A TMEM106B LOCUS IS IMPLICATED IN COGNITIVE DECLINE IN ALZHEIMER’S DISEASE

Abstract

TDP-43 (transactive response DNA-binding protein 43kDa) proteinopathy is closely associated with Alzheimer's disease (AD), and affects clinical outcome in AD. TMEM106B rs1990622Ais a risk allele for TDP-43 proteinopathy, and its implications in clinical presentations of AD remains to be elucidated. Our subjects are from Religious Orders Study and the Rush Memory and Aging Project (ROS-MAP), two community-based longitudinal cohort studies of older adults. Our analyses included 841 subjects with genotyping, cognitive, and pathology data (beta-amyloid, paired helical filament tau, and TDP-43 stage). Cognitive decline was defined as the slope of change in composite cognitive z-score in a general linear mixed model, controlling for age at enrollment, sex, and education. The imputed dosage of TMEM106B rs1990622A was tested for its association with cognitive decline after adjusting for AD pathology. Then, TDP-43 was included in the model, and a subsequent mediation analysis (quasi-Bayesian Monte Carlo method with 10,000 simulations) was done to evaluate whether the TMEM106Bvariant's effect was mediated by TDP-43 proteinopathy. Of note, all analyses were adjusted for study cohort (ROS vs MAP), genotyping platform, and first three principal components from the genotype covariance matrix. TMEM106B rs1990622A was associated with more rapid cognitive decline when controlled for the AD pathology (EE=-0.0098, 95% confidence interval (CI) -0.018 to -0.0016, p=0.020). When TDP-43 stage was also controlled, the association of rs1990622A with cognitive decline loses statistical significance (p=0.078). A mediation analysis shows that about 15% of the association between rs1990622A and more rapid cognitive decline is mediated by more advanced TDP-43 stages (average causal mediation effect p<0.0001). TMEM106B rs1990622A, a known TDP-43 proteinopathy risk variant, is associated with more rapid cognitive decline in people with similar degree of AD pathology, and this association is mediated by more advanced TDP-43 stages. Nonetheless, the association of rs1990622A with more rapid cognitive decline in AD is only partially explained by the link between rs1990622A and more advanced TDP-43 stages.