Anna Lorenz, Aditi Sathe, Dimitrios Zaras, Yisu Yang, Alaina Durant, Michael E. Kim, Chenyu Gao, Nancy R. Newlin, Karthik Ramadass, Praitayini Kanakaraj, Nazirah Mohd Khairi, Zhiyuan Li, Tianyuan Yao, Yuankai Huo, Logan Dumitrescu, Niranjana Shashikumar, Kimberly R. Pechman, Trevor Bryan Jackson, Abigail W. Workmeister, Shannon L. Risacher, Lori L. Beason-Held, Yang An, Konstantinos Arfanakis, Guray Erus, Christos Davatzikos, Mohamad Habes, Di Wang, Duygu Tosun, Arthur W. Toga, Paul M. Thompson, Elizabeth C. Mormino, Panpan Zhang, Kurt Schilling, Alzheimer's Disease Neuroimaging Initiative (ADNI)The BIOCARD Study TeamThe Alzheimer's Disease Sequencing Project (ADSP), Marilyn Albert, Walter Kukull, Sarah A. Biber, Bennett A. Landman, Sterling C. Johnson, Barbara Bendlin, Julie Schneider, Lisa L. Barnes, David A. Bennett, Angela L. Jefferson, Susan M. Resnick, Andrew J. Saykin, Timothy J. Hohman, Derek B. Archer
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Archer","doi":"10.1002/alz.70130","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> INTRODUCTION</h3>\n \n <p>White matter (WM) microstructure is essential for brain function but deteriorates with age and in neurodegenerative conditions such as Alzheimer's disease (AD). Diffusion MRI, enhanced by advanced bi-tensor models accounting for free water (FW), enables in vivo quantification of WM microstructural differences.</p>\n </section>\n \n <section>\n \n <h3> METHODS</h3>\n \n <p>To evaluate how AD genetic risk factors affect limbic WM microstructure – crucial for memory and early impacted in disease – we conducted linear regression analyses in a cohort of 2,614 non-Hispanic 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.</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p>AD PGSs, variants in <i>TMEM106B</i>, <i>PTK2B</i>, <i>WNT3</i>, and apolipoprotein E (<i>APOE</i>), and interactions involving <i>MS4A6A</i> were significantly linked to WM microstructure.</p>\n </section>\n \n <section>\n \n <h3> DISCUSSION</h3>\n \n <p>These findings implicate AD-related genetic factors related to neurodevelopment (<i>WNT3</i>), lipid metabolism (<i>APOE</i>), and inflammation (<i>TMEM106B</i>, <i>PTK2B, MS4A6A</i>) that contribute to alternations in WM microstructure in older adults.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li>AD risk variants in <i>TMEM106B</i>, <i>PTK2B</i>, <i>WNT3</i>, and <i>APOE</i> genes showed distinct associations with limbic FW-corrected WM microstructure metrics.</li>\n \n <li>Interaction effects were observed between <i>MS4A6A</i> variants and cognitive status.</li>\n \n <li>PGS for AD was associated with higher FW content in the limbic system.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 4","pages":""},"PeriodicalIF":13.0000,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70130","citationCount":"0","resultStr":"{\"title\":\"The effect of Alzheimer's disease genetic factors on limbic white matter microstructure\",\"authors\":\"Anna Lorenz, Aditi Sathe, Dimitrios Zaras, Yisu Yang, Alaina Durant, Michael E. 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The effect of Alzheimer's disease genetic factors on limbic white matter microstructure
INTRODUCTION
White matter (WM) microstructure is essential for brain function but deteriorates with age and in neurodegenerative conditions such as Alzheimer's disease (AD). Diffusion MRI, enhanced by advanced bi-tensor models accounting for free water (FW), enables in vivo quantification of WM microstructural differences.
METHODS
To evaluate how AD genetic risk factors affect limbic WM microstructure – crucial for memory and early impacted in disease – we conducted linear regression analyses in a cohort of 2,614 non-Hispanic 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.
RESULTS
AD PGSs, variants in TMEM106B, PTK2B, WNT3, and apolipoprotein E (APOE), and interactions involving MS4A6A were significantly linked to WM microstructure.
DISCUSSION
These findings implicate AD-related genetic factors related to neurodevelopment (WNT3), lipid metabolism (APOE), and inflammation (TMEM106B, PTK2B, MS4A6A) that contribute to alternations in WM microstructure in older adults.
Highlights
AD risk variants in TMEM106B, PTK2B, WNT3, and APOE genes showed distinct associations with limbic FW-corrected WM microstructure metrics.
Interaction effects were observed between MS4A6A variants and cognitive status.
PGS for AD was associated with higher FW content in the limbic system.
期刊介绍：
Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.
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