•~250,000 individuals in the U.S. have Down syndrome (DS) have genetically driven early-onset Alzheimer’s disease (AD), with dementia onset averaging ~55 years. AD is the leading cause of death in adults with DS over age 35 1,2.

•Amyloid accumulation begins early (often in the 30s) with PET positivity typically in the early 40s, followed by a ~15–20 year preclinical window before dementia, during which anti-amyloid therapies could potentially delay cognitive decline 3.

•Despite this, individuals with DS have been excluded from anti-amyloid therapy (AAT) trials, due to concerns about increased cerebral amyloid angiopathy (CAA) and microhemorrhages (mHs), raising risk for amyloid-related imaging abnormalities (ARIA) 4,5.

•DS patients show increasing cerebrovascular changes (mHs, WMH, enlarged perivascular spaces) from their late 30s, often independent of traditional risk factors; although mHs correlate with age and APOE4 (not amyloid/tau), autopsy data show high CAA prevalence, suggesting elevated ARIA risk, but longitudinal mH burden and safe inclusion thresholds (e.g., ≤1 mH in ALADDIN trial) remain poorly studied 6,7

•Participants included in this analysis were enrolled in ABC-DS and/or TRC-DS, had a karyotype-confirmed trisomy 21, brain MRI with T2* GRE for mH assessment and FLAIR for white matter hyperintensity (WMH) burden quantification, and amyloid PET in a subset of participants.

•Amyloid PET imaging and MRI of the brain from baseline visit were used to quantify definite mH by a radiologist with automated quantification of WMH normalized to total intracranial volume (TIV). 

•We estimated the proportion of participants who were amyloid-positive (centiloid value > 18), who had ≤1 mH on MRI, and had low burden of WMH (WMH/TIV<1.15%). 

•We evaluated 303 participants (age 38.2 ± 8.4 years, 41.3% women. Nine participants (3.0%) had one mH, 11 (3.6%) had 2-4 mH, and seven participants (2.3%) had >4 mH.

•In a subset of 133 participants with amyloid PET,  31 (23.3%) of them were amyloid-positive. Of 114 participants with complete multimodal imaging, 25 participants were amyloid PET positive and 20 of them (80%) would be eligible for anti-amyloid therapies by radiographic criteria.

•In  88 participants with cognitive status available, there were no participants with a clinical diagnosis of dementia, with 14 of 18 (77.8%) amyloid PET positive individuals eligible for asymptomatic and early symptomatic intervention trials.

•Most adults with Down syndrome who are amyloid-positive meet baseline radiographic eligibility for anti-amyloid trials, with low rates of exclusion markers like microhemorrhages (mH).

•Microhemorrhage burden was generally low, even among amyloid-positive individuals, suggesting a potential window in midlife for trial eligibility before cerebrovascular changes increase. However, ARIA risk, treatment safety, and efficacy were not assessed.

•Limitations include young cohort bias able to participate in observational studies. Further studies are needed to evaluate safety, scalability, and inclusion of more symptomatic individuals.