Genetic architecture of the limbic white matter microstructure in aging and Alzheimer's Disease

INTRODUCTION: Limbic white matter (WM) abnormalities are prevalent in aging and Alzheimer's disease (AD), but genetic drivers are unclear. METHODS: In 2614 older adults (mean age ± SD: 73.7 ± 9.8 years; 26% cognitively impaired) from seven harmonized cohorts enriched for cognitive impairment, we quantified free-water-corrected diffusion MRI (dMRI) metrics in seven limbic tracts. We estimated single nucleotide polymorphism (SNP) heritability, performed cohort genome-wide association studies (GWASs) with meta-analysis, evaluated shared genetic architecture and enriched pathways, and assessed AD relevance using brain RNA-seq data. RESULTS: Limbic WM is heritable (h² = 0.26-0.60; pFDR < 0.05). Meta-GWAS identified six loci (p < 5 × 10⁻ ⁸), including a signal implicating CDH19, an oligodendrocyte-enriched cell-adhesion gene. Additional loci were near the KC6, SENP5, RORA, FAM107B, and MIR548A1 genes. In brain tissue, RORA, FAM107B, and KC6 expression was associated with cognition and AD neuropathology. Results converged on insulin and immune biology and shared genetic architecture with lipid and cardiovascular traits. DISCUSSION: Limbic WM microstructure is genetically influenced and links oligodendrocyte and vascular-inflammatory biology to AD-relevant outcomes.