Overview

Pathogenicity: Alzheimer's Disease : Pathogenic, Cerebral Amyloid Angiopathy, Down's Syndrome
ACMG/AMP Pathogenicity Criteria: PS1, PS2, PS3, PS4, PM1
Clinical Phenotype: Alzheimer's Disease, Cerebral Amyloid Angiopathy, Down's Syndrome
Coding/Non-Coding: Both
DNA Change: Duplication
Expected RNA Consequence: Duplication
Expected Protein Consequence: Duplication
Genomic Region: Chromosome 21

Findings

The presence of three copies of chromosome 21, which harbors the amyloid precursor protein (APP) gene, is the most common genetic cause of Alzheimer’s disease. Carriers of this alteration have Down syndrome (DS), a condition that results in cognitive disability, alterations in craniofacial morphology, increased risk of congenital heart defects, immune disorders, reduced sense of smell, and a very high risk of developing AD (Antonarakis et al., 2020). Most commonly, trisomy 21 arises because of meiotic nondisjunction in which a pair of chromosomes 21 fail to separate in either the sperm or egg. The frequency of this alteration is relatively high, approximately 0.001 worldwide, according to the World Health Organization. 

Dating back to 1948, multiple studies have shown that middle-aged individuals with DS are likely to develop AD dementia and pathology, including amyloid plaques, neurofibrillary tangles, and neuronal loss (Jervis, 1948; for review see Lott and Head, 2019).  Of note, the original description of amyloid β (Aβ) was in DS (Glenner and Wong, 1984) and contributed to the formulation of the Aβ hypothesis (Lott and Head, 2019).

Mean age at onset of AD in DS is 54.5 years (Rubenstein et al., 2024), with nearly all individuals with DS developing amyloid plaques by age 40, and more than 95 percent diagnosed with AD dementia by age 70 (Fortea et al., 2021). In a study of more than 130,000 adults with DS in the US, the probability of an incident AD diagnosis over 8 years was 0.63 (95% CI, 0.62-0.64) for those between 55 and 64 years of age when entering the study (Rubenstein et al., 2024). Indeed, AD is currently a leading cause of death in DS adults and may explain their shortened life expectancy (Iulita et al., 2022). Of note, both disease onset and death occurred, on average, later in White non-Hispanics than in Hispanics and Native Americans (Rubenstein et al., 2024).

Like AD in the general population, AD in individuals with DS is characterized by dementia and can also be accompanied by gait disturbance, sleep disruption, and seizures. The latter are particularly frequent in DS AD, commonly developing after the third decade of life and before the onset of dementia (Lott and Head, 2019).

Overall, AD in DS appears to be the same disease as AD in the general population. Although not identical (Carmona-Iragui et al., 2024), AD biomarker trajectories in DS are very similar to those in autosomal dominant AD and sporadic late onset AD, with very similar links to AD symptomology (Fortea et al., 2020; Hartley et al., 2024). In addition, as in sporadic and familial AD, APOE4 accelerates the onset of AD in individuals with DS (Bejanin et al., 2021; Jul 2021 news). Also, AD polygenic risk scores were associated with cognitive phenotypes and cerebrospinal biomarkers in DS adults, suggesting common pathways influence memory decline in both (Gorijala et al., 2023). 

Interestingly, in the general population, trisomy 21 mosaicism in the brain—affecting only a subpopulation of cells—may contribute to AD and other neurodegenerative diseases (for review see Potter et al., 2016). The effects of mosaicism in individuals with the DS phenotype and trisomy 21 remains uncertain. For example, while one study reported lower plasma Aβ40 and Aβ42 concentrations and lower incidence and prevalence of dementia in mosaic DS individuals compared to non-mosaic DS individuals (Xicota et al., 2024), another found mosaic DS individuals were more susceptible to neurodegenerative conditions, including AD (Rubenstein et al., 2024). 

Neuropathology | Biological Effects | Clinical Trials | Research Models

Neuropathology
AD neuropathology in DS surfaces at a young age. Amyloid plaques can start depositing in carriers as early as during the teen years and 20s (e.g., Lemere et al., 1996; Mori et al., 2002), and are seen routinely after age 30. After age 40, when virtually all DS individuals have AD neuropathology, amyloid accumulation ramps up at an exponential rate (Lott and Head, 2019).

The spread of amyloid and tau pathologies in DS AD generally follows the pattern observed in sporadic AD, as do levels of biomarkers in cerebrospinal fluid and blood (e.g., Fortea et al., 2020; Janelidze et al., 2022; July 2022 news; Schworer et al., 2024; Petersen et al., 2024). Also, the structure of tau fibrils—both paired helical and straight filaments—as well as Aβ42 filaments, appear to be very similar in the two conditions (Fernandez et al., 2024; Ghosh et al., 2024), although two Aβ40 filaments have been identified in DS AD that appear to be distinct from those found in sporadic AD (Fernandez et al., 2024). Moreover, similar amyloid plaque proteomes were identified in DS, early onset AD, and late onset AD, as described in a preprint (Martá-Ariza et al., 2024). 

However, as reported in a preprint that details the progression of AD pathology and symptoms in 167 DS adults, the time from Aβ positivity and tau deposition to initial cognitive decline and dementia is reduced in DS AD (Schworer et al., 2024). Consistent with this shortened timeline, amyloid has been reported to accumulate particularly rapidly in DS, with tau neurofibrillary tangles emerging very soon after (Zammit et al., 2024). In addition, compared with autosomal dominant AD, tau pathology in DS AD appears to be moderately more widespread, more abundant for a given level of amyloid, and more strongly associated with amyloid accumulation (Wisch et al., 2024). Comparing levels of plasma glial fibrillary acidic protein (GFAP), a marker of astrogliosis, to markers of amyloid and tau pathologies, one study suggested amyloid may stimulate astrogliosis, which in turn may play an important role in fueling tau pathology in the compressed DS AD timecourse (Boerwinkle et al., 2024). 

Of note, specific brain regions appear to be affected differentially. For example, in DS, PET imaging suggests the striatum is burdened with amyloid very early on and neurofibrillary tangles are particularly dense in DS brains compared with non-DS brains (Lao et al., 2016, Annus et al., 2016). Also, Aβ and tau pathologies in the locus coeruleus, a brain region affected very early in sporadic AD, differed from those observed in early onset AD (EOAD), and especially late-onset AD (LOAD) (Saternos et al., 2024). Oligomeric tau and Aβ levels in this brain region were particularly elevated in DS AD, with phospho-tau231 and neuronal tau staining being more similar in DS AD and EOAD than LOAD.

Interestingly, the extent of cerebrovascular disease (CVD) in DS AD appears to correlate with the severity of amyloid and tau pathologies, suggesting it is a core feature of DS AD tied to AD progression (Aug 2023 conference news). This characteristic seems to be independent of conventional age-related vascular risk factors, such as hypertension and heart disease, which are less prevalent in DS individuals. A brain imaging study identified enlarged perivascular spaces and infarcts in the early 30s, before global amyloid and tau pathologies reached an inflection point at age 35 (Lao et al., 2024). Microbleeds and white matter hyperintensities surfaced in the 30s and 40s. A detailed study of microbleeds further showed that microbleeds in DS increase with age and AD clinical stage, are more common in APOE4 carriers, and are predominantly found in posterior, lobar brain regions (Zsadanyi et al., 2024). White matter hyperintensities also increased with age, surfacing 10 years before AD symptom onset with progression closely linked to AD pathology, particularly in periventricular regions, and frontal, parietal, and occipital lobes (Morcillo-Nieto et al., 2024). Also of note, in DS patients who had yet to develop AD, white matter hyperintensities were associated with plasma markers of astrocytosis (GFAP) and tau pathology (phospho-tau 217), the latter which was associated with neurofilament light chain, a marker of neurodegeneration, in participants with mild cognitive impairment (Edwards et al., 2024). Female gender, lower body mass index, hypertension, and carrying the APOE4 allele were associated with higher levels of cerebrovascular biomarkers for a given age (Lao et al., 2024). 

Individuals with DS appear to have a higher frequency and severity of cerebral amyloid angiopathy (CAA) and have a unique neuroinflammatory phenotype possibly due to serum proteins infiltrating the brain via microbleeds. Indeed, microbleeds correlate with CAA in postmortem cortical tissue from individuals with DS beginning in the mid-30s, mirroring the rise in amyloid plaques (Helman et al., 2019). Also of note, cortical microinfarcts, mostly clustered in the parietal lobes, were found in 12 percent of DS patients and may be tied to a specific ischemic CAA phenotype (Aranha et al., 2024). Despite these pathologies, compared with CAA in carriers of other APP duplications limited to APP with or without a few neighboring genes, CAA in DS appears to be less severe and individuals with DS have a lower frequency of cerebral hematoma (Mann et al., 2018). This may be due to carriers of APP duplications having higher brain levels of total Aβ and shorter Aβ peptides than individuals with DS (Aug 2023 conference news).

DS AD can present with other neurodegenerative pathologies as well. A post-mortem study of 33 DS AD cases, for example, detected Lewy body pathology in the amygdala of 55 percent of individuals between the ages of 41 and 59, and in 75 percent of individuals aged 61 to 72 (Wegiel et al., 2022). In some cases, the distribution of Lewy pathology is atypical (Ichimata et al., 2022). Moreover, TDP-43 pathology has been reported in 6 to 18 percent of DS patients (e.g., Lippa et al., 2009; Davidson et al., 2011; Ichimata et al., 2022; Wegiel et al., 2022) and hippocampal sclerosis in 6 percent (e.g., Davidson et al., 2011).

An international consortium of brain banks—the Down Syndrome Biobank Consortium—has been established to collect and distribute brain tissue from individuals with DS throughout their lifespan (Aldecoa et al., 2024). It includes 11 sites in Europe, India, and the US.

Biological Effect
APP overexpression and the accumulation of Aβ in the brain is considered the primary driver of dementia in individuals with trisomy 21 (for reviews see Wiseman et al., 2015; Lott and Head, 2019). Consistent with this, at least two individuals with partial trisomy 21, carrying three copies of some parts of chromosome 21 but only two copies of APP, have lived past the age of 70 without developing either dementia or AD pathology (Prasher et al., 1998, Doran et al., 2017). Conversely, families with small chromosome 21 duplications consisting of only a few genes including APP have been reported to suffer from early onset AD. Indeed, there are AD families in which APP is the only gene present within the disease-associated duplication or triplication (APP Duplication 1104 [APP-APP]; see also APP Triplication [APP-APP]). Data from mouse models of DS also support accumulation of Aβ as playing a critical role in DS AD (e.g., Chen et al., 2024; Staurenghi et al., 2024).

Consistent with the clinical and genetic findings described above, increasing evidence at the cellular and molecular levels indicate DS AD is mechanistically very similar to AD in the general population. For example, a preprint describing spatial transcriptomics and single-nucleus RNA-seq analyses of cortical samples from patients with sporadic AD and DS AD reported broad similarities between the two conditions (Miyoshi et al., 2023), and a transcriptomic analysis of microisolated DS AD cortical neurons revealed alterations predicted to be relevant to sporadic AD (Alldred et al., 2024). Also, a pathway involving the binding of APP β-CTF to a lysosomal proton pump appears to lead to lysosomal dysfunction in both AD and DS AD (Jul 2023 news, Im et al., 2023). 

DS AD may have unique aspects, however, stemming from the overexpression of non-APP genes on chromosome 21, numbering over 200 (see Lott and Head, 2019 for review). For example, increased expression of DYRK1A—which encodes a kinase that phosphorylates many proteins including tau, and splicing factors that modulate tau mRNA splicing resulting in imbalanced 3R-tau and 4R-tau expression—appears to accelerate the emergence of neurofibrillary tangles, along with increased RCAN1, which regulates calcineurin. DYRK1A also phosphorylates APP and its elevation has been reported to increase APP levels as well (e.g., Ferrer et al., 2005, Ryoo et al., 2008, Garcia-Cerro et al., 2017).

On the other hand, some genes on chromosome 21 may delay AD pathology. Age at onset for DS AD varies widely, with many individuals suffering from cognitive decline only after age 55, later than the mean age of onset (~52 years) for APP duplication carriers (Wiseman et al., 2015). One study identified a subregion of chromosome 21 that decreases Aβ accumulation in mouse brain (Mumford et al., 2022). This region included BACE2, previously reported as protective against AD pathology (Feb 2020 news, Alić et al., 2021) and, paradoxically, DYRK1A. 

In addition to genetic modifiers of Aβ and tau pathologies, other factors likely modulate the expression of AD in DS individuals. For example, trisomy 21-associated alterations in brain structure, elevated incidence of epilepsy, and disruptions of the immune system that arise during development might increase susceptibility to AD (Lott and Head, 2019). Studies of how gene expression is altered in DS brains may reveal additional DS vulnerabilities, such as observed disruptions in RNA splicing that affect cytoskeletal proteins and axonal polarization (Rastogi et al., 2024).

Interestingly, some individuals with DS remain cognitively stable despite developing AD neuropathology (Liou et al., 2024 preprint). These cases could provide insights into AD resilience both in DS and in the general population. Indeed, as described in another preprint, a trisomy 21-linked genetic variant in the microglial-expressed CSF2RB gene was identified as potentially neuroprotective (e.g., Jin et al., 2024).

Clinical Trials

Several efforts to better understand and therapeutically tackle AD in DS individuals are underway. For example, blood-based biomarkers for AD detection, monitoring of progression, and assessing therapeutic outcomes—specifically in DS individuals—are being evaluated (Petersen et al., 2024). Moreoever, several groups are collecting information for testing anti-amyloid antibodies in DS AD. Prescribing criteria are being adapted for these patients (Hillerstrom et al., 2024) and guidelines for amyloid-targeting trials are being developed (Geerts et al., 2024; Krasny et al., 2024). Importantly, these include strategies to mitigate the risk of amyloid-related imaging abnormalities (ARIA) associated with these treatments, a risk which is elevated in individuals with CAA (Aug 2023 conference news) and microbleeds (Zsadanyi et al., 2024), pathologies often found in DS AD. Indeed, a study of postmortem brain tissue from 15 DS patients revealed that the anti-amyloid antibody lecanemab labeled amyloid plaques, indicating potential target engagement, but it also labeled brain blood vessels extensively, indicating a potential safety hazard (Liu et al., 2024). 

Clinical trials for DS already in the works (May 2021a news) include testing of the anti-amyloid vaccine ACI-24 (May 2021b news) and subdermal pulses of gonadotropin-releasing hormone (Sep 2022 news).

Research Models

Multiple rodent models of DS have been generated (Herault et al., 2017), with a subset being particularly relevant to AD-DS (Farrell et al., 2022). The models have been used for in vivo studies, as well as experiments using cultured cells and organotypic slice cultures. In addition, human induced pluripotent stem cells with trisomy 21 have been used to create cerebral organoids that model the early pathology of AD (Fertan et al., 2024).

Pathogenicity

Alzheimer's Disease : Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

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References

Mutations Citations

1. APOE C130R (ApoE4)
2. APP Duplication 1104 [APP-APP]
3. APP Triplication [APP-APP]

News Citations

1. ApoE4 Hastens Alzheimer’s Disease in Down’s Syndrome 16 Jul 2021
2. In Down's Syndrome, Blood P-Tau217 Detects Plaques and Tangles 8 Jul 2022
3. At the Heart of Alzheimer’s in Down’s: Cerebrovascular Disease 25 Aug 2023
4. Too Basic: APP β-CTF's YENTPY Motif Binds Proton Pump, Thwarts Lysosomes 26 Jul 2023
5. Can BACE2 Protect Against Amyloidosis? 18 Feb 2020
6. Gearing Up for Down’s Syndrome Clinical Trials 21 May 2021
7. In Down's Syndrome, Amyloid Vaccine Opens Door to Trials 20 May 2021
8. Can a Sex Hormone Boost Cognition in Down’s Syndrome? 16 Sep 2022

Mutation Position Table Citations

1. APP Duplication - Mutations 8 Mar 2023

Therapeutics Citations

1. Leqembi

Paper Citations

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