Damme, Markus

Variants in TMEM106B and GRN , which encode lysosomal proteins, interact through unknown mechanisms to increase the risk of age-related cognitive decline and neurodegeneration. Here, we show that these variants converge on a single molecular intermediate: the cleaved intra-lysosomal fibril core of TMEM106B, a precursor to amyloid fibrils that accumulate in the aging brain. A protein-coding TMEM106B risk variant (p.T185) drives fibril core accumulation by impairing its degradation and GRN risk variants amplify this effect. Mice over-expressing the fibril core develop hallmarks of neurodegeneration, and cryo-electron tomography reveals intra-lysosomal fibrils in cultured neurons, mice, and diseased human brain. In GRN -mutation carriers, in whom fibril burden is greatest, fibrils extrude through ruptured lysosomal membranes. These findings identify intra-lysosomal TMEM106B fibrillization as a convergent neurodegeneration mechanism and potential therapeutic target.

Abstract Background Genome‐wide association studies (GWAS) linked TMEM106B variants to susceptibility for neurodegenerative diseases, but the causal genetic elements remain unclear. Method We used genotyping data from 5,792 Alzheimer disease cases and controls, and applied COJO to identify haplotypes in the TMEM106B locus that independently associated with AD. Then, we used long‐read sequencing data from 513 individuals to annotate these haplotypes with structural variations that map into them. Results Analysis of the genotyping data revealed that the TMEM106B locus consists of four major haplotypes: HA/Ha (covering the coding region), and HB/Hb (covering the upstream regulatory region). These combine into four combinations with varying population‐frequencies: HAB (57%), HaB (34%), Hab (9%), and HAb (<1%). Long‐read sequencing of 513 individuals showed that HA haplotypes (marked by 185‐Threonine) carry unique methylated CpG sites and an AluYb8‐retrotransposon in the 3' UTR, while the Ha haplotypes are marked by the 185‐Serine allele. Hb haplotypes carry several structural variants (SVs) in nearby distal enhancers, including a 19 Kbp rearrangement, absent in all other haplotypes. Joint association models revealed that the HAB combination (AluYb8+185‐Threonine) is risk‐increasing, while Hab (SVs+185‐Serine) confers the protective effect. HaB (185‐Serine only) is neutral, while HAb was too rare to assess. Relative to middle‐aged non‐demented controls, cognitively healthy centenarians were more enriched with Hab (OR=1.49, padj=2.18×10‐2) than with HaB (OR=1.23, padj=5.06×10‐2). Proteomic analysis of temporal cortex tissues ( n = 182) indicated that relative to the neutral HaB combination, the protective Hab is associated with 1.1‐fold lower TMEM106B C‐terminal peptide abundance, while the risk‐increasing HAB is associated with 1.16‐fold higher abundance. Conclusion Our data indicates that the genetic structure underlying the association of the TMEM106B locus with neurodegenerative diseases is driven by the effect of multiple haplotypes.

ABSTRACT Genetic variation at the TMEM106B locus has been associated with Alzheimer’s disease (AD) and related neurodegenerative phenotypes, yet its haplotypic architecture remains incompletely resolved. We refined the genetic landscape of TMEM106B by integrating AD-GWAS summary statistics (∼978K individuals) with haplotype analyses in 5,873 Dutch genomes including AD-cases, age-matched controls, and cognitively healthy centenarians. In addition to the known linkage disequilibrium (LD) block defining risk and protective haplotypes characterized by the amino acid substitution at residue 185 (Threonine/Serine), we identify a second conditionally independent LD block. Together these form four haplotypes (T1-T4), with T3 strongly enriched in centenarians. Long-read whole-genome sequencing in 493 individuals reveals haplotype-linked structural variation and methylation patterns, including a ∼19 Kbp genomic rearrangement carried by T3. These findings indicate that the TMEM106B locus comprises multiple haplotypes defined by methylation patterns and structural variants, offering insights into GWAS associations with AD risk and preserved cognition at extreme age.