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

Background: Limbic white matter (WM) abnormalities are prevalent in aging and Alzheimer's disease (AD), yet their underlying biological mechanisms remain unclear. This study aims to identify the genetic architecture of limbic WM microstructure in older adults by leveraging harmonized data from multiple cohorts, including those enriched for cognitively impaired individuals.

Methods: We analyzed diffusion MRI (dMRI) data from 2,614 non-Hispanic White older adults (mean age = 73.7 ± 9.8 years; 57% female; 26% cognitively impaired) across 7 harmonized aging cohorts. WM microstructure was assessed in 7 limbic tracts, including the cingulum, fornix, inferior longitudinal fasciculus (ILF), uncinate fasciculus (UF), and transcallosal tracts of the inferior, middle, and superior temporal gyri (ITG, MTG, STG) using advanced diffusion MRI metrics corrected for free-water (FW): fractional anisotropy (FA ), axial diffusivity (AxD ), mean diffusivity (MD ), radial diffusivity (RD ). We performed heritability estimations, genome-wide association studies (GWAS) and post-GWAS analyses (genetic covariance, gene-level and pathway analysis, transcriptome-wide association [TWAS] studies). The AD relevance of the discovered variants was explored using bulk RNA-seq data from caudate, dorsolateral prefrontal, and posterior cingulate cortex human brain tissues.

Results: Limbic WM microstructure demonstrated significant heritability (estimates between 0.26 and 0.60, < 0.05 for 15 of 35 tract-by-microstructure combinations). GWAS identified 6 genome-wide significant loci ( < 5.0×10 ) associated with WM microstructure. Notably, for MTG RD , we identified a locus on chromosome 18 (lead SNP: rs12959877) comprising 38 SNPs that are eQTLs for , a gene involved in cell adhesion and highly expressed in oligodendrocytes. Other significant associations involved SNPs near , and . Bulk RNA-seq analyses revealed that brain tissue expression of , and was significantly associated with cognitive decline and several AD pathologies ( < 0.05). Post-GWAS analyses identified the genes and , and highlighted the involvement of insulin signaling, immune response, and neurotrophic pathways. Genetic covariance analyses indicated shared genetic architecture between limbic WM and lipid profiles (e.g., HDL cholesterol), cardiovascular traits, and neurological conditions (e.g., multiple sclerosis) ( < 0.05).

Conclusion: This multi-cohort imaging genetics study identified several novel genes and biological pathways associated with limbic WM microstructure in an aging population enriched for cognitive impairment. The association of several identified genes with cognitive decline and AD pathology underscores their AD relevance. Our findings further suggest that the genetic underpinnings of limbic WM microstructure are linked to vascular health and inflammation, highlighting these pathways as promising avenues for future AD-related therapeutic development.