TMEM106B is a selective modulator of TDP-43 pathology in Alzheimer's disease

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.

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.

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.

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.