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Down syndrome and Alzheimer's disease: Common pathways, common goals
Open accessAbstract
In the United States, estimates indicate there are between 250,000 and 400,000 individuals with Down syndrome (DS), and nearly all will develop Alzheimer's disease (AD) pathology starting in their 30s. With the current lifespan being 55 to 60 years, approximately 70% will develop dementia, and if their life expectancy continues to increase, the number of individuals developing AD will concomitantly increase. Pathogenic and mechanistic links between DS and Alzheimer's prompted the Alzheimer's Association to partner with the Linda Crnic Institute for Down Syndrome and the Global Down Syndrome Foundation at a workshop of AD and DS experts to discuss similarities and differences, challenges, and future directions for this field. The workshop articulated a set of research priorities: (1) target identification and drug development, (2) clinical and pathological staging, (3) cognitive assessment and clinical trials, and (4) partnerships and collaborations with the ultimate goal to deliver effective disease‐modifying treatments.
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“Individuals with Down syndrome (DS), caused by trisomy of chromosome 21 (chr21, T21), are strongly predisposed to Alzheimer’s disease (AD), due to triplication of the APP gene, with ∼100% penetrance of AD brain pathology by age 40 and variable onset of dementia thereafter.”
From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [11]
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“Hyperactivation of the S6K proteins correlates with increased Tau pathology and dysregulation of the insulin/IGF/mTOR signaling pathway, both in individuals with DS‐AD 55 and in idiopathic AD. 56”
From Disruption of hippocampal upstream regulators of mTOR and insulin pathways in Down syndrome with Alzheimer's disease neuropathology: Preliminary observations (2026) · cites this paper as [55]
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Cites
1 retracted
RETRACTED AND REPLACED: Nerve growth factor metabolic dysfunction in Down’s syndrome brains
Iulita, M. F., Carmo, S. D., Ower, A. K., Fortress, A. M., Aguilar, L. F., Hanna, M., Wısnıewskı, T., Granholm, A., Buhusi, M. C., Busciglio, J. A., et al. (2014) · Brain · doi:10.1093/brain/awt372 · Cited by 94
Self-citationRetractedInhibition and impulsivity: behavioral and neural basis of response control
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Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrome
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Self-citationAmyloid A4 Protein and Its Precursor in Down's Syndrome and Alzheimer's Disease
Rumble, B. A., Retallack, R. W., Hilbich, C., Simms, G., Multhaup, G., Martins, R. N., Hockey, A., Montgomery, P., Beyreuther, K. T., & Masters, C. L. (1989) · New England Journal of Medicine · doi:10.1056/nejm198906013202203 · Cited by 656
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Self-citationA Prospective Study of Alzheimer Disease in Down Syndrome
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Salehi, A., Delcroix, J.-D., Belichenko, P. V., Zhan, K., Wu, C., Valletta, J. S., Takimoto-Kimura, R., Kleschevnikov, A. M., Sambamurti, K., Chung, P. P., et al. (2006) · Neuron · doi:10.1016/j.neuron.2006.05.022 · Cited by 543
Self-citationCognitive deficits and associated neurological complications in individuals with Down's syndrome
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Hampel, H., Hardy, J., Blennow, K., Chen, C., Perry, G., Kim, S. H., Villemagne, V. L., Aisen, P., Vendruscolo, M., Iwatsubo, T., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01249-0 · Cited by 1,952
Alzheimer's disease: experimental models and reality
Drummond, E., & Wisniewski, T. (2017) · Acta Neuropathologica · doi:10.1007/s00401-016-1662-x · Cited by 810
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Dementia in Down syndrome: unique insights for Alzheimer disease research
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Self-citationWeiner, M. W., Veitch, D. P., Aisen, P. S. S., Beckett, L. A., Cairns, N. J., Green, R. C., Harvey, D. J., Jack, C. R., Jagust, W. J., Morris, J. C., et al. (2017) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2016.11.007 · Cited by 325
Metadata
- Authors
- Hartley, D., Blumenthal, T., Carrillo, M., DiPaolo, G., Esralew, L., Gardiner, K., Granholm, A.-C., Iqbal, K., Krams, M., Lemere, C., Lott, I., Mobley, W., Ness, S., Nixon, R., Potter, H., Reeves, R., Sabbagh, M., Silverman, W., Tycko, B., Whitten, M., & Wisniewski, T.
- Affiliations
- Alzheimer's Association (US)
- University of Colorado Boulder (US)
- Medical and Scientific Relations Alzheimer's Association Chicago IL USA
- Department of Pathology and Cell Biology Columbia University Medical Center and The Taub Institute for Research on Alzheimer's Disease and The Aging Brain New York NY USA
- Trinitas Regional Medical Center (US)
- University of Colorado Anschutz (US)
- Medical University of South Carolina (US)
- Department of Neurochemistry New York State Institute for Basic Research in Developmental Disabilities New York NY USA
- Janssen Research & Development (United States) (US)
- Brigham and Women's Hospital (US)
- University of California, Irvine (US)
- University of California San Diego (US)
- NYU Langone Health (US)
- Johns Hopkins University (US)
- Banner Health (US)
- Kennedy Krieger Institute (US)
- Columbia University Irving Medical Center (US)
- Global Down Syndrome Foundation (US)
- Department of Neurology, Pathology, and Psychiatry New York University, Langone Medical Center New York NY USA
- Corresponding author
- Hartley, Dean
- ORCID
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2014-12-12
- Volume
- 11
- Issue
- 6
- Pages
- 700-709
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC4817997
- OpenAlex
- W1991023630
- Cited by
- 290
- References
- 80
- Citations by year
- 2026: 12 · 2025: 26 · 2024: 24 · 2023: 33 · 2022: 27 · 2021: 46 · 2020: 27 · 2019: 26 · 2018: 15 · 2017: 19 · 2016: 20 · 2015: 13 · 2014: 2
- FWCI
- 17.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Alzheimer s & Dementia (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute on Aging (R01AG012122, R01AG037942)
- National Institute of Neurological Disorders and Stroke (R01NS076291)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Down syndrome, Alzheimer's disease
- MeSH terms
- Alzheimer Disease, Animals, Clinical Trials as Topic, Congresses as Topic, Disease Models, Animal, Down Syndrome, Humans, Neuropsychological Tests, Drug Discovery
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