Genome-wide association of tau neuroimaging and plasma biomarkers in adults with Down syndrome.

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.