Fig. 3

Hippocampal TMEM106B levels increase in carriers of the rs1990622-A risk allele. (A) (Top) Gene map of the TMEM106B locus (chromosome 7p21) with annotations of key TMEM106B SNP loci associated with neurodegenerative diseases (FTD: frontotemporal dementia; ALS: amyotrophic lateral sclerosis; AD: Alzheimer’s disease; PD: Parkinson’s disease; CTE: chronic traumatic encephalopathy; HS-ageing: hippocampal sclerosis with ageing; LATE: limbic-predominant age-related TDP-43 encephalopathy). Exons (E1-E9) are denoted in red, introns in white, and non-coding regions as a line. (Bottom) Linkage disequilibrium between rs1990622 and all SNPs located ± 500,000 bp from the TMEM106B gene as measured by the squared correlation coefficient (r², where r² = 1 is perfect linkage, depicted in red oval). Dementia risk-associated SNPs depicted in the gene map are labelled on the linkage plot. (B) TMEM106B protein levels as a function of age and rs1990622 genotype. P values refer to the interaction between rs1990622 genotype and age in multiple regression adjusted for PMI and sex. (C) TMEM106B levels as a function of rs1990622 genotype after adjusting for age, PMI, and sex (ANOVA, F = 2.7, P = 0.07). (D) Western blots for fibrillar TMEM106B in the sarkosyl-insoluble fraction using an anti-C-terminus antibody. Samples were from individuals aged 67–78 (blue) and 81–95 (red) that are homozygous for the rs1990622 G/G allele or carriers of the risk allele (A⁺). Braak stage of each individual is shown beneath the blot. Two sarkosyl-soluble samples were loaded onto the last two lanes of each blot to assess enrichment of TMEM106B fibrils (Sol LC). (E) Densitometry quantification of the 31 kDa bands observed in (D)