Background:

Adults with Down syndrome (DS) are at risk for Alzheimer's disease (AD). Recent natural history cohort studies have characterized AD biomarkers, with a focus on PET amyloid-beta (Aß) and PET tau. Leveraging these well-characterized biomarkers, the present study examined the timeline to symptomatic AD based on estimated years since reaching Aß+, referred to as "amyloid age", and in relation to tau in a large cohort of individuals with DS.

Methods:

In this multicenter cohort study, 25 - 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.

Findings:

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 Aß+ in cross-sectional models, with an estimated decline of 1.3 points per year. Increases in tau began, on average, 2.7 - 6.1 years following Aß+. On average, participants with mild cognitive impairment were 7.4 years post Aß+ and those with dementia were 12.7 years post Aß+.

Interpretation:

There is a short timeline to initial cognitive decline and dementia from Aß+ (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. Funding. National Institute on Aging and the National Institute for Child Health and Human Development. Research in Context Evidence before this study We searched PubMed for articles published involving the progression of Aß and tau deposition in adults with Down syndrome from database inception to March 1, 2024. Terms included "amyloid", "Down syndrome", "tau", "Alzheimer's disease", "cognitive decline", and "amyloid chronicity," 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 Aß 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.Added value of this study The timeline to symptomatic Alzheimer's disease in relation to amyloid, expressed as duration of Aß+, 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 Aß+.Implications of all the available evidence In a cohort study of 167 adults with Down syndrome, cognitive decline began 2.7 - 5.4 years and tau deposition began 2.7 - 6.1 years following Aß+ (Centiloid = 18). Adults with Down syndrome converted to MCI after ~7 years and dementia after ~12-13 years of Aß+. This shortened timeline to AD symptomology from Aß+ 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.