Gene-Specific Effects on Brain Volume and Cognition of TMEM106B in Frontotemporal Lobar Degeneration

has been proposed as a modifier of disease risk in FTLD-TDP, particularly in pathogenic variant carriers. Furthermore, has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study was to evaluate and compare the effect of on gray matter volume and cognition in each of the common genetic FTD groups and in patients with sporadic FTD. Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic variant in symptomatic nonpathogenic variant carriers, and noncarrier family controls. All participants were genotyped for the rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex, and CDR+NACC-FTLD sum of boxes. Subsequently, associations between and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by predictor interactions were fitted. The minor allele of rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in pathogenic variant carriers under the recessive dosage model (N = 82, beta = 3.25, 95% CI [0.37-6.19], = 0.034). This was most pronounced in the thalamus in the left hemisphere (beta = 0.03, 95% CI [0.01-0.06], = 0.006), with a retained association when considering presymptomatic pathogenic variant carriers only (N = 42, beta = 0.03, 95% CI [0.01-0.05], = 0.003). The minor allele of rs1990622 also associated with greater cognitive scores among all pathogenic variant carriers (N = 229, beta = 0.36, 95% CI [0.05-0.066], = 0.021) and in presymptomatic pathogenic variant carriers (N = 106, beta = 0.33, 95% CI [0.03-0.63], = 0.036), under the recessive dosage model. We identified associations of with gray matter volume and cognition in the presence of and pathogenic variants. The association of with outcomes of interest in presymptomatic and pathogenic variant carriers could additionally reflect TMEM106B's effect on divergent pathophysiologic changes before the appearance of clinical symptoms.