rs3173615

This longitudinal association study examined TMEM106B rs1990622 genotype effects on cognitive decline in 870 subjects with Parkinson's disease (N=179), frontotemporal dementia (N=179), Alzheimer's disease (N=300), mild cognitive impairment (N=75), and controls (N=137), plus 371 subjects from the international PPMI cohort. The rs1990622 T allele associated with more rapid cognitive decline in PD (β=0.123, p=0.019 for MMSE; β=0.463-0.776, p≤0.005 for DRS-2), and findings were replicated in the PPMI validation cohort (β=0.059-0.098, p≤0.038 for MoCA). In FTD, effects were less consistent and genetic model-dependent. No significant associations were observed in AD or MCI subjects.

This neuropathological study of 244 non-FTLD brains with TDP-43 pathology identified two distinct types based on inclusion morphology and neuronal context. TDP typeα (n=131) showed widespread TDP-43 deposition, higher prevalence of hippocampal sclerosis (60% vs 15%, p<0.001), and significant atrophy in amygdala (-10.6%, p=0.003) and hippocampus (-14.4%, p<0.001) compared to typeβ. Genetic analysis showed differences in TMEM106B haplotypes (rs3173615, p=0.01), with protective GG haplotype enriched in typeβ (24% vs 8%), supporting biological distinction between TDP-43 types.

This association study of 325 C9ORF72 expansion carriers and 586 FTD patients assessed TMEM106B variants rs3173615 and rs1990622 as genetic modifiers of frontotemporal dementia (FTD). Homozygosity for the minor rs3173615 allele was significantly protective in C9ORF72 carriers with FTD (OR=0.33, p=0.009) but not MND. In FTLD-TDP patients without C9ORF72 or GRN mutations, the minor allele showed strong protection (OR=0.26, p<0.001), indicating TMEM106B variants modify disease penetrance across multiple FTLD-TDP forms.

This study found that rs1990622 in TMEM106B is associated with a 13-year earlier age of disease onset in GRN mutation carriers (p=9.9×10⁻⁷) and with lower plasma granulin levels in both healthy individuals (p=4×10⁻⁴) and mutation carriers (p=0.0027). A non-synonymous SNP rs3173615 (Thr185Ser) was identified in perfect linkage disequilibrium with rs1990622, suggesting TMEM106B may modulate granulin protein levels and modify age of onset in frontotemporal dementia.