Genetic architecture of plasma pTau217 and related biomarkers in Alzheimer's disease via genome-wide association studies.

INTRODUCTION

We aimed to define the genetic architecture and regulatory mechanisms of Alzheimer's disease (AD) -related plasma biomarkers in an East Asian population.

METHODS

Genome-wide association studies (GWAS) of plasma phosphorylated tau at threonine 217 (pTau217), pTau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were performed in 1,972 individuals from the Korea-Registries to Overcome and Accelerate Dementia Research (K-ROAD) cohort. Results were integrated with Korean single-nucleus transcriptomics, AD-relevant brain quantitative trait loci resources, and summary-based Mendelian randomization (SMR) and colocalization analyses.

RESULTS

Genome-wide significant loci were identified for all biomarkers, including DACT1-DAAM1 (pTau217), KCNJ3 (pTau181), KLHDC4 (NfL), SLC10A7 (GFAP), and PPP4R2 (composite score). Strong associations at the apolipoprotein E locus were observed across biomarkers. Integrative analyses implicated DACT1 as a key regulatory mediator of pTau217, particularly in oligodendrocytes.

DISCUSSION: These findings link ancestry-relevant AD biomarker genetics to brain regulatory mechanisms and support integrative causal analyses.