Abstract
INTRODUCTION: Plasma biomarkers in Down syndrome (DS) accurately detect Alzheimer's disease (AD) pathology. This study aimed to identify genetic loci associated with plasma tau biomarkers (phosphorylated tau [p-tau]181, p-tau217, total tau [t-tau]) and tau positron emission tomography (PET) in DS. METHODS: We examined 375 people with DS from the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) with data on all four tau biomarkers, and 133 subjects from another study of DS with plasma t-tau. Single-trait and multi-trait genetic association analyses were conducted. AD polygenic risk scores (PRSs) were tested with tau biomarkers. RESULTS: Three genome-wide significant associations were identified for p-tau181: TUBAP/rs76523946, P = 2.21E-08; CTNND2/rs142510573, P = 3.04E-08; CLSTN2/rs112448655, P = 3.04E-08, and one for t-tau (JHY/rs77264104, P = 2.84E-08). AD PRS was associated with higher concentrations of tau PET (β = 0.30, P = 6.57E-04), p-tau217 (β = 0.11, P = 4.10E-02), and t-tau (β = 0.12, P = 3.60E-02). DISCUSSION: These data indicate the presence of novel genetic loci in DS affecting plasma tau biomarkers and that AD risk PRS may modify tau neuroimaging and plasma biomarkers in DS. HIGHLIGHTS: Four loci were linked to plasma total tau (t-tau) or phosphorylated tau (p-tau)181 with genome-wide significance. JHY/rs77264104 stays genome-wide significant for plasma t-tau in a meta genome-wide association study (GWAS). Alzheimer's disease (AD) polygenic risk score is associated with tau positron emission tomography (PET), regardless of apolipoprotein E genotype and region. Tau-PET genes in Down syndrome (DS) are enriched in the cerebrospinal fluid phosphorylated tau Alzheimer's disease dementia GWAS catalog. T-tau genes in DS are enriched in a verbal memory GWAS catalog within a mild cognitive impairment cohort.