Comparison of amyloid burden in individuals with Down syndrome versus autosomal dominant Alzheimer's disease: a cross-sectional study
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Background Important insights into the early pathogenesis of Alzheimer's disease can be provided by studies of autosomal dominant Alzheimer's disease and Down syndrome. However, it is unclear whether the timing and spatial distribution of amyloid accumulation differs between people with autosomal dominant Alzheimer's disease and those with Down syndrome. We aimed to directly compare amyloid changes between these two groups of people. Methods In this cross-sectional study, we included participants (aged ≥25 years) with Down syndrome and sibling controls who had MRI and amyloid PET scans in the first data release (January, 2020) of the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study. We also included carriers of autosomal dominant Alzheimer's disease genetic mutations and non-carrier familial controls who were within a similar age range to ABC-DS participants (25-73 years) and had MRI and amyloid PET scans at the time of a data freeze (December, 2020) of the Dominantly Inherited Alzheimer Network (DIAN) study. Controls from the two studies were combined into a single group. All DIAN study participants had genetic testing to determine PSEN1, PSEN2, or APP mutation status. APOE genotype was determined from blood samples. CSF samples were collected in a subset of ABC-DS and DIAN participants and the ratio of amyloid β42 (Aβ42) to Aβ40 (Aβ42/40) was measured to evaluate its Spearman's correlation with amyloid PET. Global PET amyloid burden was compared with regards to cognitive status, APOE ɛ4 status, sex, age, and estimated years to symptom onset. We further analysed amyloid PET deposition by autosomal dominant mutation type. We also assessed regional patterns of amyloid accumulation by estimated number of years to symptom onset. Within a subset of participants the relationship between amyloid PET and CSF Aβ42/40 was evaluated. Findings 192 individuals with Down syndrome and 33 sibling controls from the ABC-DS study and 265 carriers of autosomal dominant Alzheimer's disease mutations and 169 non-carrier familial controls from the DIAN study were included in our analyses. PET amyloid centiloid and CSF Aβ42/40 were negatively correlated in carriers of autosomal dominant Alzheimer's disease mutations (n=216; r=-0·565; p<0·0001) and in people with Down syndrome (n=32; r=-0·801; p<0·0001). There was no difference in global PET amyloid burden between asymptomatic people with Down syndrome (mean 18·80 centiloids [SD 28·33]) versus asymptomatic mutation carriers (24·61 centiloids [30·27]; p=0·11) and between symptomatic people with Down syndrome (77·25 centiloids [41·76]) versus symptomatic mutation carriers (69·15 centiloids [51·10]; p=0·34). APOE ɛ4 status and sex had no effect on global amyloid PET deposition. Amyloid deposition was elevated significantly earlier in mutation carriers than in participants with Down syndrome (estimated years to symptom onset -23·0 vs -17·5; p=0·0002). PSEN1 mutations primarily drove this difference. Early amyloid accumulation occurred in striatal and cortical regions for both mutation carriers (n=265) and people with Down syndrome (n=128). Although mutation carriers had widespread amyloid accumulation in all cortical regions, the medial occipital regions were spared in people with Down syndrome. Interpretation Despite minor differences, amyloid PET changes were similar between people with autosomal dominant Alzheimer's disease versus Down syndrome and strongly supported early amyloid dysregulation in individuals with Down syndrome. Individuals with Down syndrome aged at least 35 years might benefit from early intervention and warrant future inclusion in clinical trials, particularly given the relatively high incidence of Down syndrome. Funding The National Institute on Aging, Riney and Brennan Funds, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the German Center for Neurodegenerative Diseases, and the Japan Agency for Medical Research and Development.
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Recent PET imaging studies found no evidence that APOEε4 influences amyloid-β load in individuals with DSAD.
“However, recent PET imaging studies found no evidence that APOEε4 influences amyloid-β load in individuals with DSAD [6].”
From Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome–Alzheimer’s disease (2025) · cites this paper as [6]
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Self-citationMedial temporal lobe atrophy in Down syndrome along the Alzheimer’s disease continuum
Buehner, B. J., Morcillo-Nieto, A. O., Zsadanyi, S. E., Aranha, M. R., Arriola‐Infante, J. E., Vaqué‐Alcázar, L., Arranz, J., Rodríguez‐Baz, Í., Maure‐Blesa, L., Videla, L., et al. (2025) · Brain · doi:10.1093/brain/awaf133 · Cited by 10 · see citing works
Lessons from Down syndrome and autosomal dominant Alzheimer's disease
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Plasma p-tau217 as a biomarker of Alzheimer’s disease pathology in individuals with Down syndrome
Huber, H., Arranz, J., Arslan, B., Leuzy, A., Kittel, O., Molfetta, G. D., Benejam, B., Videla, L., Barroeta, I., Soriano, L. D. H., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-65882-x · Cited by 8 · see citing works
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Self-citationDecoding brain structure to stage Alzheimer's disease pathology in Down syndrome
Kennedy, J. T., Wisch, J. K., Dincer, A., Roman, J., Gordon, B. A., Handen, B., Benzinger, T. L. S., Head, E., Mapstone, M., Christian, B. T., et al. (2025) · Alzheimer's & Dementia · doi:10.1002/alz.14519 · Cited by 7 · see citing works
Self-citationCTAD taskforce: genetic therapies in Alzheimer’s disease
Jakabek, D., Isaacs, A. M., Strooper, B. D., Tuszynski, M. H., Lane, R. M., Uspenskaya, O., McDade, E., Rafii, M. S., & Mummery, C. J. (2025) · The Journal of Prevention of Alzheimer s Disease · doi:10.1016/j.tjpad.2025.100269 · Cited by 6 · see citing works
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Self-citationWhat Can We Learn About Alzheimer’s Disease from People with Down Syndrome?
Maure‐Blesa, L., Rodríguez‐Baz, Í., Carmona‐Iragui, M., & Fortea, J. (2024) · Current topics in behavioral neurosciences · doi:10.1007/7854_2024_546 · Cited by 5 · see citing works
Idris, M., Saini, F., Ivain, P., Baksh, R. A., Bianchi, L. A., Pape, S. E., Zetterberg, H., Wijeratne, P. A., & Strydom, A. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70446 · Cited by 3 · see citing works
The amyloid clock: mapping Alzheimer's disease in Down syndrome
Rafii, M. S. (2024) · The Lancet Neurology · doi:10.1016/s1474-4422(24)00437-x · Cited by 3 · see citing works
Self-citationDevelopment of Molecular Neuropathology in Down Syndrome across the Lifespan
Bhattacharyya, A., de la Torre-Ubieta, L., Zhu, Y., Head, E., Swarup, V., & Sousa, A. M. M. (2025) · Journal of Neuroscience · doi:10.1523/jneurosci.1365-25.2025 · Cited by 3 · see citing works
Self-citationSilva, J. A., Liou, J., Parikh, S., Edwards, N. C., Kofler, J., Ikonomovic, M. D., Lai, F., Rosas, H. D., Powell, D. K., Schmitt, F. A., et al. (2026) · npj Dementia · doi:10.1038/s44400-026-00062-2 · Cited by 2 · see citing works
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Alzheimer's disease in Down syndrome: progress and promise
Ryan, N. S. (2025) · The Lancet Neurology · doi:10.1016/s1474-4422(25)00276-5 · Cited by 1 · see citing works
Cross‐Sectional FDG in Down Syndrome and Autosomal Dominant Alzheimer's Disease
Abdelmoity, O., Wisch, J. K., Kennedy, J. T., Goyal, M. S., Vlassenko, A. G., Flores, S. E., Handen, B. L., Head, E., Keator, D. B., Rafii, M. S., et al. (2025) · Annals of Neurology · doi:10.1002/ana.78002 · Cited by 1 · see citing works
Self-citationThe immunoreactive signature of monocyte-derived dendritic cells from patients with Down syndrome
Nakashima, K., Imai, T., Shiraishi, A., Unose, R., Goto, H., Nagatomo, Y., Kojima‐Ishii, K., Mushimoto, Y., Nishiyama, K., Yamamura, K., et al. (2024) · Clinical & Experimental Immunology · doi:10.1093/cei/uxae048 · Cited by 1 · see citing works
Modeling the Impact of Research Investment on Down Syndrome–Associated Alzheimer's Disease
Weden, M. M., Wang, Z., Frank, L. B., Dick, A. W., & Marsolais, E. (2023) · RAND Corporation eBooks · doi:10.7249/rra2663-1
Amyloid age and tau PET timeline to symptomatic Alzheimer’s disease in Down syndromePreprint
Schworer, E. K., Zammit, M. D., Wang, J., Handen, B. L., Betthauser, T. J., Laymon, C. M., Tudorascu, D., Cohen, A. D., Zaman, S. H., Ances, B. M., et al. (2024) · medRxiv · doi:10.1101/2024.08.08.24311702
Self-citationSchworer, E. K., Handen, B. L., Krinsky‐McHale, S. J., Hom, C. L., Clare, I. C. H., Harp, J. P., Pulsifer, M. B., Mapstone, M. E., Head, E., Christian, B., et al. (2025) · Journal of Intellectual Disability Research · doi:10.1111/jir.13237
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Guo, Z., Zhu, Y., Xiao, H., Dai, R., Yang, W., Xue, W., Zhang, X., Hao, B., & Liao, S. (2024) · Figshare · doi:10.6084/m9.figshare.26651571
Guo, Z., Zhu, Y., Xiao, H., Dai, R., Yang, W., Xue, W., Zhang, X., Hao, B., & Liao, S. (2024) · Figshare · doi:10.6084/m9.figshare.26651568
Guo, Z., Zhu, Y., Xiao, H., Dai, R., Yang, W., Xue, W., Zhang, X., Hao, B., & Liao, S. (2024) · Figshare · doi:10.6084/m9.figshare.26651565
Guo, Z., Zhu, Y., Xiao, H., Dai, R., Yang, W., Xue, W., Zhang, X., Hao, B., & 廖世秀 (2024) · Figshare · doi:10.6084/m9.figshare.26651562
Guo, Z., Zhu, Y., Xiao, H., Dai, R., Yang, W., Xue, W., Zhang, X., Hao, B., & Liao, S. (2024) · Figshare · doi:10.6084/m9.figshare.26651574
Guo, Z., Zhu, Y., Xiao, H., Dai, R., Yang, W., Xue, W., Zhang, X., Hao, B., & Liao, S. (2023) · Figshare · doi:10.6084/m9.figshare.24779223
Millar, P. R., Gordon, B. A., Wisch, J. K., Schultz, S. A., Benzinger, T. L. S., Cruchaga, C., Hassenstab, J. J., Ibanez, L., Karch, C. M. M., Llibre‐Guerra, J. J., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26655946
Self-citationGuo, Z., Zhu, Y., Xiao, H., Dai, R., Yang, W., Xue, W., Zhang, X., Hao, B., & Liao, S. (2024) · Figshare · doi:10.6084/m9.figshare.26651577
Decoding Alzheimer's disease through down syndrome: insights from a genetically defined population
Russell, J. K., Schlachetzki, Z., & Rafii, M. S. (2026) · Current Opinion in Neurology · doi:10.1097/wco.0000000000001461
Self-citationApplication of machine learning to blood‐based biomarkers of Alzheimer's disease in Down syndrome
Luckett, P. H., Petersen, M. E., O’Bryant, S. E., Mapstone, M. E., Christian, B. T., Handen, B. L., Head, E., & Ances, B. M. (2026) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.70325
Self-citationAbdullah, L. B., Zhang, F., Petersen, M. E., Hall, J., Handen, B. L., Mapstone, M. E., Christian, B. T., Head, E., Harley, S., Andrews, H., et al. (2026) · Alzheimer s & Dementia · doi:10.1002/alz.71338
Self-citationLongitudinal Dynamics of the Blood Proteome Within the Alzheimer Spectrum in Down Syndrome
Wagemann, O., Nübling, G., Sandkühler, K., Wlasich, E., Loosli, S. V., Prix, C., Stockbauer, A., Marth, L., Forte, A., Vöglein, J., et al. (2026) · Neurology · doi:10.1212/wnl.0000000000218494
Self-citationEffects of Age on the Association between Down Syndrome and Common Disease ConditionsPreprint
Noah, A. I., Tavalire, H. F., Fitzpatrick, V., Graham, H., Verma, S., Krohn, L., Frank, K., Vockeroth, D., & Chicoine, B. A. (2026) · medRxiv · doi:10.64898/2026.09.02.26362053
Fernández, A., Molanes‐López, E. M., Zuluaga, P., Vaquero, L., Moldenhauer, F., Román, J. M. G., Bajo, R., Lagunas, N., & García‐Alba, J. (2026) · Journal of Neurology · doi:10.1007/s00415-026-14165-6
- Authors
- Boerwinkle, A. H., Gordon, B. A., Wisch, J., Flores, S., Henson, R. L., Butt, O. H., McKay, N., Chen, C. D., Benzinger, T. L. S., Fagan, A. M., Handen, B. L., Christian, B. T., Head, E., Mapstone, M., Rafii, M. S., O'Bryant, S., Lai, F., Rosas, H. D., Lee, J. H., Silverman, W., Brickman, A. M., Chhatwal, J. P., Cruchaga, C., Perrin, R. J., Xiong, C., Hassenstab, J., McDade, E., Bateman, R. J., Ances, B. M., Aizenstein, H. J., Andrews, H. F., Bell, K., Birn, R. M., Bulova, P., Cheema, A., Chen, K., Clare, I., Clark, L., Cohen, A. D., Constantino, J. N., Doran, E. W., Feingold, E., Foroud, T. M., Hartley, S. L., Hom, C., Honig, L., Ikonomovic, M. D., Johnson, S. C., Jordan, C., Kamboh, M. I., Keator, D., Klunk MD, W. E., Kofler, J. K., Kreisl, W. C., Krinsky- McHale, S. J., Lao, P., Laymon, C., Lott, I. T., Lupson, V., Mathis, C. A., Minhas, D. S., Nadkarni, N., Pang, D., Petersen, M., Price, J. C., Pulsifer, M., Reiman, E., Rizvi, B., Sabbagh, M. N., Schupf, N., Tudorascu, D. L., Tumuluru, R., Tycko, B., Varadarajan, B., White, D. A., Yassa, M. A., Zaman, S., Zhang, F., Adams, S., Allegri, R., Araki, A., Barthelemy, N., Bechara, J., Berman, S., Bodge, C., Brandon, S., Brooks, W., Brosch, J., Buck, J., Buckles, V., Carter, K., Cash, L., Mendez, P. C., Chua, J., Chui, H., Courtney, L., Day, G., DeLaCruz, C., Denner, D., Diffenbacher, A., Dincer, A., Donahue, T., Douglas, J., Duong, D., Egido, N., Esposito, B., Farlow, M., Feldman, B., Fitzpatrick, C., Fox, N., Franklin, E., Joseph-Mathurin, N., Fujii, H., Gardener, S., Ghetti, B., Goate, A., Goldberg, S., Goldman, J., Gonzalez, A., Gräber-Sultan, S., Graff-Radford, N., Graham, M., Gray, J., Gremminger, E., Grilo, M., Groves, A., Haass, C., Häslerc, L., Hellm, C., Herries, E., Hoechst-Swisher, L., Hofmann, A., Holtzman, D., Hornbeck, R., Igor, Y., Ihara, R., Ikeuchi, T., Ikonomovic, S., Ishii, K., Jack, C., Jerome, G., Johnson, E., Jucker, M., Karch, C., Käser, S., Kasuga, K., Keefe, S., Klunk, W., Koeppe, R., Koudelis, D., Kuder-Buletta, E., Laske, C., Levey, A., Levin, J., Li, Y., Lopez, O., Marsh, J., Martins, R., Mason, N. S., Masters, C., Mawuenyega, K., McCullough, A., Mejia, A., Morenas-Rodriguez, E., Morris, J. C., Mountz, J., Mummery, C., Nadkarni, N., Nagamatsu, A., Neimeyer, K., Niimi, Y., Noble, J., Norton, J., Nuscher, B., Obermüller, U., O'Connor, A., Patira, R., Ping, L., Preische, O., Renton, A., Ringman, J., Salloway, S., Schofield, P., Senda, M., Seyfried, N. T., Shady, K., Shimada, H., Sigurdson, W., Smith, J., Smith, L., Snitz, B., Sohrabi, H., Stephens, S., Taddei, K., Thompson, S., Vöglein, J., Wang, P., Wang, Q., Weamer, E., Xu, J., & Xu, X.
- Affiliations
- Washington University in St. Louis (US)
- University of Pittsburgh (US)
- University of Wisconsin–Madison (US)
- University of California, Irvine (US)
- University of Southern California (US)
- Brigham and Women's Hospital (US)
- Columbia University Irving Medical Center (US)
- Harvard University (US)
- University of Cambridge (GB)
- Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (AR)
- Mayo Clinic in Florida (US)
- UCL Queen Square Institute of Neurology (GB)
- Icahn School of Medicine at Mount Sinai (US)
- German Center for Neurodegenerative Diseases (DE)
- Brown University (US)
- UNSW Sydney (AU)
- Corresponding author
- Ances, Beau M
- ORCID
- Boerwinkle, Anna H
- Gordon, Brian A
- Wisch, Julie
- Flores, Shaney
- Henson, Rachel L
- Butt, Omar H
- McKay, Nicole
- Chen, Charles D
- Benzinger, Tammie L S
- Fagan, Anne M
- Handen, Benjamin L
- Christian, Bradley T
- Head, Elizabeth
- Mapstone, Mark
- Rafii, Michael S
- Lai, Florence
- Rosas, H Diana
- Lee, Joseph H
- Silverman, Wayne
- Brickman, Adam M
- Chhatwal, Jasmeer P
- Cruchaga, Carlos
- Perrin, Richard J
- Xiong, Chengjie
- Hassenstab, Jason
- McDade, Eric
- Bateman, Randall J
- Ances, Beau M
- Aizenstein, Howard J
- Andrews, Howard F
- Bell, Karen
- Birn, Rasmus M
- Cheema, Amrita
- Chen, Kewei
- Clare, Isabel
- Clark, Lorraine
- Cohen, Ann D
- Constantino, John N
- Feingold, Eleanor
- Foroud, Tatiana M
- Hartley, Sigan L
- Hom, Christy
- Honig, Lawrence
- Johnson, Sterling C
- Kamboh, M Ilyas
- Keator, David
- Kofler, Julia K
- Lao, Patrick
- Laymon, Charles
- Lott, Ira T
- Mathis, Chester A
- Minhas, Davneet S
- Petersen, Melissa
- Price, Julie C
- Reiman, Eric
- Rizvi, Batool
- Sabbagh, Marwan N
- Schupf, Nicole
- Tudorascu, Dana L
- Tycko, Benjamin
- Yassa, Michael A
- Zaman, Shahid
- Zhang, Fan
- Allegri, Ricardo
- Bechara, Jacob
- Berman, Sarah
- Brooks, William
- Brosch, Jared
- Chui, Helena
- Day, Gregory
- Dincer, Aylin
- Duong, Duc
- Egido, Noelia
- Fitzpatrick, Colleen
- Fox, Nick
- Franklin, Erin
- Fujii, Hisako
- Gardener, Samantha
- Ghetti, Bernardino
- Goate, Alison
- Goldberg, Sarah
- Goldman, Jill
- Haass, Christian
- Holtzman, David
- Hornbeck, Russ
- Ihara, Ryoko
- Ikeuchi, Takeshi
- Ishii, Kenji
- Jack, Clifford
- Johnson, Erik
- Jucker, Mathias
- Karch, Celeste
- Kasuga, Kensaku
- Keefe, Sarah
- Koeppe, Robert
- Laske, Christoph
- Levey, Allan
- Levin, Johannes
- Li, Yan
- Marsh, Jacob
- Martins, Ralph
- Masters, Colin
- McCullough, Austin
- Morris, John C
- Mountz, James
- Mummery, Catherine
- Niimi, Yoshiki
- Noble, James
- Nuscher, Brigitte
- Patira, Riddhi
- Renton, Alan
- Ringman, John
- Salloway, Stephen
- Schofield, Peter
- Senda, Michio
- Seyfried, Nicholas T
- Smith, Jennifer
- Snitz, Beth
- Sohrabi, Hamid
- Taddei, Kevin
- Thompson, Sarah
- Vöglein, Jonathan
- Wang, Peter
- Xu, Jinbin
- Venue
- The Lancet Neurology
- Publisher
- Elsevier BV
- Published
- 2023-01
- Volume
- 22
- Issue
- 1
- Pages
- 55-65
- ISSN
- 1474-4422 (ISSN-L)
- PMC
- PMC9979840
- OpenAlex
- W4312095442
- Cited by
- 55
- References
- 46
- Citations by year
- 2026: 7 · 2025: 21 · 2024: 16 · 2023: 10 · 2022: 1
- FWCI
- 8.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (am, 162 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- The Lancet Neurology (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Funders
- Hope Center for Neurological Disorders
- Alzheimer's Association (SG-20-690363-DIAN)
- Fleni
- Canadian Institutes of Health Research
- Foundation for Barnes-Jewish Hospital
- NIHR Cambridge Biomedical Research Centre (BRC-1215-20014*)
- Fonds de Recherche du Québec - Santé
- Fondation Brain Canada
- Korea Health Industry Development Institute
- Japan Agency for Medical Research and Development
- Instituto de Salud Carlos III
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U19AG032438)
- National Institute on Aging
- Deutsches Zentrum für Neurodegenerative Erkrankungen
- National Institutes of Health (U01AG051406, U01AG051412)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Keywords
- Down syndrome, autosomal dominant Alzheimer's disease, amyloid PET, amyloid burden, cerebrospinal fluid biomarkers, presenilin 1, presenilin 2, APP mutations, APOE ε4, Alzheimer's disease pathogenesis, cognitive status
- MeSH terms
- Adult, Aged, Alzheimer Disease, Apolipoproteins E, Cerebral Cortex, Cross-Sectional Studies, Down Syndrome, Humans, Middle Aged, Biomarkers, Amyloid beta-Peptides, Positron-Emission Tomography
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