Tau pathway‐based gene analysis in the Alzheimer’s disease continuum identifies CLU and FYN associated with tau deposition on PET in a Korean Cohort

Abstract

AbstractBackgroundAbnormal tau protein aggregation and spreading in the brain is closely linked to cognitive impairment and neurodegeneration in Alzheimer’s disease (AD). The role of genetic variation in brain tau aggregation has not been fully elucidated. Here, we performed pathway‐based candidate gene association analysis to identify novel genes associated with brain tau deposition on PET in a well‐characterized Korean AD continuum Cohort.MethodWe analyzed data for 145 older adults (69 cognitively normal (CN), 38 mild cognitive impairment (MCI), and 38 AD) from the Korean Brain Aging Study for the Early Diagnosis and Prediction of AD (KBASE). We selected 15 candidate genes related to both tau pathways and AD, curated from existing pathway databases, literature mining, and genome‐wide association study findings. We performed gene‐based association analysis of tau deposition measured by 18F‐AV‐1451 PET scans using PLINK. In addition, we performed whole brain voxel‐wise association analysis of identified single nucleotide polymorphisms (SNPs) to investigate their topographic distributions of differences in tau deposition across the whole brain using SPM12. We examined the interaction of the identified SNPs with APOE ε4 carrier status.ResultGene‐based analysis identified CLU and FYN as significantly associated with tau deposition after adjusting for multiple testing. The most significant signals originated from rs149413552 in CLU and rs57650567 in FYN. A voxel‐wise analysis for the two SNPs showed that individuals carrying at least one minor allele demonstrated greater tau throughout the temporal, parietal, and frontal lobes than individuals having no minor alleles (Fig. 1). The two SNPs were associated with greater cortical atrophy of AD‐signature regions and worse global cognition. rs149413552 in CLU was also associated with longitudinal decline in global cognition and immediate verbal memory over two years. APOE ε4 and the two SNPs appeared to exert additive effects on tau levels (Fig. 2). An interaction between rs57650567 in FYN and APOE ε4 carrier status was observed (Fig. 2)Conclusion CLU and FYN may play a specific role in tau pathophysiology. These risk genes may prove useful for biomarker and therapeutic development. Larger and multiethnic studies are needed to confirm these findings and to determine generalizability across populations.