TY - JOUR
T1 - The effect of Alzheimer's disease genetic factors on limbic white matter microstructure
AU - Alzheimer's Disease Neuroimaging Initiative (ADNI)The BIOCARD Study TeamThe Alzheimer's Disease Sequencing Project (ADSP)
AU - Lorenz, Anna
AU - Sathe, Aditi
AU - Zaras, Dimitrios
AU - Yang, Yisu
AU - Durant, Alaina
AU - Kim, Michael E.
AU - Gao, Chenyu
AU - Newlin, Nancy R.
AU - Ramadass, Karthik
AU - Kanakaraj, Praitayini
AU - Khairi, Nazirah Mohd
AU - Li, Zhiyuan
AU - Yao, Tianyuan
AU - Huo, Yuankai
AU - Dumitrescu, Logan
AU - Shashikumar, Niranjana
AU - Pechman, Kimberly R.
AU - Jackson, Trevor Bryan
AU - Workmeister, Abigail W.
AU - Risacher, Shannon L.
AU - Beason-Held, Lori L.
AU - An, Yang
AU - Arfanakis, Konstantinos
AU - Erus, Guray
AU - Davatzikos, Christos
AU - Habes, Mohamad
AU - Wang, Di
AU - Tosun, Duygu
AU - Toga, Arthur W.
AU - Thompson, Paul M.
AU - Mormino, Elizabeth C.
AU - Zhang, Panpan
AU - Schilling, Kurt
AU - Albert, Marilyn
AU - Kukull, Walter
AU - Biber, Sarah A.
AU - Landman, Bennett A.
AU - Johnson, Sterling C.
AU - Bendlin, Barbara
AU - Schneider, Julie
AU - Barnes, Lisa L.
AU - Bennett, David A.
AU - Jefferson, Angela L.
AU - Resnick, Susan M.
AU - Saykin, Andrew J.
AU - Hohman, Timothy J.
AU - Archer, Derek B.
N1 - Publisher Copyright:
© 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
PY - 2025/4
Y1 - 2025/4
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - diffusion MRI
KW - free water
KW - genetic risk variants
KW - polygenic risk
KW - white matter microstructure
UR - https://www.scopus.com/pages/publications/105002714037
U2 - 10.1002/alz.70130
DO - 10.1002/alz.70130
M3 - Article
C2 - 40219815
AN - SCOPUS:105002714037
SN - 1552-5260
VL - 21
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 4
M1 - e70130
ER -