{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:42:52Z","timestamp":1768567372804,"version":"3.49.0"},"posted":{"date-parts":[[2024,8,9]]},"group-title":"Neurology","reference-count":42,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,8,9]],"date-time":"2024-08-09T00:00:00Z","timestamp":1723161600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,8,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Adults with Down syndrome (DS) are at risk for Alzheimer\u2019s disease (AD). Recent natural history cohort studies have characterized AD biomarkers, with a focus on PET amyloid-beta (A\u03b2) and PET tau. Leveraging these well-characterized biomarkers, the present study examined the timeline to symptomatic AD based on estimated years since reaching A\u03b2+, referred to as \u201camyloid age\u201d, and in relation to tau in a large cohort of individuals with DS.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>In this multicenter cohort study, 25 \u2013 57-year-old adults with DS (n = 167) were assessed twice from 2017 to 2022, with approximately 32 months between visits as part of the Alzheimer Biomarker Consortium - Down Syndrome. Adults with DS completed amyloid and tau PET scans, and were administered the modified Cued Recall Test and the Down Syndrome Mental Status Examination. Study partners completed the National Task Group-Early Detection Screen for Dementia.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Findings<\/jats:title>\n                  <jats:p>Mixed linear regressions showed significant quadratic associations between amyloid age and cognitive performance and cubic associations between amyloid age and tau, both at baseline and across 32 months. Using broken stick regression models, differences in mCRT scores were detected beginning 2.7 years following A\u03b2+ in cross-sectional models, with an estimated decline of 1.3 points per year. Increases in tau began, on average, 2.7 \u2013 6.1 years following A\u03b2+. On average, participants with mild cognitive impairment were 7.4 years post A\u03b2+ and those with dementia were 12.7 years post A\u03b2+.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Interpretation<\/jats:title>\n                  <jats:p>\n                    There is a short timeline to initial cognitive decline and dementia from A\u03b2+ (Centiloid = 18) and tau deposition in DS relative to late onset AD. The established timeline based on amyloid age (or equivalent Centiloid values) is important for clinical practice and informing AD clinical trials, and avoids limitations of timelines based on chronological age.\n                    <jats:bold>Funding.<\/jats:bold>\n                    National Institute on Aging and the National Institute for Child Health and Human Development.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Research in Context<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Evidence before this study<\/jats:title>\n                    <jats:p>We searched PubMed for articles published involving the progression of A\u03b2 and tau deposition in adults with Down syndrome from database inception to March 1, 2024. Terms included \u201camyloid\u201d, \u201cDown syndrome\u201d, \u201ctau\u201d, \u201cAlzheimer\u2019s disease\u201d, \u201ccognitive decline\u201d, and \u201camyloid chronicity,\u201d with no language restrictions. One previous study outlined the progression of tau in adults with Down syndrome without consideration of cognitive decline or clinical status. Other studies reported cognitive decline associated with A\u03b2 burden and estimated years to AD symptom onset in Down syndrome. Amyloid age estimates have also been created for older neurotypical adults and compared to cognitive performance, but this has not been investigated in Down syndrome.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Added value of this study<\/jats:title>\n                    <jats:p>The timeline to symptomatic Alzheimer\u2019s disease in relation to amyloid, expressed as duration of A\u03b2+, and tau has yet to be described in adults with Down syndrome. Our longitudinal study is the first to provide a timeline of cognitive decline and transition to mild cognitive impairment and dementia in relation to A\u03b2+.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Implications of all the available evidence<\/jats:title>\n                    <jats:p>In a cohort study of 167 adults with Down syndrome, cognitive decline began 2.7 \u2013 5.4 years and tau deposition began 2.7 \u2013 6.1 years following A\u03b2+ (Centiloid = 18). Adults with Down syndrome converted to MCI after ~7 years and dementia after ~12-13 years of A\u03b2+. This shortened timeline to AD symptomology from A\u03b2+ and tau deposition in DS based on amyloid age (or corresponding Centiloid values) can inform clinical AD intervention trials and is of use in clinical settings.<\/jats:p>\n                  <\/jats:sec>\n                <\/jats:sec>","DOI":"10.1101\/2024.08.08.24311702","type":"posted-content","created":{"date-parts":[[2024,8,9]],"date-time":"2024-08-09T12:25:15Z","timestamp":1723206315000},"source":"Crossref","is-referenced-by-count":0,"title":["Amyloid age and tau PET timeline to symptomatic Alzheimer\u2019s disease in Down syndrome"],"prefix":"10.64898","author":[{"given":"Emily K.","family":"Schworer","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew D.","family":"Zammit","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiebiao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin L.","family":"Handen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tobey","family":"Betthauser","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles M.","family":"Laymon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dana L.","family":"Tudorascu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annie D.","family":"Cohen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shahid H.","family":"Zaman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beau M.","family":"Ances","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Mapstone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Head","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William E.","family":"Klunk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bradley T.","family":"Christian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sigan L.","family":"Hartley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"Alzheimer Biomarker Consortium \u2013 Down Syndrome (ABC-DS)","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024081209450566000_2024.08.08.24311702v1.1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2022.12910"},{"key":"2024081209450566000_2024.08.08.24311702v1.2","doi-asserted-by":"publisher","DOI":"10.1111\/jir.12390"},{"key":"2024081209450566000_2024.08.08.24311702v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-019-0143-7"},{"key":"2024081209450566000_2024.08.08.24311702v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3983"},{"key":"2024081209450566000_2024.08.08.24311702v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2015.05.013"},{"key":"2024081209450566000_2024.08.08.24311702v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.dadm.2017.05.001"},{"key":"2024081209450566000_2024.08.08.24311702v1.7","doi-asserted-by":"publisher","DOI":"10.1002\/dad2.12020"},{"key":"2024081209450566000_2024.08.08.24311702v1.8","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1202753"},{"key":"2024081209450566000_2024.08.08.24311702v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2015.07.490"},{"key":"2024081209450566000_2024.08.08.24311702v1.10","doi-asserted-by":"publisher","DOI":"10.1212\/wnl.0000000000200148"},{"key":"2024081209450566000_2024.08.08.24311702v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/0197-4580(95)00021-6"},{"key":"2024081209450566000_2024.08.08.24311702v1.12","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abc0655"},{"key":"2024081209450566000_2024.08.08.24311702v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.01.028"},{"key":"2024081209450566000_2024.08.08.24311702v1.14","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-022-00204-0"},{"issue":"1","key":"2024081209450566000_2024.08.08.24311702v1.15","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/S1474-4422(22)00408-2","article-title":"Comparison of amyloid burden in individuals with Down syndrome versus autosomal dominant Alzheimer\u2019s disease: a cross-sectional study","volume":"22","year":"2023","journal-title":"The Lancet Neurology"},{"key":"2024081209450566000_2024.08.08.24311702v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2021.117728"},{"key":"2024081209450566000_2024.08.08.24311702v1.17","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac213"},{"key":"2024081209450566000_2024.08.08.24311702v1.18","doi-asserted-by":"publisher","DOI":"10.1002\/dad2.12007"},{"key":"2024081209450566000_2024.08.08.24311702v1.19","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13444"},{"key":"2024081209450566000_2024.08.08.24311702v1.20","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awu173"},{"key":"2024081209450566000_2024.08.08.24311702v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30689-9"},{"key":"2024081209450566000_2024.08.08.24311702v1.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2017.05.019"},{"key":"2024081209450566000_2024.08.08.24311702v1.23","doi-asserted-by":"publisher","DOI":"10.1002\/dad2.12096"},{"key":"2024081209450566000_2024.08.08.24311702v1.24","doi-asserted-by":"publisher","DOI":"10.1002\/dad2.12256"},{"key":"2024081209450566000_2024.08.08.24311702v1.25","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13446"},{"key":"2024081209450566000_2024.08.08.24311702v1.26","doi-asserted-by":"publisher","DOI":"10.1002\/dad2.12065"},{"key":"2024081209450566000_2024.08.08.24311702v1.27","first-page":"193","article-title":"Neuropsychological evaluaton of adults with Down\u2019s syndrome: patterns of selective impairment in non-demented old adults","volume":"33","year":"1989","journal-title":"Journal of Mental Deficiency Research"},{"key":"2024081209450566000_2024.08.08.24311702v1.28","doi-asserted-by":"publisher","DOI":"10.1002\/dad2.12044"},{"key":"2024081209450566000_2024.08.08.24311702v1.29","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2788.2002.00417.x"},{"key":"2024081209450566000_2024.08.08.24311702v1.30","doi-asserted-by":"publisher","DOI":"10.1002\/dad2.12361"},{"key":"2024081209450566000_2024.08.08.24311702v1.31","doi-asserted-by":"crossref","unstructured":"Esralew L , Janicki MP , Keller SM . National Task Group Early Detection Screen for Dementia (NTG-EDSD). In: Prasher VP , ed. Neuropsychological Assessments of Dementia in Down Syndrome and Intellectual Disabilities. Springer International Publishing; 2018:197\u2013213.","DOI":"10.1007\/978-3-319-61720-6_11"},{"key":"2024081209450566000_2024.08.08.24311702v1.32","doi-asserted-by":"publisher","DOI":"10.1111\/jar.12849"},{"key":"2024081209450566000_2024.08.08.24311702v1.33","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.118.210518"},{"key":"2024081209450566000_2024.08.08.24311702v1.34","doi-asserted-by":"publisher","DOI":"10.31219\/osf.io\/fzqxv"},{"key":"2024081209450566000_2024.08.08.24311702v1.35","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.571"},{"key":"2024081209450566000_2024.08.08.24311702v1.36","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-022-01064-x"},{"key":"2024081209450566000_2024.08.08.24311702v1.37","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.23827"},{"key":"2024081209450566000_2024.08.08.24311702v1.38","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2021.1893"},{"key":"2024081209450566000_2024.08.08.24311702v1.39","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(21)00245-3"},{"issue":"11","key":"2024081209450566000_2024.08.08.24311702v1.40","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1002\/gps.2039","article-title":"Significant effect of APOE epsilon 4 genotype on the risk of dementia in Alzheimer\u2019s disease and mortality in persons with Down syndrome","volume":"23","year":"2008","journal-title":"International Journal of Geriatric Psychiatry: A journal of the psychiatry of late life and allied sciences"},{"key":"2024081209450566000_2024.08.08.24311702v1.41","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3182918ca6"},{"key":"2024081209450566000_2024.08.08.24311702v1.42","doi-asserted-by":"publisher","DOI":"10.1002\/dad2.12360"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.08.08.24311702","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:09:00Z","timestamp":1768507740000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2024.08.08.24311702"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,9]]},"references-count":42,"URL":"https:\/\/doi.org\/10.1101\/2024.08.08.24311702","relation":{},"subject":[],"published":{"date-parts":[[2024,8,9]]},"subtype":"preprint"}}