Molecular mapping of alzheimer‐type dementia in Down's syndrome
Abstract
Previous research has hypothesized an association between Alzheimer's disease and the amyloid precursor protein (APP) gene found on chromosome 21. We report the case of a 78‐year‐old woman with Down's syndrome with partial trisomy 21 [46,XX,rec(21)dup q, inv(21) (p12q22.1)]. No evidence of Alzheimer's disease was found on neuropsychological, magnetic resonance imaging, and neuropathological assessment. The gene sequence for APP was present in only two copies. This case further supports the hypothesis that Alzheimer's disease is associated with trisomy for proximal chromosome 21q, including the APP gene.
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DSAD is in part a result of triplication of the APP gene on Hsa21, which results in increased production of amyloid-β peptide and other APP gene products.
“and is in part a result of triplication of the amyloid precursor protein gene (APP) on Hsa21, which results in the increased production of the amyloid-β peptide and other APP gene products [12, 54].”
From Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome–Alzheimer’s disease (2025) · cites this paper as [54]
DSAD is the most commonly occurring single genetic cause of AD.
“Down syndrome–Alzheimer’s disease (DSAD) is the most commonly occurring single genetic cause of AD”
From Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome–Alzheimer’s disease (2025) · cites this paper as [54]
Raised APP abundance in the DSAD cases is driven by the additional copy of APP on Hsa21.
“Importantly here, we know that raised APP abundance in our DSAD cases is driven by the additional copy of APP on Hsa21, as indicated by both human-genetics studies and preclinical modelling [12, 54, 58].”
From Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome–Alzheimer’s disease (2025) · cites this paper as [54]
Cites
The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor
Kang, J., Lemaire, H.-G., Unterbeck, A., Salbaum, J. M., Masters, C. L., Grzeschik, K.-H., Multhaup, G., Beyreuther, K., & Müller-Hill, B. (1987) · Nature · doi:10.1038/325733a0 · Cited by 4,619 · see citing works
Genetic associations with human longevity at the APOE and ACE loci
Schächter, F., Faure-Delanef, L., Guénot, F., Rouger, H., Froguel, P., Lesueur-Ginot, L., & Cohen, D. (1994) · Nature Genetics · doi:10.1038/ng0194-29 · Cited by 1,095 · see citing works
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The amyloid hypothesis of Alzheimer's disease at 25 years
Selkoe, D. J., & Hardy, J. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201606210 · Cited by 6,164 · see citing works
Alzheimer's Disease: Genes, Proteins, and Therapy
Selkoe, D. J. (2001) · Physiological Reviews · doi:10.1152/physrev.2001.81.2.741 · Cited by 6,063 · see citing works
Aβ Oligomers – a decade of discovery
Walsh, D. M., & Selkoe, D. J. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04426.x · Cited by 1,938 · see citing works
Alzheimer Mechanisms and Therapeutic Strategies
Huang, Y., & Mucke, L. (2012) · Cell · doi:10.1016/j.cell.2012.02.040 · Cited by 1,758 · see citing works
Deciphering the Molecular Basis of Memory Failure in Alzheimer's Disease
Walsh, D. M., & Selkoe, D. J. (2004) · Neuron · doi:10.1016/j.neuron.2004.09.010 · Cited by 1,207 · see citing works
Axonopathy and Transport Deficits Early in the Pathogenesis of Alzheimer’s Disease
Stokin, G. B., Lillo, C., Falzone, T. L., Brusch, R. G., Rockenstein, E., Mount, S. L., Raman, R., Davies, P., Masliah, E., Williams, D. S., et al. (2005) · Science · doi:10.1126/science.1105681 · Cited by 1,214 · see citing works
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 · see citing works
The molecular bases of Alzheimer’s disease and other neurodegenerative disorders
Maccioni, R. B., Muñoz, J. P., & Barbeito, L. (2001) · Archives of Medical Research · doi:10.1016/s0188-4409(01)00316-2 · Cited by 474 · see citing works
Dementia in Down syndrome: unique insights for Alzheimer disease research
Lott, I. T., & Head, E. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-018-0132-6 · Cited by 383 · see citing works
Genes associated with Alzheimer's disease: an overview and current status
Giri, M., Lü, Y., & Zhang, M. (2016) · Clinical Interventions in Aging · doi:10.2147/cia.s105769 · Cited by 311 · see citing works
Down syndrome and Alzheimer's disease: common pathways, common goals
Hartley, D., Blumenthal, T., Carrillo, M., DiPaolo, G., Esralew, L., Gardiner, K., Granholm, A.-C., Iqbal, K., Krams, M., Lemere, C., et al. (2015) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2014.10.007 · Cited by 290 · see citing works
Down Syndrome, Partial Trisomy 21, and Absence of Alzheimer’s Disease: The Role of APP
Doran, E., Keator, D., Head, E., Phelan, M. J., Kim, R., Totoiu, M., Barrio, J. R., Small, G. W., Potkin, S. G., & Lott, I. T. (2017) · Journal of Alzheimer’s Disease · doi:10.3233/jad-160836 · Cited by 244 · see citing works
Genetics of β-Amyloid Precursor Protein in Alzheimer's Disease
TCW, J., & Goate, A. M. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a024539 · Cited by 242 · see citing works
Gene expression profiling in the adult Down syndrome brain
Lockstone, H. E., Harris, L. W., Swatton, J. E., Wayland, M. T., Holland, A. J., & Bahn, S. (2007) · Genomics · doi:10.1016/j.ygeno.2007.08.005 · Cited by 240 · see citing works
Association of Dementia With Mortality Among Adults With Down Syndrome Older Than 35 Years
Hithersay, R., Startin, C. M., Hamburg, S., Mok, K. Y., Hardy, J., Fisher, E. M. C., Tybulewicz, V. L. J., Nizetic, D., & Strydom, A. (2019) · JAMA Neurology · doi:10.1001/jamaneurol.2018.3616 · Cited by 176 · see citing works
Self-citationAlzheimer disease pathology as a host response
Castellani, R. J., Lee, H.-G., Zhu, X., Perry, G., & Smith, M. A. (2008) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e318177eaf4 · Cited by 171 · see citing works
Outcome Measures for Clinical Trials in Down Syndrome
Esbensen, A. J., Hooper, S. R., Fidler, D., Hartley, S. L., Edgin, J., d'Ardhuy, X. L., Capone, G., Conners, F. A., Mervis, C. B., Abbeduto, L., et al. (2017) · American Journal on Intellectual and Developmental Disabilities · doi:10.1352/1944-7558-122.3.247 · Cited by 153 · see citing works
Endo‐lysosomal and autophagic dysfunction: a driving factor in Alzheimer's disease?
Whyte, L. S., Lau, A. A., Hemsley, K. M., Hopwood, J. J., & Sargeant, T. J. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.13935 · Cited by 150 · see citing works
Haass, C., & Selkoe, D. (2022) · PLOS Biology · doi:10.1371/journal.pbio.3001694 · Cited by 145 · see citing works
Bushman, D. M., Kaeser, G. E., Siddoway, B., Westra, J. W., Rivera, R. R., Rehen, S. K., Yung, Y. C., & Chun, J. (2015) · eLife · doi:10.7554/elife.05116 · Cited by 136 · see citing works
Kazuki, Y., Gao, F. J., Li, Y., Moyer, A. J., Devenney, B., Hiramatsu, K., Miyagawa-Tomita, S., Abe, S., Kazuki, K., Kajitani, N., et al. (2020) · eLife · doi:10.7554/elife.56223 · Cited by 125 · see citing works
Alzheimer's disease in Down syndrome: an overlooked population for prevention trials
Strydom, A., Coppus, A., Blesa, R., Danek, A., Fortea, J., Hardy, J., Levin, J., Nuebling, G., Rebillat, A., Ritchie, C., et al. (2018) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2018.10.006 · Cited by 110 · see citing works
Cerebrovascular pathology in Down syndrome and Alzheimer disease
Head, E., Phelan, M. J., Doran, E., Kim, R. C., Poon, W. W., Schmitt, F. A., & Lott, I. T. (2017) · Acta Neuropathologica Communications · doi:10.1186/s40478-017-0499-4 · Cited by 105 · see citing works
Genetic Heterogeneity in Alzheimer Disease and Implications for Treatment Strategies
Dominantly Inherited Alzheimer Network, Ringman, J. M., Goate, A., Masters, C. L., Cairns, N. J., Danek, A., Graff-Radford, N., Ghetti, B., & Morris, J. C. (2014) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-014-0499-8 · Cited by 96 · see citing works
Pelleri, M. C., Cicchini, E., Locatelli, C., Vitale, L., Caracausi, M., Piovesan, A., Rocca, A., Poletti, G., Seri, M., Strippoli, P., et al. (2016) · Human Molecular Genetics · doi:10.1093/hmg/ddw116 · Cited by 83 · see citing works
Mann, D. M. A., Davidson, Y. S., Robinson, A. C., Allen, N., Hashimoto, T., Richardson, A., Jones, M., Snowden, J. S., Pendleton, N., Potier, M.-C., et al. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1866-3 · Cited by 73 · see citing works
Self-citationCerebrovascular contributions to aging and Alzheimer's disease in Down syndrome
Wilcock, D. M., Schmitt, F. A., & Head, E. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2015.11.007 · Cited by 56 · see citing works
Impact of increased <i>APP</i> gene dose in Down syndrome and the Dp16 mouse model
Sawa, M., Overk, C., Becker, A., Derse, D., Albay, R., Weldy, K., Salehi, A., Beach, T. G., Doran, E., Head, E., et al. (2022) · Alzheimer's & Dementia · doi:10.1002/alz.12463 · Cited by 54 · see citing works
Wu, Y., Mumford, P., Noy, S., Cleverley, K., Mrzyglod, A., Luo, D., van Dalen, F., Verdoes, M., Fisher, E. M. C., & Wiseman, F. K. (2023) · Acta Neuropathologica Communications · doi:10.1186/s40478-023-01632-8 · Cited by 16 · see citing works
Self-citationMartá-Ariza, M., Leitner, D. F., Kanshin, E., Suazo, J., Giusti Pedrosa, A., Thierry, M., Lee, E. B., Devinsky, O., Drummond, E., Fortea, J., et al. (2025) · Acta Neuropathologica · doi:10.1007/s00401-025-02844-z · Cited by 15 · see citing works
Farrell, C., Buhidma, Y., Mumford, P., Heywood, W. E., Hällqvist, J., Flores-Aguilar, L., Andrews, E. J., Rahimzadah, N., Taso, O. S., Doran, E., et al. (2025) · Acta Neuropathologica · doi:10.1007/s00401-025-02889-0 · Cited by 9 · see citing works
“Importantly here, we know that raised APP abundance in our DSAD cases is driven by the additional copy of APP on Hsa21, as indicated by both human-genetics studies and preclinical modelling [12, 54, 58].”
- Authors
- Prasher, V. P., Farrer, M. J., Kessling, A. M., Fisher, E. M. C., West, R. J., Barber, P. C., & Butler, A. C.
- Affiliations
- University of Birmingham (GB)
- St Mark's Hospital (GB)
- St Mary's Hospital (GB)
- Queen Elizabeth Hospital Birmingham (GB)
- Corresponding author
- Prasher, V. P.
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 1998-03
- Volume
- 43
- Issue
- 3
- Pages
- 380-383
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- OpenAlex
- W2018358250
- Cited by
- 414
- References
- 2
- Citations by year
- 2026: 8 · 2025: 24 · 2024: 29 · 2023: 21 · 2022: 18 · 2021: 23 · 2020: 22 · 2019: 24 · 2018: 15 · 2017: 19 · 2016: 21 · 2015: 14 · 2014: 18 · 2013: 12 · 2012: 12
- FWCI
- 7.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Down syndrome, Alzheimer's disease, amyloid precursor protein gene, APP gene, partial trisomy 21, chromosome 21q, molecular mapping, genetic association, neuropathology
- MeSH terms
- Aged, Alzheimer Disease, Brain, Chromosome Mapping, Chromosomes, Human, Pair 21, Down Syndrome, Female, Humans, Amyloid beta-Protein Precursor, Gene Dosage
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