TMEM106B haplotypes show distinct associations with tau and TDP-43 pathologies in the aging brain

A central challenge in post-GWAS biology is determining how inherited variation within disease-associated loci shapes molecular mechanisms and clinical phenotypes. Here, we examined four previously identified TMEM106B haplotypes (T1-T4), defined by distinct combinations of coding, structural and regulatory variants. We integrated transcriptomic, proteomic, and neuropathological data from 1,209 individuals across two independent complementary ageing cohorts. Although T2 and T3 both carry the p.Ser185 coding variant, they showed opposing associations with tau pathology, indicating that the surrounding haplotypic background modifies disease susceptibility. T3, which is enriched in cognitively healthy centenarians, was associated with lower tau pathology, lower C-terminal TMEM106B abundance, and reduced detection of an inflammatory microglial state, differing from the association pattern observed for T2. By contrast, T1 was associated with more extensive TDP-43 pathology, neuronal endolysosomal dysregulation, and increased C-terminal TMEM106B abundance. These findings identify haplotype-specific associations with differential proteinopathy burden, illustrating how haplotype-resolved analyses can connect GWAS signals to candidate molecular pathways.