Mutations

Trisomy 21

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 dementia in DS is 55 years (Sinai et al., 2018), by 60 years 70 percent of individuals with DS have been diagnosed with dementia, and by 65, 88 percent (McCarron et al., 2017). 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. Fortea and colleagues, for example, found almost identical AD biomarker trajectories in DS as in autosomal dominant AD (Fortea et al., 2020). 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, some studies suggest that, 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).

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). Neuropathology is also characterized by Aβ accumulation around the cerebral vasculature. The extent of cerebrovascular disease (CVD) 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). Indeed, data reported in a preprint suggest that CVD promotes neurodegeneration in individuals with DS by increasing astrocytosis and tau pathophysiology during the presymptomatic stage of AD (Edwards et al., 2023). 

The spread of amyloid and tau pathologies in DS AD generally follows the pattern observed in late-onset AD, as do levels of biomarkers in cerebrospinal fluid and blood (e.g., Janelidze et al., 2022; July 2022 news). However, some differences in pathology have been noted (Lott and Head, 2019). 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., 2016Annus et al., 2016).

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). However, 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). Nine percent of the 33 cases had TDP-43 pathology.

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., 2015Lott 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]).

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). 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).  

Nevertheless, the overexpression of non-APP genes on chromosome 21, numbering over 200, may also modify AD risk and presentation (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, and RCAN1, which regulates calcineurin, may accelerate the emergence of neurofibrillary tangles. DYRK1A, which also phosphorylates APP, 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 newsAlić 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 vulnerability to AD (Lott and Head, 2019).

Several clinical trials for DS are in the works (May 2021a news), including testing of the anti-amyloid vaccine ACI-24 (May 2021b news) and subdermal pulses of gonadotropin-releasing hormone (Sep 2022 news). Of note, anti-amyloid antibodies have yet to be tested in DS AD. Researchers are proceeding cautiously because CAA, very often present in DS AD, is a strong risk factor for amyloid-related imaging abnormalities (ARIA), a side-effect of amyloid antibody treatments (Aug 2023 conference 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.

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.

PS1-M

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Trisomy 21: Includes an extra copy of APP like multiple APP duplications known to be pathogenic.

PS2-S

De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

PS4-S

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.

PM1-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. Trisomy 21: Mutation encompasses the APP gene, a mutational hotspot and a gene known to play a well-established functional role in AD.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 09 Feb 2024

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References

News Citations

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

Mutation Position Table Citations

  1. APP Duplication - Mutations

Mutations Citations

  1. APP Duplication 1104 [APP-APP]
  2. APP Triplication [APP-APP]

Therapeutics Citations

  1. ACI-24

Paper Citations

  1. . Early senile dementia in mongoloid idiocy. Am J Psychiatry. 1948 Aug;105(2):102-6. PubMed.
  2. . Dementia in Down syndrome: unique insights for Alzheimer disease research. Nat Rev Neurol. 2019 Mar;15(3):135-147. PubMed.
  3. . Alzheimer's disease and Down's syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun. 1984 Aug 16;122(3):1131-5. PubMed.
  4. . Predictors of Age of Diagnosis and Survival of Alzheimer's Disease in Down Syndrome. J Alzheimers Dis. 2018;61(2):717-728. PubMed.
  5. . Clinical and biomarker changes of Alzheimer's disease in adults with Down syndrome: a cross-sectional study. Lancet. 2020 Jun 27;395(10242):1988-1997. PubMed.
  6. . Association of Apolipoprotein E ɛ4 Allele With Clinical and Multimodal Biomarker Changes of Alzheimer Disease in Adults With Down Syndrome. JAMA Neurol. 2021 Aug 1;78(8):937-947. PubMed.
  7. . Alzheimer's polygenic risk scores are associated with cognitive phenotypes in Down syndrome. Alzheimers Dement. 2024 Feb;20(2):1038-1049. Epub 2023 Oct 19 PubMed.
  8. . Role of Trisomy 21 Mosaicism in Sporadic and Familial Alzheimer's Disease. Curr Alzheimer Res. 2016;13(1):7-17. PubMed.
  9. . Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol Dis. 1996 Feb;3(1):16-32. PubMed.
  10. . Intraneuronal Abeta42 accumulation in Down syndrome brain. Amyloid. 2002 Jun;9(2):88-102. PubMed.
  11. . Cerebrovascular disease drives Alzheimer plasma biomarker concentrations in adults with Down syndrome. 2023 Nov 30 10.1101/2023.11.28.23298693 (version 2) medRxiv.
  12. . Detection of Brain Tau Pathology in Down Syndrome Using Plasma Biomarkers. JAMA Neurol. 2022 Aug 1;79(8):797-807. PubMed.
  13. . The effects of normal aging on amyloid-β deposition in nondemented adults with Down syndrome as imaged by carbon 11-labeled Pittsburgh compound B. Alzheimers Dement. 2016 Apr;12(4):380-90. Epub 2015 Jun 13 PubMed.
  14. . The pattern of amyloid accumulation in the brains of adults with Down syndrome. Alzheimers Dement. 2016 May;12(5):538-45. Epub 2015 Sep 9 PubMed.
  15. . Microbleeds and Cerebral Amyloid Angiopathy in the Brains of People with Down Syndrome with Alzheimer's Disease. J Alzheimers Dis. 2019;67(1):103-112. PubMed.
  16. . Patterns and severity of vascular amyloid in Alzheimer's disease associated with duplications and missense mutations in APP gene, Down syndrome and sporadic Alzheimer's disease. Acta Neuropathol. 2018 Oct;136(4):569-587. Epub 2018 May 16 PubMed.
  17. . Developmental deficits and staging of dynamics of age associated Alzheimer's disease neurodegeneration and neuronal loss in subjects with Down syndrome. Acta Neuropathol Commun. 2022 Jan 4;10(1):2. PubMed.
  18. . Down Syndrome Biobank Consortium: A perspective. Alzheimers Dement. 2024 Jan 25; PubMed.
  19. . A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome. Nat Rev Neurosci. 2015 Sep;16(9):564-74. Epub 2015 Aug 5 PubMed.
  20. . Molecular mapping of Alzheimer-type dementia in Down's syndrome. Ann Neurol. 1998 Mar;43(3):380-3. PubMed.
  21. . Down Syndrome, Partial Trisomy 21, and Absence of Alzheimer's Disease: The Role of APP. J Alzheimers Dis. 2017;56(2):459-470. PubMed.
  22. . Spatial and single-nucleus transcriptomic analysis of genetic and sporadic forms of Alzheimer's Disease. 2023 Jul 26 10.1101/2023.07.24.550282 (version 1) bioRxiv.
  23. . Lysosomal dysfunction in Down syndrome and Alzheimer mouse models is caused by v-ATPase inhibition by Tyr682-phosphorylated APP βCTF. Sci Adv. 2023 Jul 28;9(30):eadg1925. Epub 2023 Jul 26 PubMed.
  24. . Constitutive Dyrk1A is abnormally expressed in Alzheimer disease, Down syndrome, Pick disease, and related transgenic models. Neurobiol Dis. 2005 Nov;20(2):392-400. PubMed.
  25. . Dual-specificity tyrosine(Y)-phosphorylation regulated kinase 1A-mediated phosphorylation of amyloid precursor protein: evidence for a functional link between Down syndrome and Alzheimer's disease. J Neurochem. 2008 Mar;104(5):1333-44. Epub 2007 Nov 14 PubMed.
  26. . Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes. Neurobiol Dis. 2017 Oct;106:76-88. Epub 2017 Jun 21 PubMed.
  27. . Genetic Mapping of APP and Amyloid-β Biology Modulation by Trisomy 21. J Neurosci. 2022 Aug 17;42(33):6453-6468. Epub 2022 Jul 14 PubMed.
  28. . Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain. Mol Psychiatry. 2021 Oct;26(10):5766-5788. Epub 2020 Jul 10 PubMed. bioRxiv
  29. . Rodent models in Down syndrome research: impact and future opportunities. Dis Model Mech. 2017 Oct 1;10(10):1165-1186. PubMed.
  30. . Rodent Modeling of Alzheimer's Disease in Down Syndrome: In vivo and ex vivo Approaches. Front Neurosci. 2022;16:909669. Epub 2022 Jun 7 PubMed.

Other Citations

  1. duplications

Further Reading

Papers

  1. . Association of biological sex with clinical outcomes and biomarkers of Alzheimer's disease in adults with Down syndrome. Brain Commun. 2023;5(2):fcad074. Epub 2023 Mar 17 PubMed.
  2. . Individualized estimated years from onset of Alzheimer's disease- related decline for adults with Down syndrome. Alzheimers Dement (Amst). 2023;15(2):e12444. Epub 2023 Jun 27 PubMed.
  3. . Timing of Alzheimer's Disease by Intellectual Disability Level in Down Syndrome. J Alzheimers Dis. 2023;95(1):213-225. PubMed.

Protein Diagram

Primary Papers

  1. . Early senile dementia in mongoloid idiocy. Am J Psychiatry. 1948 Aug;105(2):102-6. PubMed.

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