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Diffusion MRI, enhanced by advanced bi\u2010tensor models accounting for free water (FW), enables in vivo quantification of WM microstructural differences.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>To evaluate how AD genetic risk factors affect limbic WM microstructure \u2013 crucial for memory and early impacted in disease \u2013 we conducted linear regression analyses in a cohort of 2,614 non\u2010Hispanic White aging adults (aged 50.12 to 100.85 years). The study evaluated 36 AD risk variants across 26 genes, the association between AD polygenic scores (PGSs) and WM metrics, and interactions with cognitive status.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>AD PGSs, variants in <jats:italic>TMEM106B<\/jats:italic>, <jats:italic>PTK2B<\/jats:italic>, <jats:italic>WNT3<\/jats:italic>, and apolipoprotein E (<jats:italic>APOE<\/jats:italic>), and interactions involving <jats:italic>MS4A6A<\/jats:italic> were significantly linked to WM microstructure.<\/jats:p><\/jats:sec><jats:sec><jats:title>DISCUSSION<\/jats:title><jats:p>These findings implicate AD\u2010related genetic factors related to neurodevelopment (<jats:italic>WNT3<\/jats:italic>), lipid metabolism (<jats:italic>APOE<\/jats:italic>), and inflammation (<jats:italic>TMEM106B<\/jats:italic>, <jats:italic>PTK2B, MS4A6A<\/jats:italic>) that contribute to alternations in WM microstructure in older adults.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>AD risk variants in <jats:italic>TMEM106B<\/jats:italic>, <jats:italic>PTK2B<\/jats:italic>, <jats:italic>WNT3<\/jats:italic>, and <jats:italic>APOE<\/jats:italic> genes showed distinct associations with limbic FW\u2010corrected WM microstructure metrics.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Interaction effects were observed between <jats:italic>MS4A6A<\/jats:italic> variants and cognitive status.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>PGS for AD was associated with higher FW content in the limbic 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