2021 Nov;142(5):807-825. Epub 2021 Aug 28 PubMed.
208. Jin Y, Li F, Sonoustoun B, Kondru NC, Martens YA, Qiao W, Heckman MG, Ikezu TC, Li Z, Burgess JD, Amerna D, O'Leary J, DeTure MA, Zhao J, McLean PJ, Dickson DW, Ross OA, Bu G, Zhao N. APOE4 exacerbates α-synuclein seeding activity and contributes to neurotoxicity in Alzheimer's disease with Lewy body pathology. Acta Neuropathol. 2022 Jun;143(6):641-662. Epub 2022 Apr 26 PubMed.
209. Hatters DM, Peters-Libeu CA, Weisgraber KH. Engineering conformational destabilization into mouse apolipoprotein E. A model for a unique property of human apolipoprotein E4. J Biol Chem. 2005 Jul 15;280(28):26477-82. Epub 2005 May 11 PubMed.
210. Xu Q, Brecht WJ, Weisgraber KH, Mahley RW, Huang Y. Apolipoprotein E4 domain interaction occurs in living neuronal cells as determined by fluorescence resonance energy transfer. J Biol Chem. 2004 Jun 11;279(24):25511-6. Epub 2004 Mar 30 PubMed.
211. Chen Y, Strickland MR, Soranno A, Holtzman DM. Apolipoprotein E: Structural Insights and Links to Alzheimer Disease Pathogenesis. Neuron. 2021 Jan 20;109(2):205-221. Epub 2020 Nov 10 PubMed.
212. Stuchell-Brereton MD, Zimmerman MI, Miller JJ, Mallimadugula UL, Incicco JJ, Roy D, Smith LG, Cubuk J, Baban B, DeKoster GT, Frieden C, Bowman GR, Soranno A. Apolipoprotein E4 has extensive conformational heterogeneity in lipid-free and lipid-bound forms. Proc Natl Acad Sci U S A. 2023 Feb 14;120(7):e2215371120. Epub 2023 Feb 7 PubMed.
213. Nemergut M, Marques SM, Uhrik L, Vanova T, Nezvedova M, Gadara DC, Jha D, Tulis J, Novakova V, Planas-Iglesias J, Kunka A, Legrand A, Hribkova H, Pospisilova V, Sedmik J, Raska J, Prokop Z, Damborsky J, Bohaciakova D, Spacil Z, Hernychova L, Bednar D, Marek M. Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer's Disease drug candidate. Mol Neurodegener. 2023 Jun 6;18(1):38. PubMed.
214. Strickland MR, Rau MJ, Summers B, Basore K, Wulf J 2nd, Jiang H, Chen Y, Ulrich JD, Randolph GJ, Zhang R, Fitzpatrick JA, Cashikar AG, Holtzman DM. Apolipoprotein E secreted by astrocytes forms antiparallel dimers in discoidal lipoproteins. Neuron. 2024 Apr 3;112(7):1100-1109.e5. Epub 2024 Jan 23 PubMed.
215. Blumenfeld J, Yip O, Kim MJ, Huang Y. Cell type-specific roles of APOE4 in Alzheimer disease. Nat Rev Neurosci. 2024 Feb;25(2):91-110. Epub 2024 Jan 8 PubMed.
216. Haney MS, Pálovics R, Munson CN, Long C, Johansson PK, Yip O, Dong W, Rawat E, West E, Schlachetzki JC, Tsai A, Guldner IH, Lamichhane BS, Smith A, Schaum N, Calcuttawala K, Shin A, Wang YH, Wang C, Koutsodendris N, Serrano GE, Beach TG, Reiman EM, Glass CK, Abu-Remaileh M, Enejder A, Huang Y, Wyss-Coray T. APOE4/4 is linked to damaging lipid droplets in Alzheimer's disease microglia. Nature. 2024 Apr;628(8006):154-161. Epub 2024 Mar 13 PubMed.
217. Windham IA, Cohen S. The cell biology of APOE in the brain. Trends Cell Biol. 2023 Oct 5; PubMed.
218. Windham IA, Powers AE, Ragusa JV, Wallace ED, Zanellati MC, Williams VH, Wagner CH, White KK, Cohen S. APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size. J Cell Biol. 2024 Apr 1;223(4) Epub 2024 Feb 9 PubMed.
219. Feringa FM, Koppes-denHertog SJ, Wang L, Derks RJ, Kruijff I, Erlebach L, Heijneman J, Miramontes R, Pömpner N, Blomberg N, Olivier-Jimenez D, Johanson LE, Cammack AJ, Giblin A, Toomey CE, Rose IV, Yuan H, Ward ME, Isaacs A, Kampmann M, Kronenberg-Versteeg D, Lashley T, Thompson LM, Ori A, Mohammed Y, Giera M, vanderKant RH. The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases uncovers cholesterol as a regulator of astrocyte reactivity impaired by ApoE4. 2024 Jul 03 10.1101/2024.07.01.601474 (version 1) bioRxiv.
220. Lee S, Devanney NA, Golden LR, Smith CT, Schwartz JL, Walsh AE, Clarke HA, Goulding DS, Allenger EJ, Morillo-Segovia G, Friday CM, Gorman AA, Hawkinson TR, MacLean SM, Williams HC, Sun RC, Morganti JM, Johnson LA. APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge. Cell Rep. 2023 Mar 28;42(3):112196. Epub 2023 Mar 3 PubMed.
221. Yin Z, Rosenzweig N, Kleemann KL, Zhang X, Brandão W, Margeta MA, Schroeder C, Sivanathan KN, Silveira S, Gauthier C, Mallah D, Pitts KM, Durao A, Herron S, Shorey H, Cheng Y, Barry JL, Krishnan RK, Wakelin S, Rhee J, Yung A, Aronchik M, Wang C, Jain N, Bao X, Gerrits E, Brouwer N, Deik A, Tenen DG, Ikezu T, Santander NG, McKinsey GL, Baufeld C, Sheppard D, Krasemann S, Nowarski R, Eggen BJ, Clish C, Tanzi RE, Madore C, Arnold TD, Holtzman DM, Butovsky O. APOE4 impairs the microglial response in Alzheimer's disease by inducing TGFβ-mediated checkpoints. Nat Immunol. 2023 Nov;24(11):1839-1853. Epub 2023 Sep 25 PubMed.
222. Liu CC, Wang N, Chen Y, Inoue Y, Shue F, Ren Y, Wang M, Qiao W, Ikezu TC, Li Z, Zhao J, Martens Y, Doss SV, Rosenberg CL, Jeevaratnam S, Jia L, Raulin AC, Qi F, Zhu Y, Alnobani A, Knight J, Chen Y, Linares C, Kurti A, Fryer JD, Zhang B, Wu LJ, Kim BY, Bu G. Cell-autonomous effects of APOE4 in restricting microglial response in brain homeostasis and Alzheimer's disease. Nat Immunol. 2023 Nov;24(11):1854-1866. Epub 2023 Oct 19 PubMed.
223. Romero-Molina C, Garretti F, Andrews SJ, Marcora E, Goate AM. Microglial efferocytosis: Diving into the Alzheimer's disease gene pool. Neuron. 2022 Nov 2;110(21):3513-3533. PubMed.
224. Zhou J, Wang Y, Huang G, Yang M, Zhu Y, Jin C, Jing D, Ji K, Shi Y. LilrB3 is a putative cell surface receptor of APOE4. Cell Res. 2023 Feb;33(2):116-130. Epub 2023 Jan 2 PubMed.
225. Sepulveda J, Kim JY, Binder J, Vicini S, Rebeck GW. APOE4 genotype and aging impair injury-induced microglial behavior in brain slices, including toward Aβ, through P2RY12. Mol Neurodegener. 2024 Mar 11;19(1):24. PubMed.
226. Millet A, Ledo JH, Tavazoie SF. An exhausted-like microglial population accumulates in aged and APOE4 genotype Alzheimer's brains. Immunity. 2024 Jan 9;57(1):153-170.e6. Epub 2023 Dec 29 PubMed.
227. Lin YT, Seo J, Gao F, Feldman HM, Wen HL, Penney J, Cam HP, Gjoneska E, Raja WK, Cheng J, Rueda R, Kritskiy O, Abdurrob F, Peng Z, Milo B, Yu CJ, Elmsaouri S, Dey D, Ko T, Yankner BA, Tsai LH. APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer's Disease Phenotypes in Human iPSC-Derived Brain Cell Types. Neuron. 2018 Jun 27;98(6):1141-1154.e7. Epub 2018 May 31 PubMed.
228. Qi G, Mi Y, Shi X, Gu H, Brinton RD, Yin F. ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism. Cell Rep. 2021 Jan 5;34(1):108572. PubMed.
229. de Leeuw SM, Kirschner AW, Lindner K, Rust R, Budny V, Wolski WE, Gavin AC, Nitsch RM, Tackenberg C. APOE2, E3, and E4 differentially modulate cellular homeostasis, cholesterol metabolism, and inflammatory response in isogenic iPSC-derived astrocytes. Stem Cell Reports. 2022 Jan 11;17(1):110-126. Epub 2021 Dec 16 PubMed.
230. Tcw J, Qian L, Pipalia NH, Chao MJ, Liang SA, Shi Y, Jain BR, Bertelsen SE, Kapoor M, Marcora E, Sikora E, Andrews EJ, Martini AC, Karch CM, Head E, Holtzman DM, Zhang B, Wang M, Maxfield FR, Poon WW, Goate AM. Cholesterol and matrisome pathways dysregulated in astrocytes and microglia. Cell. 2022 Jun 23;185(13):2213-2233.e25. PubMed. BioRxiv.
231. Watanabe H, Murakami R, Tsumagari K, Morimoto S, Hashimoto T, Imaizumi K, Sonn I, Yamada K, Saito Y, Murayama S, Iwatsubo T, Okano H. Astrocytic APOE4 genotype-mediated negative impacts on synaptic architecture in human pluripotent stem cell model. Stem Cell Reports. 2023 Sep 12;18(9):1854-1869. Epub 2023 Aug 31 PubMed.
232. Shi Y, Manis M, Long J, Wang K, Sullivan PM, Remolina Serrano J, Hoyle R, Holtzman DM. Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model. J Exp Med. 2019 Nov 4;216(11):2546-2561. Epub 2019 Oct 10 PubMed.
233. Wang C, Xiong M, Gratuze M, Bao X, Shi Y, Andhey PS, Manis M, Schroeder C, Yin Z, Madore C, Butovsky O, Artyomov M, Ulrich JD, Holtzman DM. Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia. Neuron. 2021 May 19;109(10):1657-1674.e7. Epub 2021 Apr 7 PubMed.
234. Serrano-Pozo A, Li Z, Noori A, Nguyen HN, Mezlini A, Li L, Hudry E, Jackson RJ, Hyman BT, Das S. Effect of APOE alleles on the glial transcriptome in normal aging and Alzheimer's disease. Nat Aging. 2021 Oct;1(10):919-931. Epub 2021 Oct 11 PubMed.
235. Chernyaeva L, Ratti G, Teirilä L, Fudo S, Rankka U, Pelkonen A, Korhonen P, Leskinen K, Keskitalo S, Salokas K, Gkolfinopoulou C, Crompton KE, Javanainen M, Happonen L, Varjosalo M, Malm T, Leinonen V, Chroni A, Saavalainen P, Meri S, Kajander T, Wollman AJ, Nissilä E, Haapasalo K. Reduced binding of apoE4 to complement factor H promotes amyloid-β oligomerization and neuroinflammation. EMBO Rep. 2023 Jul 5;24(7):e56467. Epub 2023 May 8 PubMed.
236. Gratuze M, Schlachetzki JC, D'Oliveira Albanus R, Jain N, Novotny B, Brase L, Rodriguez L, Mansel C, Kipnis M, O'Brien S, Pasillas MP, Lee C, Manis M, Colonna M, Harari O, Glass CK, Ulrich JD, Holtzman DM. TREM2-independent microgliosis promotes tau-mediated neurodegeneration in the presence of ApoE4. Neuron. 2023 Jan 18;111(2):202-219.e7. Epub 2022 Nov 10 PubMed.
237. Cheng GW, Mok KK, Yeung SH, Kofler J, Herrup K, Tse KH. Apolipoprotein E ε4 Mediates Myelin Breakdown by Targeting Oligodendrocytes in Sporadic Alzheimer Disease. J Neuropathol Exp Neurol. 2022 Aug 16;81(9):717-730. PubMed.
238. Blanchard JW, Akay LA, Davila-Velderrain J, von Maydell D, Mathys H, Davidson SM, Effenberger A, Chen CY, Maner-Smith K, Hajjar I, Ortlund EA, Bula M, Agbas E, Ng A, Jiang X, Kahn M, Blanco-Duque C, Lavoie N, Liu L, Reyes R, Lin YT, Ko T, R'Bibo L, Ralvenius WT, Bennett DA, Cam HP, Kellis M, Tsai LH. APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes. Nature. 2022 Nov;611(7937):769-779. Epub 2022 Nov 16 PubMed.
239. Mok KK, Yeung SH, Cheng GW, Ma IW, Lee RH, Herrup K, Tse KH. Apolipoprotein E ε4 disrupts oligodendrocyte differentiation by interfering with astrocyte-derived lipid transport. J Neurochem. 2023 Apr;165(1):55-75. Epub 2023 Jan 12 PubMed.
240. Victor MB, Leary N, Luna X, Meharena HS, Scannail AN, Bozzelli PL, Samaan G, Murdock MH, von Maydell D, Effenberger AH, Cerit O, Wen HL, Liu L, Welch G, Bonner M, Tsai LH. Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity. Cell Stem Cell. 2022 Aug 4;29(8):1197-1212.e8. PubMed.
241. Li X, Zhang J, Li D, He C, He K, Xue T, Wan L, Zhang C, Liu Q. Astrocytic ApoE reprograms neuronal cholesterol metabolism and histone-acetylation-mediated memory. Neuron. 2021 Mar 17;109(6):957-970.e8. Epub 2021 Jan 26 PubMed.
242. Tabuena DR, Jang S-S, Grone B, Yip O, AeryJones EA, Blumenfeld J, Liang Z, Koutsodendris N, Rao A, Ding L, Zhang AR, Hao Y, Xu Q, Yoon SY, DeLeon S, Huang Y, Zilberter M. Neuronal APOE4-induced Early Hippocampal Network Hyperexcitability in Alzheimers Disease Pathogenesis. 2024 Jul 03 10.1101/2023.08.28.555153 (version 3) bioRxiv.
243. Koutsodendris N, Blumenfeld J, Agrawal A, Traglia M, Grone B, Zilberter M, Yip O, Rao A, Nelson MR, Hao Y, Thomas R, Yoon SY, Arriola P, Huang Y. Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits. Nat Aging 2023 Nature Aging
244. Rao A, Chen N, Kim MJ, Blumenfeld J, Yip O, Hao Y, Liang Z, Nelson MR, Koutsodendris N, Grone B, Ding L, Yoon SY, Arriola P, Huang Y. Microglia Depletion Reduces Human Neuronal APOE4-Driven Pathologies in a Chimeric Alzheimer's Disease Model. 2023 Nov 14 10.1101/2023.11.10.566510 (version 1) bioRxiv.
245. Hou X, Zhang X, Zou H, Guan M, Fu C, Wang W, Zhang ZR, Geng Y, Chen Y. Differential and substrate-specific inhibition of γ-secretase by the C-terminal region of ApoE2, ApoE3, and ApoE4. Neuron. 2023 Jun 21;111(12):1898-1913.e5. Epub 2023 Apr 10 PubMed.
246. Paradise V, Sabu M, Bafia J, Sharif NA, Nguyen C, DhanrajMukim R, Wang X, Fu J, Ndubisi J, Maldonado G, Strickland M, Figueroa H, Almeida DL, Hyman BT, Holtzman DM, Nuriel T, Ramachandran KV. ApoE isoforms differentially regulate neuronal membrane proteasomes to shift the threshold for pathological aggregation of endogenous Tau. 2022 Nov 29 10.1101/2022.11.29.518293 (version 1) bioRxiv.
247. Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, Holtzman DM, Betsholtz C, Armulik A, Sallstrom J, Berk BC, Zlokovic BV. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature. 2012 May 24;485(7399):512-6. PubMed. Correction.
248. Montagne A, Nikolakopoulou AM, Huuskonen MT, Sagare AP, Lawson EJ, Lazic D, Rege SV, Grond A, Zuniga E, Barnes SR, Prince J, Sagare M, Hsu CJ, LaDu MJ, Jacobs RE, Zlokovic BV. APOE4 accelerates advanced-stage vascular and neurodegenerative disorder in old Alzheimer's mice via cyclophilin A independently of amyloid-β. Nat Aging. 2021 Jun;1(6):506-520. Epub 2021 Jun 14 PubMed.
249. Blanchard JW, Bula M, Davila-Velderrain J, Akay LA, Zhu L, Frank A, Victor MB, Bonner JM, Mathys H, Lin YT, Ko T, Bennett DA, Cam HP, Kellis M, Tsai LH. Reconstruction of the human blood-brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes. Nat Med. 2020 Jun;26(6):952-963. Epub 2020 Jun 8 PubMed. Correction.
250. Xiong M, Wang C, Gratuze M, Saadi F, Bao X, Bosch ME, Lee C, Jiang H, Serrano JR, Gonzales ER, Kipnis M, Holtzman DM. Astrocytic APOE4 removal confers cerebrovascular protection despite increased cerebral amyloid angiopathy. Mol Neurodegener. 2023 Mar 16;18(1):17. PubMed.
252. Rasmussen KL, Tybjaerg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. APOE and dementia - resequencing and genotyping in 105,597 individuals. Alzheimers Dement. 2020 Dec;16(12):1624-1637. Epub 2020 Aug 18 PubMed.
253. Giannisis A, Al-Grety A, Carlsson H, Patra K, Twohig D, Sando SB, Lauridsen C, Berge G, Grøntvedt GR, Bråthen G, White LR, Kultima K, Nielsen HM. Plasma apolipoprotein E levels in longitudinally followed patients with mild cognitive impairment and Alzheimer's disease. Alzheimers Res Ther. 2022 Aug 24;14(1):115. PubMed.
254. Guo Q, Ping L, Dammer EB, Duong DM, Yin L, Xu K, Shantaraman A, Fox EJ, Johnson EC, Roberts BR, Lah JJ, Levey AI, Seyfried NT. Global analysis of the heparin-enriched plasma proteome captures matrisome-associated proteins in Alzheimer's disease. 2023 Nov 07 10.1101/2023.11.06.565824 (version 1) bioRxiv.
255. Ramakrishnan A, Piehl N, Simonton B, Parikh M, Zhang Z, Teregulova V, van Olst L, Gate D. Epigenetic dysregulation in Alzheimer's disease peripheral immunity. Neuron. 2024 Apr 17;112(8):1235-1248.e5. Epub 2024 Feb 9 PubMed.
256. van Olst L, Kamermans A, Halters S, van der Pol SM, Rodriguez E, Verberk IM, Verberk SG, Wessels DW, Rodriguez-Mogeda C, Verhoeff J, Wouters D, Van den Bossche J, Garcia-Vallejo JJ, Lemstra AW, Witte ME, van der Flier WM, Teunissen CE, de Vries HE. Adaptive immune changes associate with clinical progression of Alzheimer's disease. Mol Neurodegener. 2024 Apr 24;19(1):38. PubMed.
257. Huynh TV, Wang C, Tran AC, Tabor GT, Mahan TE, Francis CM, Finn MB, Spellman R, Manis M, Tanzi RE, Ulrich JD, Holtzman DM. Lack of hepatic apoE does not influence early Aβ deposition: observations from a new APOE knock-in model. Mol Neurodegener. 2019 Oct 17;14(1):37. PubMed.
258. Giannisis A, Patra K, Edlund AK, Nieto LA, Benedicto-Gras J, Moussaud S, de la Rosa A, Twohig D, Bengtsson T, Fu Y, Bu G, Bial G, Foquet L, Hammarstedt C, Strom S, Kannisto K, Raber J, Ellis E, Nielsen HM. Brain integrity is altered by hepatic APOE ε4 in humanized-liver mice. Mol Psychiatry. 2022 Apr 13; PubMed.
259. Liu CC, Zhao J, Fu Y, Inoue Y, Ren Y, Chen Y, Doss SV, Shue F, Jeevaratnam S, Bastea L, Wang N, Martens YA, Qiao W, Wang M, Zhao N, Jia L, Yamazaki Y, Yamazaki A, Rosenberg CL, Wang Z, Kong D, Li Z, Kuchenbecker LA, Trottier ZA, Felton L, Rogers J, Quicksall ZS, Linares C, Knight J, Chen Y, Kurti A, Kanekiyo T, Fryer JD, Asmann YW, Storz P, Wang X, Peng J, Zhang B, Kim BY, Bu G. Peripheral apoE4 enhances Alzheimer's pathology and impairs cognition by compromising cerebrovascular function. Nat Neurosci. 2022 Aug;25(8):1020-1033. PubMed.
260. Golden LR, Johnson LA. Liver-ing in your head rent free: peripheral ApoE4 drives CNS pathology. Mol Neurodegener. 2022 Oct 4;17(1):65. PubMed.
261. Rosenzweig N, Kleemann KL, Rust T, Carpenter M, Grucci M, Aronchik M, Brouwer N, Valenbreder I, Cooper-Hohn J, Iyer M, Krishnan RK, Sivanathan KN, Brandão W, Yahya T, Durao A, Yin Z, Chadarevian JP, Properzi MJ, Nowarski R, Davtyan H, Weiner HL, Blurton-Jones M, Yang HS, Eggen BJ, Sperling RA, Butovsky O. Sex-dependent APOE4 neutrophil-microglia interactions drive cognitive impairment in Alzheimer's disease. Nat Med. 2024 Jul 3; PubMed.
262. Tao Q, Alvin Ang TF, Akhter-Khan SC, Itchapurapu IS, Killiany R, Zhang X, Budson AE, Turk KW, Goldstein L, Mez J, Alosco ML, Qiu WQ, Alzheimer’s Disease Neuroimaging Initiative. Impact of C-Reactive Protein on Cognition and Alzheimer Disease Biomarkers in Homozygous Apolipoprotein E ɛ4 Carriers. Neurology. 2021 Jul 15; PubMed.
263. Royall DR, Al-Rubaye S, Bishnoi R, Palmer RF. Few serum proteins mediate APOE's association with dementia. PLoS One. 2017;12(3):e0172268. Epub 2017 Mar 14 PubMed.
264. Wu HM, Goate AM, O'Reilly PF. Heterogeneous effects of genetic risk for Alzheimer's disease on the phenome. Transl Psychiatry. 2021 Jul 23;11(1):406. PubMed.
265. Zajac DJ, Green SJ, Johnson LA, Estus S. APOE genetics influence murine gut microbiome. Sci Rep. 2022 Feb 3;12(1):1906. PubMed.
266. Seo DO, O'Donnell D, Jain N, Ulrich JD, Herz J, Li Y, Lemieux M, Cheng J, Hu H, Serrano JR, Bao X, Franke E, Karlsson M, Meier M, Deng S, Desai C, Dodiya H, Lelwala-Guruge J, Handley SA, Kipnis J, Sisodia SS, Gordon JI, Holtzman DM. ApoE isoform- and microbiota-dependent progression of neurodegeneration in a mouse model of tauopathy. Science. 2023 Jan 13;379(6628):eadd1236. PubMed.
267. Yang A, Kantor B, Chiba-Falek O. APOE: The New Frontier in the Development of a Therapeutic Target towards Precision Medicine in Late-Onset Alzheimer's. Int J Mol Sci. 2021 Jan 27;22(3) PubMed.
268. Raulin AC, Doss SV, Trottier ZA, Ikezu TC, Bu G, Liu CC. ApoE in Alzheimer's disease: pathophysiology and therapeutic strategies. Mol Neurodegener. 2022 Nov 8;17(1):72. PubMed.
269. Jackson RJ, Keiser MS, Meltzer JC, Fykstra DP, Dierksmeier SE, Hajizadeh S, Kreuzer J, Morris R, Melloni A, Nakajima T, Tecedor L, Ranum PT, Carrell E, Chen Y, Nishtar MA, Holtzman DM, Haas W, Davidson BL, Hyman BT. APOE2 gene therapy reduces amyloid deposition and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease. Mol Ther. 2024 May 1;32(5):1373-1386. Epub 2024 Mar 19 PubMed.
270. Wang C, Najm R, Xu Q, Jeong DE, Walker D, Balestra ME, Yoon SY, Yuan H, Li G, Miller ZA, Miller BL, Malloy MJ, Huang Y. Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Nat Med. 2018 May;24(5):647-657. Epub 2018 Apr 9 PubMed.
271. Ossenkoppele R, van der Flier WM. APOE Genotype in the Era of Disease-Modifying Treatment With Monoclonal Antibodies Against Amyloid-β. JAMA Neurol. 2023 Dec 1;80(12):1269-1271. PubMed.
272. Garcia MJ, Leadley R, Ross J, Bozeat S, Redhead G, Hansson O, Iwatsubo T, Villain N, Cummings J. Prognostic and Predictive Factors in Early Alzheimer's Disease: A Systematic Review. J Alzheimers Dis Rep. 2024;8(1):203-240. Epub 2024 Feb 16 PubMed.
273. Loomis SJ, Miller R, Castrillo-Viguera C, Umans K, Cheng W, O'Gorman J, Hughes R, Budd Haeberlein S, Whelan CD. Genome-Wide Association Studies of ARIA From the Aducanumab Phase 3 ENGAGE and EMERGE Studies. Neurology. 2024 Feb 13;102(3):e207919. Epub 2023 Dec 28 PubMed.
274. Foley KE, Wilcock DM. Three major effects of APOEε4 on Aβ immunotherapy induced ARIA. Front Aging Neurosci. 2024;16:1412006. Epub 2024 May 2 PubMed.
275. Schmid B, Holst B, Clausen C, Bahnassawy L, Reinhardt P, Bakker MH, Díaz-Guerra E, Vicario C, Martino-Adami PV, Thoenes M, Ramirez A, Fliessbach K, Grezella C, Brüstle O, Peitz M, Ebneth A, Cabrera-Socorro A. Generation of a set of isogenic iPSC lines carrying all APOE genetic variants (Ɛ2/Ɛ3/Ɛ4) and knock-out for the study of APOE biology in health and disease. Stem Cell Res. 2021 Apr;52:102180. Epub 2021 Feb 2 PubMed.
276. Raman S, Brookhouser N, Brafman DA. Using human induced pluripotent stem cells (hiPSCs) to investigate the mechanisms by which Apolipoprotein E (APOE) contributes to Alzheimer's disease (AD) risk. Neurobiol Dis. 2020 May;138:104788. Epub 2020 Feb 5 PubMed.
277. van Heuvelen MJ, van der Lei MB, Alferink PM, Roemers P, van der Zee EA. Cognitive deficits in human ApoE4 knock-in mice: A systematic review and meta-analysis. Behav Brain Res. 2024 Jul 6;471:115123. PubMed.
278. Kotredes KP, Pandey RS, Persohn S, Elderidge K, Burton CP, Miner EW, Haynes KA, Santos DF, Williams SP, Heaton N, Ingraham CM, Lloyd C, Garceau D, O'Rourke R, Herrick S, Rangel-Barajas C, Maharjan S, Wang N, Sasner M, Lamb BT, Territo PR, Sukoff Rizzo SJ, Carter GW, Howell GR, Oblak AL. Characterizing Molecular and Synaptic Signatures in mouse models of Late-Onset Alzheimer's Disease Independent of Amyloid and Tau Pathology. bioRxiv. 2023 Dec 20; PubMed.
279. Pandey RS, Arnold M, Batra R, Krumsiek J, Kotredes KP, Garceau D, Williams H, Sasner M, Howell GR, Kaddurah-Daouk R, Carter GW. Metabolomics profiling reveals distinct, sex-specific signatures in serum and brain metabolomes in mouse models of Alzheimer's disease. Alzheimers Dement. 2024 Jun;20(6):3987-4001. Epub 2024 Apr 27 PubMed.
280. Stanton AE, Bubnys A, Agbas E, James B, Park DS, Jiang A, Pinals RL, Truong N, Loon A, Staab C, Liu L, Cerit O, Wen H-L, Kellis M, Blanchard JW, Langer RS, Tsai L-H. Engineered 3D Immuno-Glial-Neurovascular Human Brain Model. 2023 Aug 17 10.1101/2023.08.15.553453 (version 1) bioRxiv.
281. Lee W-P, Choi SH, Shea MG, Cheng P-L, Dombroski BA, Pitsillides AN, Heard-Costa NL, Wang H, Bulekova K, Kuzma AB, Leung YY, Farrell JJ, Lin H, Naj A, Blue EE, Nusetor F, Wang D, Boerwinkle E, Bush WS, Zhang X, DeJager PL, Dupuis J, Farrer LA, Fornage M, Martin E, Pericak-Vance M, Seshadri S, Wijsman EM, Wang L-S, Schellenberg GD, Destefano AL, Haines JL, Peloso GM. Association of Common and Rare Variants with Alzheimer's Disease in over 13,000 Diverse Individuals with Whole-Genome Sequencing from the Alzheimer's Disease Sequencing Project. 2023 Sep 02 10.1101/2023.09.01.23294953 (version 1) medRxiv.
282. Jun G, Naj AC, Beecham GW, Wang LS, Buros J, Gallins PJ, Buxbaum JD, Ertekin-Taner N, Fallin MD, Friedland R, Inzelberg R, Kramer P, Rogaeva E, St George-Hyslop P, Cantwell LB, Dombroski BA, Saykin AJ, Reiman EM, Bennett DA, Morris JC, Lunetta KL, Martin ER, Montine TJ, Goate AM, Blacker D, Tsuang DW, Beekly D, Cupples LA, Hakonarson H, Kukull W, Foroud TM, Haines J, Mayeux R, Farrer LA, Pericak-Vance MA, Schellenberg GD. Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes. Arch Neurol. 2010 Dec;67(12):1473-84. PubMed.
283. Huggins LK, Min SH, Kaplan S, Wei J, Welsh-Bohmer K, Xu H. Meta-Analysis of Variations in Association between APOE ɛ4 and Alzheimer's Disease and Related Dementias Across Hispanic Regions of Origin. J Alzheimers Dis. 2023;93(3):1095-1109. PubMed.
284. Hendrie HC, Murrell J, Baiyewu O, Lane KA, Purnell C, Ogunniyi A, Unverzagt FW, Hall K, Callahan CM, Saykin AJ, Gureje O, Hake A, Foroud T, Gao S. APOE ε4 and the risk for Alzheimer disease and cognitive decline in African Americans and Yoruba. Int Psychogeriatr. 2014 Jun;26(6):977-85. Epub 2014 Feb 24 PubMed.
285. Evans DA, Bennett DA, Wilson RS, Bienias JL, Morris MC, Scherr PA, Hebert LE, Aggarwal N, Beckett LA, Joglekar R, Berry-Kravis E, Schneider J. Incidence of Alzheimer disease in a biracial urban community: relation to apolipoprotein E allele status. Arch Neurol. 2003 Feb;60(2):185-9. PubMed.
286. Tang MX, Stern Y, Marder K, Bell K, Gurland B, Lantigua R, Andrews H, Feng L, Tycko B, Mayeux R. The APOE-epsilon4 allele and the risk of Alzheimer disease among African Americans, whites, and Hispanics. JAMA. 1998 Mar 11;279(10):751-5. PubMed.
287. Henderson JN, Crook R, Crook J, Hardy J, Onstead L, Carson-Henderson L, Mayer P, Parker B, Petersen R, Williams B. Apolipoprotein E4 and tau allele frequencies among Choctaw Indians. Neurosci Lett. 2002 May 10;324(1):77-9. PubMed.

Other Citations

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External Citations

1. GWAS catalog
2. May 2024 news

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