Timeline to symptomatic Alzheimer's disease in people with Down syndrome as assessed by amyloid-PET and tau-PET: a longitudinal cohort study.

backgroundAdults with Down syndrome are at risk for Alzheimer's disease. Natural history cohort studies have characterised the progression of Alzheimer's disease biomarkers in people with Down syndrome, with a focus on amyloid β-PET and tau-PET. In this study, we aimed to leverage these well characterised imaging biomarkers in a large cohort of individuals with Down syndrome, to examine the timeline to symptomatic Alzheimer's disease based on estimated years since the detection on PET of amyloid β-positivity, referred to here as amyloid age, and in relation to tau burden as assessed by PET.

methodsIn this prospective, longitudinal, observational cohort study, data were collected at four university research sites in the UK and USA as part of the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study. Eligible participants were aged 25 years or older with Down syndrome, had a mental age of at least 3 years (based on a standardised intelligence quotient test), and had trisomy 21 (full, mosaic, or translocation) confirmed through karyotyping. Participants were assessed twice between 2017 and 2022, with approximately 32 months between visits. Participants had amyloid-PET and tau-PET scans, and underwent cognitive assessment with the modified Cued Recall Test (mCRT) and the Down Syndrome Mental Status Examination (DSMSE) to assess cognitive functioning. Study partners completed the National Task Group-Early Detection Screen for Dementia (NTG-EDSD). Generalised linear models were used to assess the association between amyloid age (whereby 0 years equated to 18 centiloids) and mCRT, DSMSE, NTG-EDSD, and tau PET at baseline and the 32-month follow-up. Broken stick regression was used to identify the amyloid age that corresponded to decreases in cognitive performance and increases in tau PET after the onset of amyloid β positivity.

findings167 adults with Down syndrome, of whom 92 had longitudinal data, were included in our analyses. Generalised linear regressions showed significant quadratic associations between amyloid age and cognitive performance and cubic associations between amyloid age and tau, both at baseline and at the 32-month follow-up. Using broken stick regression models, differences in mCRT total scores were detected beginning 2·7 years (95% credible interval [CrI] 0·2 to 5·4; equating to 29·8 centiloids) after the onset of amyloid β positivity in cross-sectional models. Based on cross-sectional data, increases in tau deposition started a mean of 2·7-6·1 years (equating to 29·8-47·9 centiloids) after the onset of amyloid β positivity. Mild cognitive impairment was observed at a mean amyloid age of 7·4 years (SD 6·6; equating to 56·8 centiloids) and dementia was observed at a mean amyloid age of 12·7 years (5·6; equating to 97·4 centiloids).

interpretationThere is a short timeline to initial cognitive decline and dementia from onset of amyloid β positivity and tau deposition in people with Down syndrome. This newly established timeline based on amyloid age (or equivalent centiloid values) is important for clinical practice and informing the design of Alzheimer's disease clinical trials, and it avoids the limitations of timelines based on chronological age.

fundingNational Institute on Aging and the National Institute for Child Health and Human Development.