Madison M Reeves, Anna Calliari, Tiffany W Todd, Candela Maroto Cidfuentes, Karen Jansen-West, Mei Yue, Yuping Song, Judith Dunmore, Bailey Rawlinson, Erica Engelberg-Cook, Michael DeTure, Gregory S Day, Neill R Graff-Radford, Bradley F Boeve, David S Knopman, Ronald C Petersen, Casey N Cook, Melissa E Murray, Dennis W Dickson, Keith A Josephs, Leonard Petrucelli, Mercedes Prudencio
The TMEM106B risk variant was significantly enriched in AD cases with transactive response DNA-binding protein 43 kDa (TDP-43) pathology - associating with increased odds of developing AD TDP-43 subtype α - but failed to associate with Lewy body or vascular pathology. In contrast, APOE ε4 associated with increased risk for multiple co-pathologies in AD.
INTRODUCTION: Co-pathologies - including Lewy body, vascular, and TDP-43 lesions - are common in Alzheimer's disease (AD), contributing to its clinical and pathological heterogeneity. Genetic risk factors may drive mixed pathology presentation, but their influence on the development of specific co-pathologies remains unclear.
METHODS: We evaluated the TMEM106B coding variant rs3173615 and apolipoprotein E (APOE) diplotype (rs429358, rs7412) in post mortem brains from 2604 individuals with a primary neuropathologic diagnosis of AD. Binary logistic regression models linked each genetic modifier with co-pathology risk.
RESULTS: The TMEM106B risk variant was significantly enriched in AD cases with transactive response DNA-binding protein 43 kDa (TDP-43) pathology - associating with increased odds of developing AD TDP-43 subtype α - but failed to associate with Lewy body or vascular pathology. In contrast, APOE ε4 associated with increased risk for multiple co-pathologies in AD.
DISCUSSION: We find that genetic factors individually influence AD pathological heterogeneity: TMEM106B selectively modulates TDP-43 co-pathology, while APOE ε4 appears broadly permissive to co-pathology development.