Overview

Clinical Phenotype: Alzheimer's Disease, Multiple Conditions
Position: (GRCh38/hg38):Chr19:44908822 C>T
Position: (GRCh37/hg19):Chr19:45412079 C>T
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs7412
Coding/Non-Coding: Coding
DNA Change: Allele
Expected RNA Consequence: Allele
Expected Protein Consequence: Allele
Codon Change: CGC to TGC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4
Research Models: 1

Findings

This variant has been associated with decreased risk of Alzheimer’s disease (AD), reduced AD neuropathology, and delayed AD onset. These protective effects appear to depend, at least in part, on ancestry, with people of European ancestry being the most protected, those of African ancestry less, and those of East Asian or Hispanic ancestry even less or not at all.

APOE2 was originally studied in the context of blood lipids and cardiovascular disease and 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 cysteines at both positions, ApoE2 is the most acidic of the three species and was designated 2 based on its migration upon isoelectric focusing. APOE2 is thought to have arisen 200,000 to 300,000 years ago as a variant of the ancestral APOE allele, C176R (APOE4). Worldwide, its frequency is approximately seven percent, but its distribution is uneven. Whereas it is fairly common in Southeast Asia, Australia, and some African populations (up to 19 percent), it is absent from most indigenous American groups (Singh et al., 2006; Abondio et al., 2019).

In the mid-1990s, APOE2 caught the attention of neuroscientists as it was underrepresented in AD patients, suggesting it reduced the risk of late-onset AD (Corder et al., 1994; Smith et al., 1994; West et al., 1994; Farrer et al., 1997). Since then, multiple studies, including several large, genome-wide association studies, have confirmed its protective nature, at least in non-Hispanic Whites (see table below). Moreover, APOE2 appears to have a strong dose-dependent effect. While one APOE2 allele cuts AD risk down to about half of that of carriers of two APOE3 alleles, two alleles reduce it to 13 percent (Feb 2020 news; Aug 2019 conference news; Nov 2019 news; Reiman et al., 2020; table below). Of note, APOE2 carriers are still susceptible to AD (Stipho et al., 2018), but seem to have a milder phenotype (Groot et al., 2018).

Whether APOE2 affects the rate of cognitive decline in AD is uncertain (e.g., Katzourou et al., 2021), as are its effects on baseline cognition (for review see Li et al., 2020). Studies of cognitively healthy young to middle-aged individuals have shown minimal or null effects. Moreover, a study of nearly 10,000 English individuals aged 17–85  years identified an age-by-APOE2 interaction effect on cogntivie performance, but it did not survive correction for multiple testing (Rahman et al., 2024). On the other hand, cross-sectional studies of elderly non-demented individuals showed APOE2 carriers performed better on tests of memory, visuospatial skills, and global cognition than non-carriers, and longitudinal tests showed a slower decline of episodic memory, executive function, verbal learning, and global cognition (e.g., Kang et al., 2023). Also, APOE2 appears to delay cognitive decline and the elevation of an AD plasma biomarker in autosomal dominant AD, at least in carriers of the PSEN1 E280A (Paisa) variant (Vélez et al., 2015, Langella et al., 2023, Langella et al., 2024).

Neuropathology | Other AD-relevant factors | Non-AD Neurological disorders | Non-neurological conditions | Biological effects of neurological relevance | Other biological effects | Molecular underpinnings | Research Models | Note on nomenclature |

Neuropathology

Multiple studies have also examined the effects of APOE2, compared with APOE3, on neuropathology. In general, the presence of APOE2 has been tied to milder Aβ pathology (for review see Li et al., 2020). Amyloid-β accumulation has been consistently found to be lower in post-mortem brain tissues of both non-demented aged individuals and AD patients carrying APOE2 (e.g., Nagy et al., 1995; Oyama et al., 1995; Lippa et al., 1997; Berlau et al., 2013; Tiraboschi et al., 2004; Serrano-Pozo et al., 2015; Reiman et al., 2020; Rohde et al., 2023). Moreover, PET imaging and fluid biomarker studies of cognitively healthy older adults have also found robust associations between APOE2 and decreased levels of Aβ pathology (e.g,, Morris 2010; Grothe et al., 2017; Jansen et al., 2015; Palmqvist et al., 2015; Salvadó et al., 2021a). Reducing Aβ pathology, however, may not be the only way APOE2 protects the brain. For example, in individuals with minimal Aβ accumulation, APOE2 carriers were still more likely to be cognitively intact compared with APOE3 homozygotes (Shinohara et al., 2016).

The relationship between APOE2 and tau pathology is still uncertain. Several analyses of post-mortem brain tissue revealed reduced neurofibrillary tangles in APOE2 carriers (e.g., Nagy et al., 1995; Serrano-Pozo et al., 2015). Moreover, Reiman and colleagues reported a lower tau tangle burden in APOE2 individuals, even after controlling for neuritic Aβ plaques (Feb 2020 news; Reiman et al., 2020). However, some studies of living, non-demented older adults have failed to detect an association (Morris et al., 2010; Salvadó et al., 2021a).  For example, using PET imaging in older adults without dementia, Salvadó et al. reported that, although APOE2 carriers had a lower global Aβ burden than APOE3 homozygotes, regional tau burden and tau accumulation over time were similar in the two groups. The authors proposed that the protective effect of the APOE2 allele may be primarily tied to resistance against Aβ deposition rather than tau pathology, consistent with the observation that APOE2 negatively correlated with tau pathology in Aβ-positive, but not Aβ-negative, individuals (Farfel et al., 2016). Using a larger sample and mediation analyses, however, a more recent study reported a direct association between APOE2 and reduced regional tau in the medial temporal lobe and early neocortical regions, beyond the effects of amyloid burden (Young et al., 2023).

Of note, in primary tauopathies, APOE2 may even be harmful. APOE2 was associated with increased risk of progressive supranuclear palsy (PSP), as revealed by the first whole-genome sequencing analysis of PSP including 1,700 patients (Wang et al., 2024; Feb 2024 news). Moreover, APOE2 homozygosity was associated with more severe PSP pathology and corticobasal degeneration (Zhao et al., 2018). However, two other studies failed to identify these associations (Sabir et al., 2019; Goldberg et al., 2020).

Studies of hippocampal volume, cortical thickness, brain connectivity patterns, and brain vascular health have yielded mixed results. Although a few studies have tied APOE2 to reduced hippocampal shrinkage (e.g., Hostage et al., 2013, Chiang et al., 2010), others have failed to detect a link (e.g., Grothe et al., 2017; Serra-Grabulosa 2003; Den Heijer et al., 2002). As reported in a preprint, APOE2 heterozygosity may delay hippocampal volume decline, but only in adults over 75 years of age (Chaloemtoem et al., 2024). Moreover, an association with greater cortical thickness has been observed multiple times (e.g., Shaw et al., 2007; Liu et al., 2010; Fan et al., 2010), but not always (e.g., Groot et al., 2018). Also, whereas one study of brain connectivity found opposite aging trajectories in carriers of the APOE2 allele versus those carrying the AD risk allele APOE4 (Shu et al., 2016), another reported surprising similarities in the connectivity of individuals carrying either APOE2 or APOE4 alleles (Trachtenberg et al., 2012). No difference in FDG-PET imaging was detected, at least in one study (Grothe et al., 2017). Also of note, cognitively unimpaired APOE2 carriers were reported to have larger volumes of gray matter in brain regions typically affected by AD compared with non-carriers, and, in homozygotes, this also applied to regions related to successful aging (Salvadó et al., 2021b). However, a review of the literature concluded that APOE2’s association with several AD imaging markers, including brain structure, function, and metabolism, remained uncertain because of inconsistent results (Kim et al., 2022). One important factor that may contribute to these inconsistencies is the variabile reliability of many widely used APOE genotyping methods (Belloy et al., 2022).

Highlighting the uncertainties of how APOE2 protects the brain, a few studies have shown unexpected correlations between AD pathologies and symptoms in APOE2 carriers. For example, one study showed that APOE2 protection persisted even after controlling for AD neuropathological changes and comorbid pathologies (Qian et al., 2021). Moreover, in the oldest old, APOE2 carriers with intact cognition harbored a higher plaque burden than non-carriers (Berlau et al., 2009).

Interestingly, although APOE2 may be protective against some comorbid neurodegenerative proteinopathies presenting with AD (e.g., Walker and Richardson 2022), it does not seem to be protective against cerebrovascular-disease pathology compared with APOE3 (Goldberg et al., 2020). In fact, several studies have linked APOE2 to increased pathology, including white matter hyperintensities and microbleeds (e.g., Greenberg 1998; Westlye et al., 2012; Groot et al., 2018; Kim et al., 2022). The association may be due to direct effects of APOE2 on brain vasculature, effects on cardiovascular health which develop years before dementia onset, and/or result from a higher disease threshold in APOE2 carriers such that co-morbidities are more often required to overcome APOE2’s protective effect. Adding to the uncertainty of these considerations, at least one study reported APOE2 as being protective for white matter hyperintensities in cognitively healthy individuals (Salvadó et al., 2019).

A particularly interesting case is the connection between APOE2 and cerebral amyloid angiopathy (CAA), a condition that often co-exists with AD. Given that APOE2 is protective against Aβ deposition in brain parenchyma and CAA involves Aβ deposition in cerebral vessel walls, one might expect CAA risk to be lower in APOE2 carriers. However, in one study, allelic dose was not associated with a significantly lower odds ratio for CAA before or after adjustment for AD pathology (Reiman et al., 2020). In fact, several studies have found that APOE2 carriers are at higher risk of having this disease and with more severe pathology (Nelson et al., 2013; Yu et al., 2015; for review see Li et al., 2020). Some studies suggest APOE2-associated accumulation of Aβ in vessels leads to vessel rupture and hemorrhages and, indeed, APOE2 has been tied to increased severity and frequency of hemorrhage in patients with CAA and lobar intracerebral hemorrhage (e.g., Brouwers et al., 2012; O’Donnell et al., 2000; Goldberg et al., 2020; Hostettler et al., 2022; Wu et al., 2024), although these associations may vary with ancestry (Kittner et al., 2021). Of note, APOE2 is also a risk factor for stroke (e.g., Schilling et al., 2013). 

Studies of the lipoprotein and lipid profiles of the cerebrospinal fluid and brain tissue of APOE2 carriers have yielded varying results. ApoE levels appear to be elevated in cortices of ApoE2 carriers, but studies of cerebrospinal fluid (CSF) have been inconsistent (Li et al., 2020). One study found that CSF ApoE2 was the lowest of the three common isoforms in heterozygote individuals, before or after subdividing the samples according to Aβ42/Aβ40 ratios, a proxy for brain amyloid deposition (Minta et al., 2020). Also of note, similar lipidomic profiles were reported in APOE2 carriers and non-carriers in AD postmortem brains (Lefterov et al., 2019).

Other AD-relevant factors

Several studies have reported associations between APOE2 and other proteins and lipid species in blood, in the context of neurological function. For example, two reports noted increased levels of phospholipids in the blood of APOE2 carriers, a trait tied to lower risk of cognitive decline in cognitively normal individuals (Wong et al., 2019; Zhao et al., 2020). Some findings have been unexpected. For example, two studies including blood samples from hundreds of thousands of individuals found that while APOE2 was associated with low levels of ApoA, a protein whose elevation has been tied to AD, it was also associated with low levels of insulin-like growth factor 1 (IGF-1), a protein whose reduction has been implicated in AD, and high levels of the marker of low-grade inflammation CRP which is associated with an elevated risk of neurodegenerative disease (Ferguson et al., 2020; Wu et al., 2021). Also, although APOE2 associations with many biomarkers were in the opposite direction of biomarker associations with APOE4 as expected (e.g., LDL, IGF-1, CRP, alanine aminotransferase, and ApoA), a few associations were in the same direction (e.g. with hemoglobin A1c, lipoprotein A, and sex hormone-binding globulin). One study predicted that up to 30 percent of the protective effect of APOE2 may be mediated by plasma lipid species (Wang et al., 2022).

Genetic and environmental factors contribute to APOE2’s effects and may help explain differences in reported findings. In particular, differing effects have been reported between groups of different ancestries. As shown in the table below, the protective effect of APOE2 was not observed in Hispanics (Belloy et al., 2023; Xiao et al., 2023), or found to be considerably weaker compared with Europeans or Whites (Blue et al., 2019; Rajabli et al., 2023). At least in one study, analysis of global ancestry was unable to explain this reduced effect (Belloy et al., 2023). Moreover, a large meta-analysis of East Asian cohorts indicated APOE2 had no effect on AD risk (Belloy et al., 2023) and another meta-analysis of Chinese cohorts suggested a lower incidence of AD associated with APOE3 than with APOE2 (Chen et al., 2022). Also, a large study of amyloid PET levels showed APOE2 has a much stronger protective effect in non-Hispanic Whites than in Asians (Ali et al., 2023). 

Many questions about how ancestry shapes APOE2'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 substantially attenuate the effects of APOE2 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).

Differences in APOE2's effects on AD risk may be shaped by nearby polymorphisms in the APOE region, as well as by variants in distant genes, including genes on other chromosomes. For example, a common variant of haptoglobin—a hemoglobin scavenger that also binds to ApoE and is thought to protect ApoE from oxidation—appears to modify both the deleterious effect of APOE4, as well as the protective effect of APOE2 (Bai et al., 2023). Moreover, two genome-wide analyses identified several APOE2 modifiers, revealing an enrichment in genes involved in inflammation, immunity, lipoprotein function, and cell-junction biology (Nazarian et al., 2022a; Nazarian et al., 2022b).

The reported influences of gender on APOE2's effects have been mixed. One meta-analysis showed that, in cognitively unimpaired non-Hispanic White adults, the APOE2/E3 genotype decreased AD risk more strongly in women than in men (Neu et al., 2017). In contrast, a  longitudinal study of two independent samples of non-Hispanic Whites, found that, relative to APOE3/E3, APOE2 protected against cognitive decline in men, but not women (Wood et al., 2023). Interestingly,  APOE2's protective effects on executive function in a large study of cognitively unimpaired individuals were found to be female-specific among Whites but male-specific among Blacks (Walters et al., 2023).

A large population-based study found that differences in brain structure between individuals—especially in areas particularly vulnerable to AD—may shape APOE2-associated protection against AD and related dementias (Savignac et al., 2022). Other phenotypes, such as personality traits, were tied to these structural variations and APOE2's effects. Gender also appeared to play a role in these associations, with social lifestyle modulating APOE2 protection in men and physical activity influencing protection in women. The effects of factors thought to influence cognitive reserve—such as years of education and literacy level—remain uncertain (e.g., Pettigrew et al., 2013; Pettigrew et al., 2023).

Non-AD Neurological Disorders

APOE2 has been found to be associated with increased risk for several neurological conditions, including age-related macular degeneration, progressive supranuclear palsy, corticobasal degeneration, and argyrophilic grain disease (for review see Li et al., 2020). APOE2 may also be associated with earlier onset or increased risk for cerebral palsy and Machado-Joseph Disease, albeit sample sizes have been small in these studies. Although no correlation between APOE and ALS risk has been detected, ALS patients homozygous for APOE2 showed decreased glucose metabolism in extra-motor areas compared with APOE3 homozygous patients (Canosa et al., 2019), and APOE2 was associated with more severe TDP-43 pathology in motor cortices of ALS post-mortem brains (Meneses et al., 2022).

The effect of APOE2 on frontotemporal lobar degeneration (FTLD) risk is uncertain, with APOE2 exerting either no effect or increasing risk (e.g., Goldberg et al., 2020), as well as potentially increasing TDP-43 pathology, at least in FTLD with motor neuron disease (Meneses et al., 2022). Other neurological disorders whose associations with APOE2 have been studied—but results remain unclear—include Creutzfeldt-Jakob disease, multiple sclerosis, and Huntington’s disease (Li et al., 2020). In at least one study, no associations between APOE2 and Lewy body disease or hippocampal sclerosis were detected (Reiman et al., 2020). 

Non-neurological conditions

A wide range of non-neurological conditions have been reported to be positively or negatively associated with APOE2, including blood biochemistry and blood-cell traits, metabolic health, cardiovascular diseases, kidney dysfunction, cancer, fertility, and longevity (see, e.g., GWAS catalog; Li et al., 2020; Li et al., 2020; Lumsden et al., 2020; Wu et al., 2021).

With some exceptions (see paragraph below on APOE2 homozygosity), APOE2 carriers tend to have normal or cardiovascular-protective profiles of lipids and lipoproteins in blood. Although findings vary between studies, compared with APOE3 carriers, on average, APOE2 carriers have lower levels of total cholesterol, low-density lipoproteins (LDL), and ApoB (e.g., Rasmussen et al., 2020; Lumsden et al., 2020; Karjalainen et al., 2020; Ferguson et al., 2020; Sebastiani et al., 2022; Pieri et al., 2022; Rasmussen et al., 2023; Compton et al., 2024). Indeed, a study of approximately half a million blood samples from the UK Biobank found that APOE2 accounted for a large percentage of the variance in blood cholesterol, LDL, and ApoB (approximately 6, 4, and 9 percent, respectively) (Wu et al., 2021). Consistent with these effects, APOE2 has been reported to decrease the risk of heart attack and angina, although not high blood pressure.

APOE2 carriers also appear to have elevated levels of ApoE, a trait correlated with a lower risk of dementia (Rasmussen et al., 2020), and reduced levels of fatty acids and sphingomyelins, the latter which have been associated with AD pathology (Compton et al., 2024). Mixed results have been reported for the association of APOE2 with levels of remnant cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol.

Interestingly, several of the differences in metabolite levels have been detected across a wide range of ages, including children and young adults, but appear to be attenuated in older carriers (Wu et al., 2021, Compton et al., 2024). Also of note, although in most cases, APOE2 and APOE4 appear to have opposite effects on traits related to fat metabolism, a couple of studies have reported similar effects for some metabolites, such as triglycerides and remnant cholesterol, and decreased lipoprotein A (Wu et al., 2021, Rasmussen et al., 2023).

Not surprisingly, multiple studies have shown an association between APOE2 and increased longevity. A higher frequency of the allele in elderly women compared with middle-aged women was first reported in 1993 (Cauley et al., 1993), and subsequent studies, including men and ranging from cross-sectional to longitudinal to genome-wide associations, have confirmed the association (for review see Li et al., 2020). Of note, the association seems to hold independently of AD, suggesting a systemic effect on aging (Shinohara et al., 2020).

However, APOE2 has also been associated with harmful peripheral phenotypes including kidney dysfunction (Kawanishi et al., 2013; Saito et al., 2020), reduced fertility (Martinez-Martinez et al., 2020), and more severe cancer phenotypes (Ostendorf et al., 2020). Moreover, two studies that included hundreds of thousands of white individuals found APOE2 homozygosity increased the risk for peripheral vascular disease (Lumsden et al., 2020, Rasmussen et al., 2023). Lumsden and colleagues also reported elevated risks for thromboembolism, arterial aneurysm, peptic ulcer, cervical disorders, and hallux valgus (Lumsden et al., 2020). Also, in one study, APOE2 dosage was found to be associated with diabetes and reduced levels of reticulocytes in blood (Wu et al., 2021). Interestingly, a study of the UK Biobank revealed APOE2 homozygotes with COVID had an increased hazard ratio for death, but it did not reach statistical significance (Ostendorf et al., 2022). In the same study, a COVID mouse model carrying APOE2 showed elevated viral loads and suppressed adaptive immune responses early after infection as compared to mice carrying APOE3.

A particularly well-studied link to APOE2 homozygosity is its association with hyperlipoproteinemia type III (HLPP3), also known as familial dysbetalipoproteinemia, characterized by the accumulation of remnants of triglyceride-rich lipoproteins, and early onset atherosclerosis and heart disease. Although it is often noted that the vast majority of HLPP3 patients are APOE2 homozygotes, the disease surfaces in only 5 to 10 percent of homozygous carriers. Current evidence points to HLPP3 being a complex disease, usually involving APOE2 homozygosity, but requiring other factors, such as obesity, hypothyroidism, estrogen deficiency, diabetes, or other genetic variants (e.g., Mahley 2016; Martinez-Martinez et al., 2020, Satny et al., 2023). Moreover, multiple genetic factors shape the clinical phenotype of APOE2 homozygotes with HLPP3—for example, in a cohort of more than 2,500 such individuals, a polygenic risk score helped predict atherosclerotic cardiovascular disease risk (Paquette et al., 2024). Also of note, the prevalence of APOE2 homozygosity in HLPP3 patients may vary between populations. A large study in Germany, for example, identified only 16 percent of 350 HLPP3 patients as APOE2 homozygotes (Evans et al., 2013).

Biological effects of neurological relevance

Both Aβ-dependent and Aβ-independent mechanisms have been proposed to explain how APOE2 confers protection against AD, but much remains unclear or controversial (for reviews see Andrews et al., 2019; Li et al., 2020; Raulin et al., 2022). At least for mouse studies, the age, brain region, type of AD mouse model, and endogenous ApoE levels are likely to be important contributors to inconsistencies in results (Li et al., 2020).

APOE2 has been associated with reduced Aβ production, slower Aβ aggregation, and more efficient degradation and clearance of the peptide, but most of these effects are still under investigation. For example, studies in human neurons derived from stem cells (iPSCs or ESCs) have shown that ApoE2 appears to be less efficient at stimulating APP transcription (Huang et al., 2019; Huang et al., 2017). However, a transcriptomic analysis of transgenic mice expressing human APOE showed no isoform-related differences in APP mRNA in the brain (Novy et al., 2021). Also, a study in human iPSC-derived neurons suggested that production of Aβ peptides is greatly reduced by ApoE2 (Brookhouser et al., 2021). Interestingly, this reduction may be the result of the direct binding of ApoE2 to γ-secretase within neurons, with the N-terminal region of ApoE modulating the inhibitory strength of the C-terminal region (Hou et al., 2023). However, studies in other experimental models have reported no effect on Aβ production (e.g., Irizarry et al., 2004; Castellano et al., 2011).

How the binding of ApoE2 to Aβ affects pathogenicity is also uncertain (for review see Li et al., 2020). Some studies have found that ApoE2 is more lipidated and binds Aβ with a higher affinity than do ApoE3 or ApoE4. Mice expressing human ApoE2 have higher levels of ApoE/Aβ complexes in their brains. It has also been reported that ApoE2 promotes Aβ clearance across the blood-brain barrier (BBB), as well as cellular uptake and degradation. Indeed, in an AD mouse model expressing human APOE4, production of ApoE2 by transduced ventricle-lining ependymal cells reduced amyloid deposition (Jackson et al., 2024). Moreover, a study using isogenic iPSCs differentiated into BBB-like microvascular endothelial cells and pericytes to generate a BBB model system, revealed enhanced clearance and reduced deposition of Aβ peptides in cells expressing APOE2 compared with cells expressing APOE3 or APOE4, although no detectable effect of APOE2 on the cells' baseline functions was observed (Ding et al., 2024).

Whether ApoE2 protects against Aβ oligomerization, which has been linked to neurotoxicity in AD, remains unclear. Nevertheless, several studies have shown ApoE2-associated anti-toxic effects, including protection against Aβ-induced cell death in cultured neurons (Miyata and Smith, 1996), and other brain-cell types, such as pericytes and endothelial cells (Wilhelmus et al., 2005; Folin et al., 2006), reduced suppression of long-term potentiation by Aβ42 or AD brain lysate in hippocampal slices (Chen et al., 2010; Trommer et al., 2005), as well as decreased synaptic loss and neuritic dystrophy in mouse models that develop amyloid pathology (Hudry et al., 2013; Lanz et al., 2003).

Of note, a growing number of studies suggest APOE2 affects microglial function (e.g., Serrano-Pozo et al., 2021; news Oct 2021; Zhou et al., 2023) For example, as reported in a preprint, human ApoE2 microglia transplanted into mice responded to amyloid by enhancing anti-inflammatory signaling, possibly via increased expression of genes regulated by the nuclear vitamin D receptor (Murphy et al., 2024; Aug 2024 conference news). ApoE2 may also have cell non-autonomous effects on microglial activation (Jackson et al., 2024). Microgliosis near plaques in AD mice expressing human APOE4 was reduced by exposure to ApoE2. Additional clues may emerge from the identification of genetic modifiers that counter APOE2’s protection against AD risk (Kim et al., 2020; Dec 2020 news).

As noted earlier, human data indicate that the relationship between APOE2 and tau pathology may depend on amyloid, and results from at least some experimental models support this possibility. In a study of human iPSC-derived neural cultures, for example, only APOE2-expressing cultures with altered Aβ42/40 ratios developed pathogenic tau (Brookhouser et al., 2021). Whether APOE2 affects tau pathology independently of Aβ in AD remains uncertain. Two studies using mouse models of tauopathy yielded different results: while one found similar levels of tau pathology and brain atrophy in a transgenic tauopathy model crossed with mice expressing human APOE2 or APOE3 (Shi et al., 2017), a study using a viral tauopathy model found more tau pathology in APOE2- than in APOE3-expressing mice (Zhao et al., 2018). The latter results support the reported increase in risk for primary tauopathies in humans. APOE2 may also have effects on other neurodegenerative pathologies. For example, in a synucleinopathy mouse model, researchers reported that ApoE2 reduced α-synuclein aggregation and neurodegeneration (Davis et al., 2020), while in a mouse model of TDP-43 pathology, it exacerbated motor function deficits, neuronal loss, and gliosis in the motor cortex (Meneses et al., 2022).

APOE2 may also have effects on the complement system (e.g., Panitch et al., 2021), as well as on the integrity of the brain-blood barrier (Li et al., 2020).

ApoE2’s effects on normal brain cell function have also been investigated. One study showed increased dendritic spine length and dendritic arborization in the cortex of one-month-old, but not older, APOE2 knockin mice as compared with APOE3 and APOE4 transgenics (Dumanis et al., 2009). The same study found no APOE isoform differences in spine density at any age in the hippocampus. In human cultured neurons derived from embryonic stem cells, ApoE2 was the least potent of the ApoE isoforms at stimulating synapse formation (Huang et al., 2019). Moreover, although aged APOE2 knockin mice performed better in a spatial memory test than APOE3 or APOE4 knockin mice, they showed similar or greater age-related changes in synaptic loss, neuroinflammation, and oxidative stress (Shinohara et al., 2016). Interestingly, lipidated ApoE2 enhanced synapse elimination by astrocytes in culture more than ApoE3 or ApoE4, a process that may reflect a protective removal of senescent synapses and debris (Chung et al., 2016). A study of the brain transcriptomes of male and female APOE-targeted replacement mice revealed patterns associated with APOE2 expression across young, middle, and old age (Zhao et al., 2020).  

Several preclinical and clinical studies are underway to evaluate APOE2’s therapeutic potential (Li et al., 2020; Serrano-Pozo et al., 2021; Raulin et al., 2022, Jackson et al., 2024). For example, a viral vector driving expression of the allele is being tested for delivery to the central nervous system in APOE4 homozygotes who are at increased risk of developing AD (LX1001, Dec 2022 conference news). 

Other biological effects

Outside the brain, the effects of ApoE2 stem from the isoform’s reduced ability to bind to several cell surface receptors, particularly the LDL receptor, its downregulation of lipolysis, and its increased levels in blood compared with ApoE3. Decreased receptor binding reduces the liver’s ability to remove remnant lipoprotein particles—partially catabolized carriers of triglycerides including chylomicrons and very-low-density lipoprotein (VLDL) (for reviews see Mahley, 2016; Martinez-Martinez et al., 2020). Also, ApoE2 has a lower capacity to promote hepatic lipase activity, and its high levels displace lipase co-factor ApoC-II which reduces the processing of lipoprotein particles, including VLDL to LDL and VLDL and intermediate-density lipoprotein (IDL) to high-density lipoprotein (HDL). Moreover, expression of ApoE2 in mouse myeloid cells has been reported to increase inflammasome activation and myelopoiesis (Igel et al., 2021). Despite these alterations, most APOE2 carriers have normal or hypolipemic profiles in blood, as previously noted, but additional genetic or environmental factors can precipitate pathology.

In addition to influencing blood, heart, and liver physiology, ApoE2 may affect reproductive physiology, as well as kidney and adipose tissue function, but the mechanisms underlying these effects remain uncertain (Martinez-Martinez et al., 2020).

Molecular underpinnings

Although R176 is eight amino acids beyond the ApoE receptor-binding site, the R176C substitution dramatically reduces receptor binding activity. Binding of ApoE2 to the LDL receptor, the most studied interaction, is very poor, as is binding to APOER2/LRP8 (for review see Li et al., 2020). However, binding to the LDL receptor-related protein (LRP1) and to heparan sulfate proteoglycans (HSPG) is less impaired, and binding to the VLDL receptor and TREM2 is normal. These different receptors have different requirements and functions: LDLR, VLDLR, LRP1, and HSPG have all been implicated in lipoprotein clearance and Aβ clearance, but only LDLR unequivocally requires lipid binding. Moreover, LRP1 appears to be also involved in neuroprotective signaling and synaptogenesis, while APOER2/LRP8 regulates trafficking of synaptic receptors, and TREM2 regulates microglial phenotypes and facilitates Aβ phagocytosis.

Many studies have examined the molecular underpinnings of ApoE2’s poor binding to LDL receptors, but open questions remain (see Chen et al., 2021 for review). One possibility is that the R176C substitution causes salt bridge rearrangements that reduce the positive charge in the receptor-binding region (Wilson et al., 1994; Dong et al., 1996). Alternatively, the R176C may alter ApoE’s initial lipid binding stage, preventing a conformational change that makes the receptor binding site accessible. R176 may be involved in unfolding ApoE, helping to pull apart two of the bundled helices in the N-terminal domain, helices 3 and 4, to allow dimerization between stretched-out monomers to form a mature lipoprotein particle (Chen et al., 2011). Of note, a high-resolution structural study suggested that once ApoE binds to lipids, it adopts an extended α-helical, antiparallel conformation on lipoproteins, consistent with the bundled helices opening up so the hydrophobic regions of the helices associate with lipid (Feb 2024 news; Strickland et al., 2024).

Although evidence from human brains is unavailable, ApoE2 appears to be more lipidated than ApoE3 or ApoE4 in human cerebrospinal fluid, as well as in astrocyte and microglial cell cultures (see Li et al., 2020; Martens et al., 2022 for reviews). Moreover, in vitro assays and the size of ApoE lipoprotein particles (e.g., Strickland et al., 2024) suggest ApoE2 is a better lipid acceptor. As proposed by Li and colleagues, this hyperlipidation may enable more efficient delivery of lipids to neurons, maintain synaptic plasticity during AD, clear Aβ via the blood-brain barrier more efficiently, and promote extracellular degradation of Aβ more effectively (Li et al., 2020).

Also of relevance to AD, ApoE2's reduced binding to HSPG may be protective against tau pathology. HSPG facilitates the dissemination and uptake of tau seeds into neurons, and limiting HSPG-ApoE binding reduces this spread. Indeed, this reduction has been implicated in AD protection associated with another ApoE variant, R154S (Christchurch), and insights into the molecular interactions involved in ApoE2-HSPG binding are beginning to emerge (e.g., Mah et al., 2023). Also of note, ApoE2 has been reported to have very low affinity for leukocyte immunoglobulin-like receptor B3 (LilrB3), a microglial receptor that binds tightly to ApoE4 and activates pro-inflammatory pathways (Zhou et al., 2023).

Research Models

Several rodent models expressing human APOE2 have been generated, including mice in which the murine Apoe gene is replaced with the human APOE2 allele, APOE2 Targeted Replacement, APOE2 Knock-In, floxed (CureAlz), and APOE2 Knock-In (JAX). 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). Gene expression patterns in switched brain cells resembled those of APOE2 mice. Knock-in rat models, which develop hyperlipidemia, have also been produced (Wu et al., 2021). In addition, several groups have created isogenic induced pluripotent stem cells expressing the three major APOE isoforms, including APOE2 (e.g., Schmid et al., 2021). 

Note on nomenclature

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 fewer positive charge were named ApoE2. Subsequent studies showed that, in most cases, these slower migrating species corresponded to R176C.

Table

^aData from GWAS Catalog rs7412, May 2022
^bAD or AD family history
^cMeta-analysis of two meta-analyses (Farrer et al., 1997, Choi et al., 2019).
^dCompare to APOE3 in same cohort: OR=0.539, CI [0.504–0.576], p< 0.001
^eData from the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) rs7412, June 2022.
^fData from MedRxiv preprint.
^gFor more information on carriers of both APOE2 and APOE4 alleles, see [R176C];[C130R].

OR=odds ratio, GWAS=genome-wide association study, HR=hazard ratio. Statistically significant associations (as assessed by the authors) are in bold. For data retrieved from NIAGADS, p-values <5x10^-8 are in bold. All data retrieved from the GWAS catalog (p-values <1x10^-5) are in bold.
All GWAS of Caucasian or mixed ancestry cohorts in this table included >2,000 cases, and all targeted association studies included >500 cases (subgroups within a study may be smaller).

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Mutations Citations

1. APOE C130R (ApoE4)
2. PSEN1 E280A (Paisa)
3. APOE R154S (Christchurch)
4. APOE [R176C];[C130R] (ApoE2/4)

News Citations

1. Paper Alert: Two ApoE2s Provide “Exceptional” Protection Against AD 5 Feb 2020
2. First Whole-Genome Sequencing of PSP Nets Six New Risk Loci 8 Feb 2024
3. Even In the Healthy, ApoE4 Stirs Up Trouble, Scientists Say 16 Oct 2021
4. Microglial Epigenetics Hints at How ApoE Toggles Alzheimer’s Risk 16 Aug 2024
5. In People Who Defy ApoE, New Alzheimer’s Risk Genes Found 29 Dec 2020
6. In Small Trial, Gene Therapy Spurs ApoE2 Production 14 Dec 2022
7. In Lipoparticles, ApoE Double Belt Keeps the Fat In 1 Feb 2024
8. Meet the Switching Mice: They Flip Their Glia APOE4 to APOE2 23 Aug 2023

Therapeutics Citations

1. LX1001

Research Models Citations

1. APOE2 Targeted Replacement
2. APOE2 Knock-In, floxed (CureAlz)
3. APOE2 Knock-In (JAX)

Paper Citations

1. 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.
2. 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.
3. Singh PP, Singh M, Mastana SS. APOE distribution in world populations with new data from India and the UK. Ann Hum Biol. 2006 May-Jun;33(3):279-308. PubMed.
4. 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.
5. Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC Jr, Rimmler JB, Locke PA, Conneally PM, Schmader KE. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet. 1994 Jun;7(2):180-4. PubMed.
6. Smith AD, Johnston C, Sim E, Nagy Z, Jobst KA, Hindley N, King E. Protective effect of apo epsilon 2 in Alzheimer's disease. Oxford Project to Investigate Memory and Ageing (OPTIMA). Lancet. 1994 Aug 13;344(8920):473-4. PubMed.
7. West HL, Rebeck GW, Hyman BT. Frequency of the apolipoprotein E epsilon 2 allele is diminished in sporadic Alzheimer disease. Neurosci Lett. 1994 Jul 4;175(1-2):46-8. PubMed.
8. 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.
9. 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.
10. Stipho F, Jackson R, Sabbagh MN. Pathologically Confirmed Alzheimer's Disease in APOE ɛ2 Homozygotes is Rare but Does Occur. J Alzheimers Dis. 2018;62(4):1527-1530. PubMed.
11. Groot C, Sudre CH, Barkhof F, Teunissen CE, van Berckel BN, Seo SW, Ourselin S, Scheltens P, Cardoso MJ, van der Flier WM, Ossenkoppele R. Clinical phenotype, atrophy, and small vessel disease in APOEε2 carriers with Alzheimer disease. Neurology. 2018 Nov 13;91(20):e1851-e1859. Epub 2018 Oct 19 PubMed.
12. 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.
13. Li Z, Shue F, Zhao N, Shinohara M, Bu G. APOE2: protective mechanism and therapeutic implications for Alzheimer's disease. Mol Neurodegener. 2020 Nov 4;15(1):63. PubMed.
14. 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.
15. 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.
16. Vélez JI, Lopera F, Sepulveda-Falla D, Patel HR, Johar AS, Chuah A, Tobón C, Rivera D, Villegas A, Cai Y, Peng K, Arkell R, Castellanos FX, Andrews SJ, Silva Lara MF, Creagh PK, Easteal S, de Leon J, Wong ML, Licinio J, Mastronardi CA, Arcos-Burgos M. APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer's disease. Mol Psychiatry. 2015 Dec 1; PubMed.
17. 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.
18. Langella S, Bonta K, Chen Y, Su Y, Vasquez D, Aguillon D, Acosta-Baena N, Baena AY, Garcia-Ospina G, Giraldo-Chica M, Tirado V, Muñoz C, Ríos-Romenets S, Guzman-Martínez C, Pruzin JJ, Ghisays V, Arboleda-Velasquez JF, Kosik KS, Tariot PN, Reiman EM, Lopera F, Quiroz YT. Impact of APOE ε4 and ε2 on plasma neurofilament light chain and cognition in autosomal dominant Alzheimer's disease. Alzheimers Res Ther. 2024 Oct 1;16(1):208. PubMed.
19. Nagy Z, Esiri MM, Jobst KA, Johnston C, Litchfield S, Sim E, Smith AD. Influence of the apolipoprotein E genotype on amyloid deposition and neurofibrillary tangle formation in Alzheimer's disease. Neuroscience. 1995 Dec;69(3):757-61. PubMed.
20. Oyama F, Shimada H, Oyama R, Ihara Y. Apolipoprotein E genotype, Alzheimer's pathologies and related gene expression in the aged population. Brain Res Mol Brain Res. 1995 Mar;29(1):92-8. PubMed.
21. Lippa CF, Smith TW, Saunders AM, Hulette C, Pulaski-Salo D, Roses AD. Apolipoprotein E-epsilon 2 and Alzheimer's disease: genotype influences pathologic phenotype. Neurology. 1997 Feb;48(2):515-9. PubMed.
22. Berlau DJ, Corrada MM, Robinson JL, Geser F, Arnold SE, Lee VM, Kawas CH, Trojanowski JQ. Neocortical β-amyloid area is associated with dementia and APOE in the oldest-old. Alzheimers Dement. 2013 Nov;9(6):699-705. Epub 2013 Mar 7 PubMed.
23. Tiraboschi P, Hansen LA, Masliah E, Alford M, Thal LJ, Corey-Bloom J. Impact of APOE genotype on neuropathologic and neurochemical markers of Alzheimer disease. Neurology. 2004 Jun 8;62(11):1977-83. PubMed.
24. Serrano-Pozo A, Qian J, Monsell SE, Betensky RA, Hyman BT. APOEε2 is associated with milder clinical and pathological Alzheimer disease. Ann Neurol. 2015 Jun;77(6):917-29. PubMed.
25. 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.
26. Morris JC, Roe CM, Xiong C, Fagan AM, Goate AM, Holtzman DM, Mintun MA. APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann Neurol. 2010 Jan;67(1):122-31. PubMed.
27. Grothe MJ, Villeneuve S, Dyrba M, Bartrés-Faz D, Wirth M, Alzheimer's Disease Neuroimaging Initiative. Multimodal characterization of older APOE2 carriers reveals selective reduction of amyloid load. Neurology. 2017 Feb 7;88(6):569-576. Epub 2017 Jan 6 PubMed.
28. Jansen WJ, Ossenkoppele R, Knol DL, Tijms BM, Scheltens P, Verhey FR, Visser PJ, Amyloid Biomarker Study Group, Aalten P, Aarsland D, Alcolea D, Alexander M, Almdahl IS, Arnold SE, Baldeiras I, Barthel H, van Berckel BN, Bibeau K, Blennow K, Brooks DJ, van Buchem MA, Camus V, Cavedo E, Chen K, Chetelat G, Cohen AD, Drzezga A, Engelborghs S, Fagan AM, Fladby T, Fleisher AS, van der Flier WM, Ford L, Förster S, Fortea J, Foskett N, Frederiksen KS, Freund-Levi Y, Frisoni GB, Froelich L, Gabryelewicz T, Gill KD, Gkatzima O, Gómez-Tortosa E, Gordon MF, Grimmer T, Hampel H, Hausner L, Hellwig S, Herukka SK, Hildebrandt H, Ishihara L, Ivanoiu A, Jagust WJ, Johannsen P, Kandimalla R, Kapaki E, Klimkowicz-Mrowiec A, Klunk WE, Köhler S, Koglin N, Kornhuber J, Kramberger MG, Van Laere K, Landau SM, Lee DY, de Leon M, Lisetti V, Lleó A, Madsen K, Maier W, Marcusson J, Mattsson N, de Mendonça A, Meulenbroek O, Meyer PT, Mintun MA, Mok V, Molinuevo JL, Møllergård HM, Morris JC, Mroczko B, Van der Mussele S, Na DL, Newberg A, Nordberg A, Nordlund A, Novak GP, Paraskevas GP, Parnetti L, Perera G, Peters O, Popp J, Prabhakar S, Rabinovici GD, Ramakers IH, Rami L, Resende de Oliveira C, Rinne JO, Rodrigue KM, Rodríguez-Rodríguez E, Roe CM, Rot U, Rowe CC, Rüther E, Sabri O, Sanchez-Juan P, Santana I, Sarazin M, Schröder J, Schütte C, Seo SW, Soetewey F, Soininen H, Spiru L, Struyfs H, Teunissen CE, Tsolaki M, Vandenberghe R, Verbeek MM, Villemagne VL, Vos SJ, van Waalwijk van Doorn LJ, Waldemar G, Wallin A, Wallin ÅK, Wiltfang J, Wolk DA, Zboch M, Zetterberg H. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA. 2015 May 19;313(19):1924-38. PubMed.
29. Palmqvist S, Zetterberg H, Mattsson N, Johansson P, Alzheimer's Disease Neuroimaging Initiative, Minthon L, Blennow K, Olsson M, Hansson O, Swedish BioFINDER Study Group. Detailed comparison of amyloid PET and CSF biomarkers for identifying early Alzheimer disease. Neurology. 2015 Oct 6;85(14):1240-9. Epub 2015 Sep 9 PubMed.
30. Salvadó G, Grothe MJ, Groot C, Moscoso A, Schöll M, Gispert JD, Ossenkoppele R, Alzheimer’s Disease Neuroimaging Initiative. Differential associations of APOE-ε2 and APOE-ε4 alleles with PET-measured amyloid-β and tau deposition in older individuals without dementia. Eur J Nucl Med Mol Imaging. 2021 Jul;48(7):2212-2224. Epub 2021 Feb 1 PubMed.
31. Shinohara M, Kanekiyo T, Yang L, Linthicum D, Shinohara M, Fu Y, Price L, Frisch-Daiello JL, Han X, Fryer JD, Bu G. APOE2 eases cognitive decline during Aging: Clinical and preclinical evaluations. Ann Neurol. 2016 May;79(5):758-774. Epub 2016 Mar 29 PubMed.
32. Farfel JM, Yu L, De Jager PL, Schneider JA, Bennett DA. Association of APOE with tau-tangle pathology with and without β-amyloid. Neurobiol Aging. 2016 Jan;37:19-25. Epub 2015 Sep 28 PubMed.
33. Young CB, Johns E, Kennedy G, Belloy ME, Insel PS, Greicius MD, Sperling RA, Johnson KA, Poston KL, Mormino EC, Alzheimer’s Disease Neuroimaging Initiative, A4 Study Team. APOE effects on regional tau in preclinical Alzheimer's disease. Mol Neurodegener. 2023 Jan 4;18(1):1. PubMed.
34. Wang H, Chang TS, Dombroski BA, Cheng PL, Patil V, Valiente-Banuet L, Farrell K, Mclean C, Molina-Porcel L, Rajput A, De Deyn PP, Le Bastard N, Gearing M, Kaat LD, Van Swieten JC, Dopper E, Ghetti BF, Newell KL, Troakes C, de Yébenes JG, Rábano-Gutierrez A, Meller T, Oertel WH, Respondek G, Stamelou M, Arzberger T, Roeber S, Müller U, Hopfner F, Pastor P, Brice A, Durr A, Le Ber I, Beach TG, Serrano GE, Hazrati LN, Litvan I, Rademakers R, Ross OA, Galasko D, Boxer AL, Miller BL, Seeley WW, Van Deerlin VM, Lee EB, White CL 3rd, Morris H, de Silva R, Crary JF, Goate AM, Friedman JS, Leung YY, Coppola G, Naj AC, Wang LS, P. S. P. genetics study group, Dalgard C, Dickson DW, Höglinger GU, Schellenberg GD, Geschwind DH, Lee WP. Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy. Mol Neurodegener. 2024 Aug 16;19(1):61. PubMed. Correction.
35. Zhao N, Liu CC, Van Ingelgom AJ, Linares C, Kurti A, Knight JA, Heckman MG, Diehl NN, Shinohara M, Martens YA, Attrebi ON, Petrucelli L, Fryer JD, Wszolek ZK, Graff-Radford NR, Caselli RJ, Sanchez-Contreras MY, Rademakers R, Murray ME, Koga S, Dickson DW, Ross OA, Bu G. APOE ε2 is associated with increased tau pathology in primary tauopathy. Nat Commun. 2018 Oct 22;9(1):4388. PubMed.
36. Sabir MS, Blauwendraat C, Ahmed S, Serrano GE, Beach TG, Perkins M, Rice AC, Masliah E, Morris CM, Pihlstrom L, Pantelyat A, Resnick SM, Cookson MR, Hernandez DG, Albert M, Dawson TM, Rosenthal LS, Houlden H, Pletnikova O, Troncoso J, Scholz SW. Assessment of APOE in atypical parkinsonism syndromes. Neurobiol Dis. 2019 Jul;127:142-146. Epub 2019 Feb 21 PubMed.
37. Goldberg TE, Huey ED, Devanand DP. Association of APOE e2 genotype with Alzheimer's and non-Alzheimer's neurodegenerative pathologies. Nat Commun. 2020 Sep 18;11(1):4727. PubMed.
38. Hostage CA, Roy Choudhury K, Doraiswamy PM, Petrella JR, . Dissecting the gene dose-effects of the APOE ε4 and ε2 alleles on hippocampal volumes in aging and Alzheimer's disease. PLoS One. 2013;8(2):e54483. PubMed.
39. Chiang GC, Insel PS, Tosun D, Schuff N, Truran-Sacrey D, Raptentsetsang ST, Jack CR, Aisen PS, Petersen RC, Weiner MW, . Hippocampal atrophy rates and CSF biomarkers in elderly APOE2 normal subjects. Neurology. 2010 Nov 30;75(22):1976-81. PubMed.
40. Serra-Grabulosa JM, Salgado-Pineda P, Junqué C, Solé-Padullés C, Moral P, López-Alomar A, López T, López-Guillén A, Bargalló N, Mercader JM, Clemente IC, Bartrés-Faz D. Apolipoproteins E and C1 and brain morphology in memory impaired elders. Neurogenetics. 2003 Apr;4(3):141-6. Epub 2002 Dec 21 PubMed.
41. den Heijer T, Oudkerk M, Launer LJ, van Duijn CM, Hofman A, Breteler MM. Hippocampal, amygdalar, and global brain atrophy in different apolipoprotein E genotypes. Neurology. 2002 Sep 10;59(5):746-8. PubMed.
42. 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.
43. Shaw P, Lerch JP, Pruessner JC, Taylor KN, Rose AB, Greenstein D, Clasen L, Evans A, Rapoport JL, Giedd JN. Cortical morphology in children and adolescents with different apolipoprotein E gene polymorphisms: an observational study. Lancet Neurol. 2007 Jun;6(6):494-500. PubMed.
44. Liu Y, Paajanen T, Westman E, Zhang Y, Wahlund LO, Simmons A, Tunnard C, Sobow T, Proitsi P, Powell J, Mecocci P, Tsolaki M, Vellas B, Muehlboeck S, Evans A, Spenger C, Lovestone S, Soininen H, AddNeuroMed Consortium. APOE ε2 allele is associated with larger regional cortical thicknesses and volumes. Dement Geriatr Cogn Disord. 2010;30(3):229-37. Epub 2010 Sep 15 PubMed.
45. Fan M, Liu B, Zhou Y, Zhen X, Xu C, Jiang T, Alzheimer's Disease Neuroimaging Initiative. Cortical thickness is associated with different apolipoprotein E genotypes in healthy elderly adults. Neurosci Lett. 2010 Aug 2;479(3):332-6. Epub 2010 Jun 8 PubMed.
46. Shu H, Shi Y, Chen G, Wang Z, Liu D, Yue C, Ward BD, Li W, Xu Z, Chen G, Guo Q, Xu J, Li SJ, Zhang Z. Opposite Neural Trajectories of Apolipoprotein E ϵ4 and ϵ2 Alleles with Aging Associated with Different Risks of Alzheimer's Disease. Cereb Cortex. 2016 Apr;26(4):1421-1429. Epub 2014 Oct 21 PubMed.
47. Trachtenberg AJ, Filippini N, Ebmeier KP, Smith SM, Karpe F, Mackay CE. The effects of APOE on the functional architecture of the resting brain. Neuroimage. 2012 Jan 2;59(1):565-72. Epub 2011 Aug 7 PubMed.
48. Salvadó G, Ferreira D, Operto G, Cumplido-Mayoral I, Arenaza-Urquijo EM, Cacciaglia R, Falcon C, Vilor-Tejedor N, Minguillon C, Groot C, van der Flier WM, Barkhof F, Scheltens P, Ossenkoppele R, Kern S, Zettergren A, Skoog I, Hort J, Stomrud E, van Westen D, Hansson O, Molinuevo JL, Wahlund LO, Westman E, Gispert JD, ALFA study†, BioFINDER, ADNI. The protective gene dose effect of the APOE ε2 allele on gray matter volume in cognitively unimpaired individuals. Alzheimers Dement. 2022 Jul;18(7):1383-1395. Epub 2021 Dec 8 PubMed.
49. Kim H, Devanand DP, Carlson S, Goldberg TE. Apolipoprotein E Genotype e2: Neuroprotection and Its Limits. Front Aging Neurosci. 2022;14:919712. Epub 2022 Jul 14 PubMed.
50. 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.
51. 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.
52. Berlau DJ, Corrada MM, Head E, Kawas CH. APOE epsilon2 is associated with intact cognition but increased Alzheimer pathology in the oldest old. Neurology. 2009 Mar 3;72(9):829-34. PubMed.
53. 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.
54. Goldberg TE, Huey ED, Devanand DP. Associations of APOE e2 genotype with cerebrovascular pathology: a postmortem study of 1275 brains. J Neurol Neurosurg Psychiatry. 2020 Nov 4; PubMed.
55. Greenberg SM. Cerebral amyloid angiopathy: prospects for clinical diagnosis and treatment. Neurology. 1998 Sep;51(3):690-4. PubMed.
56. Westlye LT, Reinvang I, Rootwelt H, Espeseth T. Effects of APOE on brain white matter microstructure in healthy adults. Neurology. 2012 Nov 6;79(19):1961-9. Epub 2012 Oct 24 PubMed.
57. Salvadó G, Brugulat-Serrat A, Sudre CH, Grau-Rivera O, Suárez-Calvet M, Falcon C, Fauria K, Cardoso MJ, Barkhof F, Molinuevo JL, Gispert JD, ALFA Study. Spatial patterns of white matter hyperintensities associated with Alzheimer's disease risk factors in a cognitively healthy middle-aged cohort. Alzheimers Res Ther. 2019 Jan 24;11(1):12. PubMed.
58. Nelson PT, Pious NM, Jicha GA, Wilcock DM, Fardo DW, Estus S, Rebeck GW. APOE-ε2 and APOE-ε4 correlate with increased amyloid accumulation in cerebral vasculature. J Neuropathol Exp Neurol. 2013 Jul;72(7):708-15. PubMed.
59. Yu L, Boyle PA, Nag S, Leurgans S, Buchman AS, Wilson RS, Arvanitakis Z, Farfel JM, De Jager PL, Bennett DA, Schneider JA. APOE and cerebral amyloid angiopathy in community-dwelling older persons. Neurobiol Aging. 2015 Nov;36(11):2946-2953. Epub 2015 Aug 15 PubMed.
60. Brouwers HB, Biffi A, McNamara KA, Ayres AM, Valant V, Schwab K, Romero JM, Viswanathan A, Greenberg SM, Rosand J, Goldstein JN. Apolipoprotein E genotype is associated with CT angiography spot sign in lobar intracerebral hemorrhage. Stroke. 2012 Aug;43(8):2120-5. Epub 2012 May 23 PubMed.
61. O'Donnell HC, Rosand J, Knudsen KA, Furie KL, Segal AZ, Chiu RI, Ikeda D, Greenberg SM. Apolipoprotein E genotype and the risk of recurrent lobar intracerebral hemorrhage. N Engl J Med. 2000 Jan 27;342(4):240-5. PubMed.
62. Hostettler IC, Seiffge D, Wong A, Ambler G, Wilson D, Shakeshaft C, Banerjee G, Sharma N, Jäger HR, Cohen H, Yousry TA, Al-Shahi Salman R, Lip GY, Brown MM, Muir K, Houlden H, Werring DJ. APOE and Cerebral Small Vessel Disease Markers in Patients With Intracerebral Hemorrhage. Neurology. 2022 Sep 20;99(12):e1290-e1298. Epub 2022 Jul 8 PubMed.
63. Wu J, Liu Z, Yao M, Zhu Y, Peng B, Ni J. Clinical characteristics of cerebral amyloid angiopathy and risk factors of cerebral amyloid angiopathy related intracerebral hemorrhage. J Neurol. 2024 Aug;271(8):5025-5034. Epub 2024 May 26 PubMed.
64. Kittner SJ, Sekar P, Comeau ME, Anderson CD, Parikh GY, Tavarez T, Flaherty ML, Testai FD, Frankel MR, James ML, Sung G, Elkind MS, Worrall BB, Kidwell CS, Gonzales NR, Koch S, Hall CE, Birnbaum L, Mayson D, Coull B, Malkoff MD, Sheth KN, McCauley JL, Osborne J, Morgan M, Gilkerson LA, Behymer TP, Demel SL, Moomaw CJ, Rosand J, Langefeld CD, Woo D. Ethnic and Racial Variation in Intracerebral Hemorrhage Risk Factors and Risk Factor Burden. JAMA Netw Open. 2021 Aug 2;4(8):e2121921. PubMed.
65. Schilling S, DeStefano AL, Sachdev PS, Choi SH, Mather KA, DeCarli CD, Wen W, Høgh P, Raz N, Au R, Beiser A, Wolf PA, Romero JR, Zhu YC, Lunetta KL, Farrer L, Dufouil C, Kuller LH, Mazoyer B, Seshadri S, Tzourio C, Debette S. APOE genotype and MRI markers of cerebrovascular disease: systematic review and meta-analysis. Neurology. 2013 Jul 16;81(3):292-300. PubMed.
66. Minta K, Brinkmalm G, Janelidze S, Sjödin S, Portelius E, Stomrud E, Zetterberg H, Blennow K, Hansson O, Andreasson U. Quantification of total apolipoprotein E and its isoforms in cerebrospinal fluid from patients with neurodegenerative diseases. Alzheimers Res Ther. 2020 Feb 13;12(1):19. PubMed.
67. Lefterov I, Wolfe CM, Fitz NF, Nam KN, Letronne F, Biedrzycki RJ, Kofler J, Han X, Wang J, Schug J, Koldamova R. APOE2 orchestrated differences in transcriptomic and lipidomic profiles of postmortem AD brain. Alzheimers Res Ther. 2019 Dec 30;11(1):113. PubMed.
68. Wong MW, Braidy N, Crawford J, Pickford R, Song F, Mather KA, Attia J, Brodaty H, Sachdev P, Poljak A. APOE Genotype Differentially Modulates Plasma Lipids in Healthy Older Individuals, with Relevance to Brain Health. J Alzheimers Dis. 2019;72(3):703-716. PubMed.
69. 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.
70. 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.
71. 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.
72. Wang T, Huynh K, Giles C, Mellett NA, Duong T, Nguyen A, Lim WL, Smith AA, Olshansky G, Cadby G, Hung J, Hui J, Beilby J, Watts GF, Chatterjee P, Martins I, Laws SM, Bush AI, Rowe CC, Villemagne VL, Ames D, Masters CL, Taddei K, Doré V, Fripp J, Arnold M, Kastenmüller G, Nho K, Saykin AJ, Baillie R, Han X, Martins RN, Moses EK, Kaddurah-Daouk R, Meikle PJ. APOE ε2 resilience for Alzheimer's disease is mediated by plasma lipid species: Analysis of three independent cohort studies. Alzheimers Dement. 2022 Jan 25; PubMed.
73. 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.
74. Xiao C, Pappas I, Aksman LM, O'Bryant SE, Toga AW, Health and Aging Brain Study (HABS-HD) Study Team, Alzheimer's Disease Neuroimaging Initiative. Comparison of genetic and health risk factors for mild cognitive impairment and Alzheimer's disease between Hispanic and non-Hispanic white participants. Alzheimers Dement. 2023 Apr 27; PubMed.
75. 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.
76. 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.
77. Chen Q, Wang T, Kang D, Chen L. Protective effect of apolipoprotein E epsilon 3 on sporadic Alzheimer's disease in the Chinese population: a meta-analysis. Sci Rep. 2022 Aug 10;12(1):13620. PubMed.
78. 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.
79. 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.
80. 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.
81. 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.
82. 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.
83. 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.
84. Wood ME, Xiong LY, Wong YY, Buckley RF, Swardfager W, Masellis M, Lim AS, Nichols E, Joie R, Casaletto KB, Kumar RG, Dams-O'Connor K, Palta P, George KM, Satizabal CL, Barnes LL, Schneider JA, Binet AP, Villeneuve S, Pa J, Brickman AM, Black SE, Rabin JS, ADNI and Prevent-AD Research Groups. Sex differences in associations between APOE ε2 and longitudinal cognitive decline. Alzheimers Dement. 2023 Mar 30; PubMed.
85. 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.
86. 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.
87. Pettigrew C, Soldan A, Li S, Lu Y, Wang MC, Selnes OA, Moghekar A, O'Brien R, Albert M, The Biocard Research Team. Relationship of cognitive reserve and APOE status to the emergence of clinical symptoms in preclinical Alzheimer's disease. Cogn Neurosci. 2013;4(3-4):136-42. Epub 2013 Aug 25 PubMed.
88. 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.
89. Canosa A, Pagani M, Brunetti M, Barberis M, Iazzolino B, Ilardi A, Cammarosano S, Manera U, Moglia C, Calvo A, Cistaro A, Chiò A. Correlation between Apolipoprotein E genotype and brain metabolism in amyotrophic lateral sclerosis. Eur J Neurol. 2019 Feb;26(2):306-312. Epub 2018 Oct 24 PubMed.
90. Meneses AD, Koga S, Li Z, O'Leary J, Li F, Chen K, Murakami A, Qiao W, Kurti A, Heckman MG, White L, Xie M, Chen Y, Finch NA, Lim MJ, Delenclos M, DeTure MA, Linares C, Martin NB, Ikezu TC, van Blitterswijk MM, Wu LJ, McLean PJ, Rademakers R, Ross OA, Dickson DW, Bu G, Zhao N. APOE2 Exacerbates TDP-43 Related Toxicity in the Absence of Alzheimer Pathology. Ann Neurol. 2023 Apr;93(4):830-843. Epub 2023 Jan 10 PubMed.
91. 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.
92. Lumsden AL, Mulugeta A, Zhou A, Hyppönen E. Apolipoprotein E (APOE) genotype-associated disease risks: a phenome-wide, registry-based, case-control study utilising the UK Biobank. EBioMedicine. 2020 Sep;59:102954. Epub 2020 Aug 17 PubMed.
93. 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.
94. Karjalainen JP, Mononen N, Hutri-Kähönen N, Lehtimäki M, Juonala M, Ala-Korpela M, Kähönen M, Raitakari O, Lehtimäki T. The effect of apolipoprotein E polymorphism on serum metabolome - a population-based 10-year follow-up study. Sci Rep. 2019 Jan 24;9(1):458. PubMed.
95. Sebastiani P, Song Z, Ellis D, Tian Q, Schwaiger-Haber M, Stancliffe E, Lustgarten MS, Funk CC, Baloni P, Yao CH, Joshi S, Marron MM, Gurinovich A, Li M, Leshchyk A, Xiang Q, Andersen SL, Feitosa MF, Ukraintseva S, Soerensen M, Fiehn O, Ordovas JM, Haigis M, Monti S, Barzilai N, Milman S, Ferrucci L, Rappaport N, Patti GJ, Perls TT. A metabolomic signature of the APOE2 allele. Geroscience. 2022 Aug 23; PubMed.
96. Pieri K, Trichia E, Neville MJ, Taylor H, Bennett D, Karpe F, Koivula RW. Polygenic risk in Type III hyperlipidaemia and risk of cardiovascular disease: An epidemiological study in UK Biobank and Oxford Biobank. Int J Cardiol. 2022 Nov 18; PubMed.
97. 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.
98. 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.
99. Cauley JA, Eichner JE, Kamboh MI, Ferrell RE, Kuller LH. Apo E allele frequencies in younger (age 42-50) vs older (age 65-90) women. Genet Epidemiol. 1993;10(1):27-34. PubMed.
100. Shinohara M, Kanekiyo T, Tachibana M, Kurti A, Shinohara M, Fu Y, Zhao J, Han X, Sullivan PM, Rebeck GW, Fryer JD, Heckman MG, Bu G. APOE2 is associated with longevity independent of Alzheimer's disease. Elife. 2020 Oct 19;9 PubMed.
101. Kawanishi K, Sawada A, Ochi A, Moriyama T, Mitobe M, Mochizuki T, Honda K, Oda H, Nishikawa T, Nitta K. Glomerulopathy with homozygous apolipoprotein e2: a report of three cases and review of the literature. Case Rep Nephrol Urol. 2013 Jul;3(2):128-35. Epub 2013 Nov 28 PubMed.
102. Saito T, Matsunaga A, Fukunaga M, Nagahama K, Hara S, Muso E. Apolipoprotein E-related glomerular disorders. Kidney Int. 2020 Feb;97(2):279-288. Epub 2019 Nov 22 PubMed.
103. Martínez-Martínez AB, Torres-Perez E, Devanney N, Del Moral R, Johnson LA, Arbones-Mainar JM. Beyond the CNS: The many peripheral roles of APOE. Neurobiol Dis. 2020 May;138:104809. Epub 2020 Feb 19 PubMed.
104. 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.
105. 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.
106. 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.
107. Satny M, Todorovova V, Altschmiedova T, Hubacek JA, Dlouha L, Lanska V, Soska V, Kyselak O, Freiberger T, Bobak M, Vrablik M. Genetic risk score in patients with the APOE2/E2 genotype as a predictor of familial dysbetalipoproteinemia. J Clin Lipidol. 2023 Nov 23; PubMed.
108. Paquette M, Trinder M, Guay SP, Brunham LR, Baass A. Predictors of cardiovascular disease in individuals with dysbetalipoproteinemia: a prospective study in the UK Biobank. J Clin Endocrinol Metab. 2024 Sep 7; PubMed.
109. Evans D, Beil FU, Aberle J. Resequencing the APOE gene reveals that rare mutations are not significant contributory factors in the development of type III hyperlipidemia. J Clin Lipidol. 2013 Nov-Dec;7(6):671-4. Epub 2013 May 25 PubMed.
110. Andrews SJ, Fulton-Howard B, Goate A. Protective Variants in Alzheimer's Disease. Curr Genet Med Rep. 2019 Mar;7(1):1-12. Epub 2019 Jan 24 PubMed.
111. 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.
112. Huang YA, Zhou B, Nabet AM, Wernig M, Südhof TC. Differential Signaling Mediated by ApoE2, ApoE3, and ApoE4 in Human Neurons Parallels Alzheimer's Disease Risk. J Neurosci. 2019 Sep 11;39(37):7408-7427. Epub 2019 Jul 22 PubMed.
113. Huang YA, Zhou B, Wernig M, Südhof TC. ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcription and Aβ Secretion. Cell. 2017 Jan 26;168(3):427-441.e21. Epub 2017 Jan 19 PubMed.
114. Novy MJ, Newbury SF, Liemisa B, Morales-Corraliza J, Alldred MJ, Ginsberg SD, Mathews PM. Expression and proteolytic processing of the amyloid precursor protein is unaffected by the expression of the three human apolipoprotein E alleles in the brains of mice. Neurobiol Aging. 2022 Feb;110:73-76. Epub 2021 Oct 30 PubMed.
115. Brookhouser N, Raman S, Frisch C, Srinivasan G, Brafman DA. APOE2 mitigates disease-related phenotypes in an isogenic hiPSC-based model of Alzheimer's disease. Mol Psychiatry. 2021 Oct;26(10):5715-5732. Epub 2021 Apr 9 PubMed.
116. 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.
117. Irizarry MC, Deng A, Lleo A, Berezovska O, Von Arnim CA, Martin-Rehrmann M, Manelli A, LaDu MJ, Hyman BT, Rebeck GW. Apolipoprotein E modulates gamma-secretase cleavage of the amyloid precursor protein. J Neurochem. 2004 Sep;90(5):1132-43. PubMed.
118. Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, Patterson BW, Fagan AM, Morris JC, Mawuenyega KG, Cruchaga C, Goate AM, Bales KR, Paul SM, Bateman RJ, Holtzman DM. Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci Transl Med. 2011 Jun 29;3(89):89ra57. PubMed.
119. 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.
120. Ding Y, Palecek SP, Shusta EV. iPSC-derived blood-brain barrier modeling reveals APOE isoform-dependent interactions with amyloid beta. Fluids Barriers CNS. 2024 Oct 11;21(1):79. PubMed.
121. Miyata M, Smith JD. Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and beta-amyloid peptides. Nat Genet. 1996 Sep;14(1):55-61. PubMed.
122. Wilhelmus MM, Otte-Höller I, Davis J, Van Nostrand WE, de Waal RM, Verbeek MM. Apolipoprotein E genotype regulates amyloid-beta cytotoxicity. J Neurosci. 2005 Apr 6;25(14):3621-7. PubMed.
123. Folin M, Baiguera S, Guidolin D, Di Liddo R, Grandi C, De Carlo E, Nussdorfer GG, Parnigotto PP. Apolipoprotein-E modulates the cytotoxic effect of beta-amyloid on rat brain endothelium in an isoform-dependent specific manner. Int J Mol Med. 2006 May;17(5):821-6. PubMed.
124. Chen Y, Durakoglugil MS, Xian X, Herz J. ApoE4 reduces glutamate receptor function and synaptic plasticity by selectively impairing ApoE receptor recycling. Proc Natl Acad Sci U S A. 2010 Jun 29;107(26):12011-6. Epub 2010 Jun 14 PubMed.
125. Hudry E, Dashkoff J, Roe AD, Takeda S, Koffie RM, Hashimoto T, Scheel M, Spires-Jones T, Arbel-Ornath M, Betensky R, Davidson BL, Hyman BT. Gene transfer of human Apoe isoforms results in differential modulation of amyloid deposition and neurotoxicity in mouse brain. Sci Transl Med. 2013 Nov 20;5(212):212ra161. PubMed.
126. Lanz TA, Carter DB, Merchant KM. Dendritic spine loss in the hippocampus of young PDAPP and Tg2576 mice and its prevention by the ApoE2 genotype. Neurobiol Dis. 2003 Aug;13(3):246-53. PubMed.
127. 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. Nature Aging, 1, 2021, pp. 919-31. Nat Aging.
128. 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.
129. Murphy KB, Hu D, Wolfs L, Mancuso R, DeStrooper B, Marzi SJ. The APOE isoforms differentially shape the transcriptomic and epigenomic landscapes of human microglia in a xenotransplantation model of Alzheimer's disease. 2024 Jul 05 10.1101/2024.07.03.601874 (version 1) bioRxiv.
130. 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.
131. Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, Tsai RM, Spina S, Grinberg LT, Rojas JC, Gallardo G, Wang K, Roh J, Robinson G, Finn MB, Jiang H, Sullivan PM, Baufeld C, Wood MW, Sutphen C, McCue L, Xiong C, Del-Aguila JL, Morris JC, Cruchaga C, Alzheimer’s Disease Neuroimaging Initiative, Fagan AM, Miller BL, Boxer AL, Seeley WW, Butovsky O, Barres BA, Paul SM, Holtzman DM. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017 Sep 28;549(7673):523-527. Epub 2017 Sep 20 PubMed.
132. Davis AA, Inman CE, Wargel ZM, Dube U, Freeberg BM, Galluppi A, Haines JN, Dhavale DD, Miller R, Choudhury FA, Sullivan PM, Cruchaga C, Perlmutter JS, Ulrich JD, Benitez BA, Kotzbauer PT, Holtzman DM. APOE genotype regulates pathology and disease progression in synucleinopathy. Sci Transl Med. 2020 Feb 5;12(529) PubMed.
133. Panitch R, Hu J, Chung J, Zhu C, Meng G, Xia W, Bennett DA, Lunetta KL, Ikezu T, Au R, Stein TD, Farrer LA, Jun GR. Integrative brain transcriptome analysis links complement component 4 and HSPA2 to the APOE ε2 protective effect in Alzheimer disease. Mol Psychiatry. 2021 Oct;26(10):6054-6064. Epub 2021 Sep 3 PubMed.
134. Dumanis SB, Tesoriero JA, Babus LW, Nguyen MT, Trotter JH, Ladu MJ, Weeber EJ, Turner RS, Xu B, Rebeck GW, Hoe HS. ApoE4 decreases spine density and dendritic complexity in cortical neurons in vivo. J Neurosci. 2009 Dec 2;29(48):15317-22. PubMed.
135. Chung WS, Verghese PB, Chakraborty C, Joung J, Hyman BT, Ulrich JD, Holtzman DM, Barres BA. Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes. Proc Natl Acad Sci U S A. 2016 Sep 6;113(36):10186-91. Epub 2016 Aug 24 PubMed.
136. 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.
137. Igel E, Haller A, Wolfkiel PR, Orr-Asman M, Jaeschke A, Hui DY. Distinct pro-inflammatory properties of myeloid cell-derived apolipoprotein E2 and E4 in atherosclerosis promotion. J Biol Chem. 2021 Sep;297(3):101106. Epub 2021 Aug 21 PubMed.
138. 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.
139. Wilson C, Mau T, Weisgraber KH, Wardell MR, Mahley RW, Agard DA. Salt bridge relay triggers defective LDL receptor binding by a mutant apolipoprotein. Structure. 1994 Aug 15;2(8):713-8. PubMed.
140. Dong LM, Parkin S, Trakhanov SD, Rupp B, Simmons T, Arnold KS, Newhouse YM, Innerarity TL, Weisgraber KH. Novel mechanism for defective receptor binding of apolipoprotein E2 in type III hyperlipoproteinemia. Nat Struct Biol. 1996 Aug;3(8):718-22. PubMed.
141. Chen J, Li Q, Wang J. Topology of human apolipoprotein E3 uniquely regulates its diverse biological functions. Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):14813-8. Epub 2011 Aug 22 PubMed.
142. 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.
143. 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.
144. Mah D, Zhu Y, Su G, Zhao J, Canning A, Gibson J, Song X, Stancanelli E, Xu Y, Zhang F, Linhardt RJ, Liu J, Wang L, Wang C. Apolipoprotein E Recognizes Alzheimer's Disease Associated 3-O Sulfation of Heparan Sulfate. Angew Chem Int Ed Engl. 2023 Jun 5;62(23):e202212636. Epub 2023 Apr 28 PubMed.
145. Wu Y, Johnson G, Zhao F, Wu Y, Zhao G, Brown A, You S, Zou MH, Song P. Features of Lipid Metabolism in Humanized ApoE Knockin Rat Models. Int J Mol Sci. 2021 Jul 31;22(15) PubMed.
146. 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.
147. Schwartzentruber J, Cooper S, Liu JZ, Barrio-Hernandez I, Bello E, Kumasaka N, Young AM, Franklin RJ, Johnson T, Estrada K, Gaffney DJ, Beltrao P, Bassett A. Genome-wide meta-analysis, fine-mapping and integrative prioritization implicate new Alzheimer's disease risk genes. Nat Genet. 2021 Mar;53(3):392-402. Epub 2021 Feb 15 PubMed. Correction.
148. Jansen IE, Savage JE, Watanabe K, Bryois J, Williams DM, Steinberg S, Sealock J, Karlsson IK, Hägg S, Athanasiu L, Voyle N, Proitsi P, Witoelar A, Stringer S, Aarsland D, Almdahl IS, Andersen F, Bergh S, Bettella F, Bjornsson S, Brækhus A, Bråthen G, de Leeuw C, Desikan RS, Djurovic S, Dumitrescu L, Fladby T, Hohman TJ, Jonsson PV, Kiddle SJ, Rongve A, Saltvedt I, Sando SB, Selbæk G, Shoai M, Skene NG, Snaedal J, Stordal E, Ulstein ID, Wang Y, White LR, Hardy J, Hjerling-Leffler J, Sullivan PF, van der Flier WM, Dobson R, Davis LK, Stefansson H, Stefansson K, Pedersen NL, Ripke S, Andreassen OA, Posthuma D. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk. Nat Genet. 2019 Mar;51(3):404-413. Epub 2019 Jan 7 PubMed.
149. Marioni RE, Harris SE, Zhang Q, McRae AF, Hagenaars SP, Hill WD, Davies G, Ritchie CW, Gale CR, Starr JM, Goate AM, Porteous DJ, Yang J, Evans KL, Deary IJ, Wray NR, Visscher PM. GWAS on family history of Alzheimer's disease. Transl Psychiatry. 2018 May 18;8(1):99. PubMed.
150. Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, Boland A, Vronskaya M, van der Lee SJ, Amlie-Wolf A, Bellenguez C, Frizatti A, Chouraki V, Martin ER, Sleegers K, Badarinarayan N, Jakobsdottir J, Hamilton-Nelson KL, Moreno-Grau S, Olaso R, Raybould R, Chen Y, Kuzma AB, Hiltunen M, Morgan T, Ahmad S, Vardarajan BN, Epelbaum J, Hoffmann P, Boada M, Beecham GW, Garnier JG, Harold D, Fitzpatrick AL, Valladares O, Moutet ML, Gerrish A, Smith AV, Qu L, Bacq D, Denning N, Jian X, Zhao Y, Del Zompo M, Fox NC, Choi SH, Mateo I, Hughes JT, Adams HH, Malamon J, Sanchez-Garcia F, Patel Y, Brody JA, Dombroski BA, Naranjo MC, Daniilidou M, Eiriksdottir G, Mukherjee S, Wallon D, Uphill J, Aspelund T, Cantwell LB, Garzia F, Galimberti D, Hofer E, Butkiewicz M, Fin B, Scarpini E, Sarnowski C, Bush WS, Meslage S, Kornhuber J, White CC, Song Y, Barber RC, Engelborghs S, Sordon S, Voijnovic D, Adams PM, Vandenberghe R, Mayhaus M, Cupples LA, Albert MS, De Deyn PP, Gu W, Himali JJ, Beekly D, Squassina A, Hartmann AM, Orellana A, Blacker D, Rodriguez-Rodriguez E, Lovestone S, Garcia ME, Doody RS, Munoz-Fernadez C, Sussams R, Lin H, Fairchild TJ, Benito YA, Holmes C, Karamujić-Čomić H, Frosch MP, Thonberg H, Maier W, Roshchupkin G, Ghetti B, Giedraitis V, Kawalia A, Li S, Huebinger RM, Kilander L, Moebus S, Hernández I, Kamboh MI, Brundin R, Turton J, Yang Q, Katz MJ, Concari L, Lord J, Beiser AS, Keene CD, Helisalmi S, Kloszewska I, Kukull WA, Koivisto AM, Lynch A, Tarraga L, Larson EB, Haapasalo A, Lawlor B, Mosley TH, Lipton RB, Solfrizzi V, Gill M, Longstreth WT Jr, Montine TJ, Frisardi V, Diez-Fairen M, Rivadeneira F, Petersen RC, Deramecourt V, Alvarez I, Salani F, Ciaramella A, Boerwinkle E, Reiman EM, Fievet N, Rotter JI, Reisch JS, Hanon O, Cupidi C, Andre Uitterlinden AG, Royall DR, Dufouil C, Maletta RG, de Rojas I, Sano M, Brice A, Cecchetti R, George-Hyslop PS, Ritchie K, Tsolaki M, Tsuang DW, Dubois B, Craig D, Wu CK, Soininen H, Avramidou D, Albin RL, Fratiglioni L, Germanou A, Apostolova LG, Keller L, Koutroumani M, Arnold SE, Panza F, Gkatzima O, Asthana S, Hannequin D, Whitehead P, Atwood CS, Caffarra P, Hampel H, Quintela I, Carracedo Á, Lannfelt L, Rubinsztein DC, Barnes LL, Pasquier F, Frölich L, Barral S, McGuinness B, Beach TG, Johnston JA, Becker JT, Passmore P, Bigio EH, Schott JM, Bird TD, Warren JD, Boeve BF, Lupton MK, Bowen JD, Proitsi P, Boxer A, Powell JF, Burke JR, Kauwe JS, Burns JM, Mancuso M, Buxbaum JD, Bonuccelli U, Cairns NJ, McQuillin A, Cao C, Livingston G, Carlson CS, Bass NJ, Carlsson CM, Hardy J, Carney RM, Bras J, Carrasquillo MM, Guerreiro R, Allen M, Chui HC, Fisher E, Masullo C, Crocco EA, DeCarli C, Bisceglio G, Dick M, Ma L, Duara R, Graff-Radford NR, Evans DA, Hodges A, Faber KM, Scherer M, Fallon KB, Riemenschneider M, Fardo DW, Heun R, Farlow MR, Kölsch H, Ferris S, Leber M, Foroud TM, Heuser I, Galasko DR, Giegling I, Gearing M, Hüll M, Geschwind DH, Gilbert JR, Morris J, Green RC, Mayo K, Growdon JH, Feulner T, Hamilton RL, Harrell LE, Drichel D, Honig LS, Cushion TD, Huentelman MJ, Hollingworth P, Hulette CM, Hyman BT, Marshall R, Jarvik GP, Meggy A, Abner E, Menzies GE, Jin LW, Leonenko G, Real LM, Jun GR, Baldwin CT, Grozeva D, Karydas A, Russo G, Kaye JA, Kim R, Jessen F, Kowall NW, Vellas B, Kramer JH, Vardy E, LaFerla FM, Jöckel KH, Lah JJ, Dichgans M, Leverenz JB, Mann D, Levey AI, Pickering-Brown S, Lieberman AP, Klopp N, Lunetta KL, Wichmann HE, Lyketsos CG, Morgan K, Marson DC, Brown K, Martiniuk F, Medway C, Mash DC, Nöthen MM, Masliah E, Hooper NM, McCormick WC, Daniele A, McCurry SM, Bayer A, McDavid AN, Gallacher J, McKee AC, van den Bussche H, Mesulam M, Brayne C, Miller BL, Riedel-Heller S, Miller CA, Miller JW, Al-Chalabi A, Morris JC, Shaw CE, Myers AJ, Wiltfang J, O'Bryant S, Olichney JM, Alvarez V, Parisi JE, Singleton AB, Paulson HL, Collinge J, Perry WR, Mead S, Peskind E, Cribbs DH, Rossor M, Pierce A, Ryan NS, Poon WW, Nacmias B, Potter H, Sorbi S, Quinn JF, Sacchinelli E, Raj A, Spalletta G, Raskind M, Caltagirone C, Bossù P, Orfei MD, Reisberg B, Clarke R, Reitz C, Smith AD, Ringman JM, Warden D, Roberson ED, Wilcock G, Rogaeva E, Bruni AC, Rosen HJ, Gallo M, Rosenberg RN, Ben-Shlomo Y, Sager MA, Mecocci P, Saykin AJ, Pastor P, Cuccaro ML, Vance JM, Schneider JA, Schneider LS, Slifer S, Seeley WW, Smith AG, Sonnen JA, Spina S, Stern RA, Swerdlow RH, Tang M, Tanzi RE, Trojanowski JQ, Troncoso JC, Van Deerlin VM, Van Eldik LJ, Vinters HV, Vonsattel JP, Weintraub S, Welsh-Bohmer KA, Wilhelmsen KC, Williamson J, Wingo TS, Woltjer RL, Wright CB, Yu CE, Yu L, Saba Y, Pilotto A, Bullido MJ, Peters O, Crane PK, Bennett D, Bosco P, Coto E, Boccardi V, De Jager PL, Lleo A, Warner N, Lopez OL, Ingelsson M, Deloukas P, Cruchaga C, Graff C, Gwilliam R, Fornage M, Goate AM, Sanchez-Juan P, Kehoe PG, Amin N, Ertekin-Taner N, Berr C, Debette S, Love S, Launer LJ, Younkin SG, Dartigues JF, Corcoran C, Ikram MA, Dickson DW, Nicolas G, Campion D, Tschanz J, Schmidt H, Hakonarson H, Clarimon J, Munger R, Schmidt R, Farrer LA, Van Broeckhoven C, C O'Donovan M, DeStefano AL, Jones L, Haines JL, Deleuze JF, Owen MJ, Gudnason V, Mayeux R, Escott-Price V, Psaty BM, Ramirez A, Wang LS, Ruiz A, van Duijn CM, Holmans PA, Seshadri S, Williams J, Amouyel P, Schellenberg GD, Lambert JC, Pericak-Vance MA, Alzheimer Disease Genetics Consortium (ADGC),, European Alzheimer’s Disease Initiative (EADI),, Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE),, Genetic and Environmental Risk in AD/Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease Consortium (GERAD/PERADES),. Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet. 2019 Mar;51(3):414-430. Epub 2019 Feb 28 PubMed. Correction.
151. Jun GR, Chung J, Mez J, Barber R, Beecham GW, Bennett DA, Buxbaum JD, Byrd GS, Carrasquillo MM, Crane PK, Cruchaga C, De Jager P, Ertekin-Taner N, Evans D, Fallin MD, Foroud TM, Friedland RP, Goate AM, Graff-Radford NR, Hendrie H, Hall KS, Hamilton-Nelson KL, Inzelberg R, Kamboh MI, Kauwe JS, Kukull WA, Kunkle BW, Kuwano R, Larson EB, Logue MW, Manly JJ, Martin ER, Montine TJ, Mukherjee S, Naj A, Reiman EM, Reitz C, Sherva R, St George-Hyslop PH, Thornton T, Younkin SG, Vardarajan BN, Wang LS, Wendlund JR, Winslow AR, Alzheimer's Disease Genetics Consortium, Haines J, Mayeux R, Pericak-Vance MA, Schellenberg G, Lunetta KL, Farrer LA. Transethnic genome-wide scan identifies novel Alzheimer's disease loci. Alzheimers Dement. 2017 Jul;13(7):727-738. Epub 2017 Feb 7 PubMed.
152. Jun G, Ibrahim-Verbaas CA, Vronskaya M, Lambert JC, Chung J, Naj AC, Kunkle BW, Wang LS, Bis JC, Bellenguez C, Harold D, Lunetta KL, Destefano AL, Grenier-Boley B, Sims R, Beecham GW, Smith AV, Chouraki V, Hamilton-Nelson KL, Ikram MA, Fievet N, Denning N, Martin ER, Schmidt H, Kamatani Y, Dunstan ML, Valladares O, Laza AR, Zelenika D, Ramirez A, Foroud TM, Choi SH, Boland A, Becker T, Kukull WA, van der Lee SJ, Pasquier F, Cruchaga C, Beekly D, Fitzpatrick AL, Hanon O, Gill M, Barber R, Gudnason V, Campion D, Love S, Bennett DA, Amin N, Berr C, Tsolaki M, Buxbaum JD, Lopez OL, Deramecourt V, Fox NC, Cantwell LB, Tárraga L, Dufouil C, Hardy J, Crane PK, Eiriksdottir G, Hannequin D, Clarke R, Evans D, Mosley TH Jr, Letenneur L, Brayne C, Maier W, De Jager P, Emilsson V, Dartigues JF, Hampel H, Kamboh MI, de Bruijn RF, Tzourio C, Pastor P, Larson EB, Rotter JI, O'Donovan MC, Montine TJ, Nalls MA, Mead S, Reiman EM, Jonsson PV, Holmes C, St George-Hyslop PH, Boada M, Passmore P, Wendland JR, Schmidt R, Morgan K, Winslow AR, Powell JF, Carasquillo M, Younkin SG, Jakobsdóttir J, Kauwe JS, Wilhelmsen KC, Rujescu D, Nöthen MM, Hofman A, Jones L, IGAP Consortium, Haines JL, Psaty BM, Van Broeckhoven C, Holmans P, Launer LJ, Mayeux R, Lathrop M, Goate AM, Escott-Price V, Seshadri S, Pericak-Vance MA, Amouyel P, Williams J, van Duijn CM, Schellenberg GD, Farrer LA. A novel Alzheimer disease locus located near the gene encoding tau protein. Mol Psychiatry. 2015 Mar 17; PubMed.
153. Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, DeStafano AL, Bis JC, Beecham GW, Grenier-Boley B, Russo G, Thorton-Wells TA, Jones N, Smith AV, Chouraki V, Thomas C, Ikram MA, Zelenika D, Vardarajan BN, Kamatani Y, Lin CF, Gerrish A, Schmidt H, Kunkle B, Dunstan ML, Ruiz A, Bihoreau MT, Choi SH, Reitz C, Pasquier F, Cruchaga C, Craig D, Amin N, Berr C, Lopez OL, De Jager PL, Deramecourt V, Johnston JA, Evans D, Lovestone S, Letenneur L, Morón FJ, Rubinsztein DC, Eiriksdottir G, Sleegers K, Goate AM, Fiévet N, Huentelman MW, Gill M, Brown K, Kamboh MI, Keller L, Barberger-Gateau P, McGuiness B, Larson EB, Green R, Myers AJ, Dufouil C, Todd S, Wallon D, Love S, Rogaeva E, Gallacher J, St George-Hyslop P, Clarimon J, Lleo A, Bayer A, Tsuang DW, Yu L, Tsolaki M, Bossù P, Spalletta G, Proitsi P, Collinge J, Sorbi S, Sanchez-Garcia F, Fox NC, Hardy J, Deniz Naranjo MC, Bosco P, Clarke R, Brayne C, Galimberti D, Mancuso M, Matthews F, European Alzheimer's Disease Initiative (EADI), Genetic and Environmental Risk in Alzheimer's Disease, Alzheimer's Disease Genetic Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology, Moebus S, Mecocci P, Del Zompo M, Maier W, Hampel H, Pilotto A, Bullido M, Panza F, Caffarra P, Nacmias B, Gilbert JR, Mayhaus M, Lannefelt L, Hakonarson H, Pichler S, Carrasquillo MM, Ingelsson M, Beekly D, Alvarez V, Zou F, Valladares O, Younkin SG, Coto E, Hamilton-Nelson KL, Gu W, Razquin C, Pastor P, Mateo I, Owen MJ, Faber KM, Jonsson PV, Combarros O, O'Donovan MC, Cantwell LB, Soininen H, Blacker D, Mead S, Mosley TH Jr, Bennett DA, Harris TB, Fratiglioni L, Holmes C, de Bruijn RF, Passmore P, Montine TJ, Bettens K, Rotter JI, Brice A, Morgan K, Foroud TM, Kukull WA, Hannequin D, Powell JF, Nalls MA, Ritchie K, Lunetta KL, Kauwe JS, Boerwinkle E, Riemenschneider M, Boada M, Hiltuenen M, Martin ER, Schmidt R, Rujescu D, Wang LS, Dartigues JF, Mayeux R, Tzourio C, Hofman A, Nöthen MM, Graff C, Psaty BM, Jones L, Haines JL, Holmans PA, Lathrop M, Pericak-Vance MA, Launer LJ, Farrer LA, van Duijn CM, Van Broeckhoven C, Moskvina V, Seshadri S, Williams J, Schellenberg GD, Amouyel P, Wang J, Uitterlinden AG, Rivadeneira F, Koudstgaal PJ, Longstreth WT Jr, Becker JT, Kuller LH, Lumley T, Rice K, Garcia M, Aspelund T, Marksteiner JJ, Dal-Bianco P, Töglhofer AM, Freudenberger P, Ransmayr G, Benke T, Toeglhofer AM, Bressler J, Breteler MM, Fornage M, Hernández I, Rosende Roca M, Ana Mauleón M, Alegrat M, Ramírez-Lorca R, González-Perez A, Chapman J, Stretton A, Morgan A, Kehoe PG, Medway C, Lord J, Turton J, Hooper NM, Vardy E, Warren JD, Schott JM, Uphill J, Ryan N, Rossor M, Ben-Shlomo Y, Makrina D, Gkatzima O, Lupton M, Koutroumani M, Avramidou D, Germanou A, Jessen F, Riedel-Heller S, Dichgans M, Heun R, Kölsch H, Schürmann B, Herold C, Lacour A, Drichel D, Hoffman P, Kornhuber J, Gu W, Feulner T, van den Bussche H, Lawlor B, Lynch A, Mann D, Smith AD, Warden D, Wilcock G, Heuser I, Wiltgang J, Frölich L, Hüll M, Mayo K, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Singleton AB, Guerreiro R, Jöckel KH, Klopp N, Wichmann HE, Dickson DW, Graff-Radford NR, Ma L, Bisceglio G, Fisher E, Warner N, Pickering-Brown S. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet. 2013 Dec;45(12):1452-8. Epub 2013 Oct 27 PubMed.
154. Sims R, van der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, Jakobsdottir J, Kunkle BW, Boland A, Raybould R, Bis JC, Martin ER, Grenier-Boley B, Heilmann-Heimbach S, Chouraki V, Kuzma AB, Sleegers K, Vronskaya M, Ruiz A, Graham RR, Olaso R, Hoffmann P, Grove ML, Vardarajan BN, Hiltunen M, Nöthen MM, White CC, Hamilton-Nelson KL, Epelbaum J, Maier W, Choi SH, Beecham GW, Dulary C, Herms S, Smith AV, Funk CC, Derbois C, Forstner AJ, Ahmad S, Li H, Bacq D, Harold D, Satizabal CL, Valladares O, Squassina A, Thomas R, Brody JA, Qu L, Sánchez-Juan P, Morgan T, Wolters FJ, Zhao Y, Garcia FS, Denning N, Fornage M, Malamon J, Naranjo MC, Majounie E, Mosley TH, Dombroski B, Wallon D, Lupton MK, Dupuis J, Whitehead P, Fratiglioni L, Medway C, Jian X, Mukherjee S, Keller L, Brown K, Lin H, Cantwell LB, Panza F, McGuinness B, Moreno-Grau S, Burgess JD, Solfrizzi V, Proitsi P, Adams HH, Allen M, Seripa D, Pastor P, Cupples LA, Price ND, Hannequin D, Frank-García A, Levy D, Chakrabarty P, Caffarra P, Giegling I, Beiser AS, Giedraitis V, Hampel H, Garcia ME, Wang X, Lannfelt L, Mecocci P, Eiriksdottir G, Crane PK, Pasquier F, Boccardi V, Henández I, Barber RC, Scherer M, Tarraga L, Adams PM, Leber M, Chen Y, Albert MS, Riedel-Heller S, Emilsson V, Beekly D, Braae A, Schmidt R, Blacker D, Masullo C, Schmidt H, Doody RS, Spalletta G, Jr WT, Fairchild TJ, Bossù P, Lopez OL, Frosch MP, Sacchinelli E, Ghetti B, Yang Q, Huebinger RM, Jessen F, Li S, Kamboh MI, Morris J, Sotolongo-Grau O, Katz MJ, Corcoran C, Dunstan M, Braddel A, Thomas C, Meggy A, Marshall R, Gerrish A, Chapman J, Aguilar M, Taylor S, Hill M, Fairén MD, Hodges A, Vellas B, Soininen H, Kloszewska I, Daniilidou M, Uphill J, Patel Y, Hughes JT, Lord J, Turton J, Hartmann AM, Cecchetti R, Fenoglio C, Serpente M, Arcaro M, Caltagirone C, Orfei MD, Ciaramella A, Pichler S, Mayhaus M, Gu W, Lleó A, Fortea J, Blesa R, Barber IS, Brookes K, Cupidi C, Maletta RG, Carrell D, Sorbi S, Moebus S, Urbano M, Pilotto A, Kornhuber J, Bosco P, Todd S, Craig D, Johnston J, Gill M, Lawlor B, Lynch A, Fox NC, Hardy J, ARUK Consortium, Albin RL, Apostolova LG, Arnold SE, Asthana S, Atwood CS, Baldwin CT, Barnes LL, Barral S, Beach TG, Becker JT, Bigio EH, Bird TD, Boeve BF, Bowen JD, Boxer A, Burke JR, Burns JM, Buxbaum JD, Cairns NJ, Cao C, Carlson CS, Carlsson CM, Carney RM, Carrasquillo MM, Carroll SL, Diaz CC, Chui HC, Clark DG, Cribbs DH, Crocco EA, DeCarli C, Dick M, Duara R, Evans DA, Faber KM, Fallon KB, Fardo DW, Farlow MR, Ferris S, Foroud TM, Galasko DR, Gearing M, Geschwind DH, Gilbert JR, Graff-Radford NR, Green RC, Growdon JH, Hamilton RL, Harrell LE, Honig LS, Huentelman MJ, Hulette CM, Hyman BT, Jarvik GP, Abner E, Jin LW, Jun G, Karydas A, Kaye JA, Kim R, Kowall NW, Kramer JH, LaFerla FM, Lah JJ, Leverenz JB, Levey AI, Li G, Lieberman AP, Lunetta KL, Lyketsos CG, Marson DC, Martiniuk F, Mash DC, Masliah E, McCormick WC, McCurry SM, McDavid AN, McKee AC, Mesulam M, Miller BL, Miller CA, Miller JW, Morris JC, Murrell JR, Myers AJ, O'Bryant S, Olichney JM, Pankratz VS, Parisi JE, Paulson HL, Perry W, Peskind E, Pierce A, Poon WW, Potter H, Quinn JF, Raj A, Raskind M, Reisberg B, Reitz C, Ringman JM, Roberson ED, Rogaeva E, Rosen HJ, Rosenberg RN, Sager MA, Saykin AJ, Schneider JA, Schneider LS, Seeley WW, Smith AG, Sonnen JA, Spina S, Stern RA, Swerdlow RH, Tanzi RE, Thornton-Wells TA, Trojanowski JQ, Troncoso JC, Van Deerlin VM, Van Eldik LJ, Vinters HV, Vonsattel JP, Weintraub S, Welsh-Bohmer KA, Wilhelmsen KC, Williamson J, Wingo TS, Woltjer RL, Wright CB, Yu CE, Yu L, Garzia F, Golamaully F, Septier G, Engelborghs S, Vandenberghe R, De Deyn PP, Fernadez CM, Benito YA, Thonberg H, Forsell C, Lilius L, Kinhult-Stählbom A, Kilander L, Brundin R, Concari L, Helisalmi S, Koivisto AM, Haapasalo A, Dermecourt V, Fievet N, Hanon O, Dufouil C, Brice A, Ritchie K, Dubois B, Himali JJ, Keene CD, Tschanz J, Fitzpatrick AL, Kukull WA, Norton M, Aspelund T, Larson EB, Munger R, Rotter JI, Lipton RB, Bullido MJ, Hofman A, Montine TJ, Coto E, Boerwinkle E, Petersen RC, Alvarez V, Rivadeneira F, Reiman EM, Gallo M, O'Donnell CJ, Reisch JS, Bruni AC, Royall DR, Dichgans M, Sano M, Galimberti D, St George-Hyslop P, Scarpini E, Tsuang DW, Mancuso M, Bonuccelli U, Winslow AR, Daniele A, Wu CK, GERAD/PERADES, CHARGE, ADGC, EADI, Peters O, Nacmias B, Riemenschneider M, Heun R, Brayne C, Rubinsztein DC, Bras J, Guerreiro R, Al-Chalabi A, Shaw CE, Collinge J, Mann D, Tsolaki M, Clarimón J, Sussams R, Lovestone S, O'Donovan MC, Owen MJ, Behrens TW, Mead S, Goate AM, Uitterlinden AG, Holmes C, Cruchaga C, Ingelsson M, Bennett DA, Powell J, Golde TE, Graff C, De Jager PL, Morgan K, Ertekin-Taner N, Combarros O, Psaty BM, Passmore P, Younkin SG, Berr C, Gudnason V, Rujescu D, Dickson DW, Dartigues JF, DeStefano AL, Ortega-Cubero S, Hakonarson H, Campion D, Boada M, Kauwe JK, Farrer LA, Van Broeckhoven C, Ikram MA, Jones L, Haines JL, Tzourio C, Launer LJ, Escott-Price V, Mayeux R, Deleuze JF, Amin N, Holmans PA, Pericak-Vance MA, Amouyel P, van Duijn CM, Ramirez A, Wang LS, Lambert JC, Seshadri S, Williams J, Schellenberg GD. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nat Genet. 2017 Sep;49(9):1373-1384. Epub 2017 Jul 17 PubMed.
155. Nazarian A, Yashin AI, Kulminski AM. Genome-wide analysis of genetic predisposition to Alzheimer's disease and related sex disparities. Alzheimers Res Ther. 2019 Jan 12;11(1):5. PubMed.
156. Lo MT, Kauppi K, Fan CC, Sanyal N, Reas ET, Sundar VS, Lee WC, Desikan RS, McEvoy LK, Chen CH, Alzheimer's Disease Genetics Consortium. Identification of genetic heterogeneity of Alzheimer's disease across age. Neurobiol Aging. 2019 Dec;84:243.e1-243.e9. Epub 2019 Mar 12 PubMed.
157. Wang H, Lo MT, Rosenthal SB, Makowski C, Andreassen OA, Salem RM, McEvoy LK, Fiecas M, Chen CH. Similar Genetic Architecture of Alzheimer's Disease and Differential APOE Effect Between Sexes. Front Aging Neurosci. 2021;13:674318. Epub 2021 May 28 PubMed.
158. 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.
159. Reitz C, Jun G, Naj A, Rajbhandary R, Vardarajan BN, Wang LS, Valladares O, Lin CF, Larson EB, Graff-Radford NR, Evans D, De Jager PL, Crane PK, Buxbaum JD, Murrell JR, Raj T, Ertekin-Taner N, Logue M, Baldwin CT, Green RC, Barnes LL, Cantwell LB, Fallin MD, Go RC, Griffith P, Obisesan TO, Manly JJ, Lunetta KL, Kamboh MI, Lopez OL, Bennett DA, Hendrie H, Hall KS, Goate AM, Byrd GS, Kukull WA, Foroud TM, Haines JL, Farrer LA, Pericak-Vance MA, Schellenberg GD, Mayeux R, . Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E ϵ4,and the risk of late-onset Alzheimer disease in African Americans. JAMA. 2013 Apr 10;309(14):1483-92. PubMed.
160. 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.

Other Citations

1. APOE region

External Citations

1. GWAS catalog
2. Jackson et al., 2024

Further Reading

No Available Further Reading