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abnormalities are prevalent in aging and Alzheimer's disease (AD), but genetic drivers are unclear.<\/jats:p>\n <\/jats:sec>\n \n METHODS<\/jats:title>\n In 2614 older adults (mean age \u00b1 SD: 73.7 \u00b1 9.8 years; 26% cognitively impaired) from seven harmonized cohorts enriched for cognitive impairment, we quantified free\u2010water\u2013corrected diffusion MRI (dMRI) metrics in seven limbic tracts. We estimated single nucleotide polymorphism (SNP) heritability, performed cohort genome\u2010wide association studies (GWASs) with meta\u2010analysis, evaluated shared genetic architecture and enriched pathways, and assessed AD relevance using brain RNA\u2010seq data.<\/jats:p>\n <\/jats:sec>\n \n RESULTS<\/jats:title>\n \n Limbic WM is heritable (\n \n h\n 2<\/jats:sup>\n <\/jats:italic>\n = 0.26\u20130.60;\n \n p\n FDR<\/jats:sub>\n <\/jats:italic>\n < 0.05). Meta\u2010GWAS identified six loci (\n p<\/jats:italic>\n < 5 \u00d7 10\n \u2212<\/jats:sup>\n 8<\/jats:sup>\n ), including a signal implicating\n CDH19<\/jats:italic>\n , an oligodendrocyte\u2010enriched cell\u2010adhesion gene. Additional loci were near the\n KC6<\/jats:italic>\n ,\n SENP5<\/jats:italic>\n ,\n RORA<\/jats:italic>\n ,\n FAM107B<\/jats:italic>\n , and\n MIR548A1<\/jats:italic>\n genes. In brain tissue,\n RORA<\/jats:italic>\n ,\n FAM107B<\/jats:italic>\n , and\n KC6<\/jats:italic>\n expression was associated with cognition and AD neuropathology. Results converged on insulin and immune biology and shared genetic architecture with lipid and cardiovascular traits.\n <\/jats:p>\n <\/jats:sec>\n \n DISCUSSION<\/jats:title>\n Limbic WM microstructure is genetically influenced and links oligodendrocyte and vascular\u2010inflammatory biology to AD\u2010relevant outcomes.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/alz.71630","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T04:32:26Z","timestamp":1783398746000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic architecture of the limbic white matter microstructure in aging and Alzheimer's Disease"],"prefix":"10.1002","volume":"22","author":[{"given":"Anna S","family":"Lorenz","sequence":"first","affiliation":[{"name":"Vanderbilt Memory and Alzheimer's Center Vanderbilt University School of Medicine Nashville Tennessee USA"},{"name":"Vanderbilt Genetics Institute Vanderbilt 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