Gene-Specific Effects on Brain Volume and Cognition of <i>TMEM106B</i> in Frontotemporal Lobar Degeneration.

Abstract

<i>TMEM106B</i> has been proposed as a modifier of disease risk in FTLD-TDP, particularly in <i>GRN</i> pathogenic variant carriers. Furthermore, <i>TMEM106B</i> 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 <i>TMEM106B</i> 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 <i>C9orf72, GRN, MAPT, VCP, TBK1, TARDBP,</i> symptomatic nonpathogenic variant carriers, and noncarrier family controls. All participants were genotyped for the <i>TMEM106B</i> rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between <i>TMEM106B</i> 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 <i>TMEM106B</i> and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by <i>TMEM106B</i> predictor interactions were fitted. The minor allele of <i>TMEM106B</i> rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in <i>GRN</i> pathogenic variant carriers under the recessive dosage model (N = 82, beta = 3.25, 95% CI [0.37-6.19], <i>p</i> = 0.034). This was most pronounced in the thalamus in the left hemisphere (beta = 0.03, 95% CI [0.01-0.06], <i>p</i> = 0.006), with a retained association when considering presymptomatic <i>GRN</i> pathogenic variant carriers only (N = 42, beta = 0.03, 95% CI [0.01-0.05], <i>p</i> = 0.003). The minor allele of <i>TMEM106B</i> rs1990622 also associated with greater cognitive scores among all <i>C9orf72</i> pathogenic variant carriers (N = 229, beta = 0.36, 95% CI [0.05-0.066], <i>p</i> = 0.021) and in presymptomatic <i>C9orf72</i> pathogenic variant carriers (N = 106, beta = 0.33, 95% CI [0.03-0.63], <i>p</i> = 0.036), under the recessive dosage model. We identified associations of <i>TMEM106B</i> with gray matter volume and cognition in the presence of <i>GRN</i> and <i>C9orf72</i> pathogenic variants. The association of <i>TMEM106B</i> with outcomes of interest in presymptomatic <i>GRN</i> and <i>C9orf72</i> pathogenic variant carriers could additionally reflect TMEM106B's effect on divergent pathophysiologic changes before the appearance of clinical symptoms.