TMEM106B (transmembrane protein 106B) is a lysosomal transmembrane protein with dual roles in viral infection and neurodegeneration. In SARS-CoV-2 infection, TMEM106B functions as an ACE2-independent entry receptor, mediating post-endocytic viral fusion through engagement of the spike protein's receptor-binding motif 1. The protein exhibits variable binding affinity based on viral variants, with spike substitution E484D enhancing TMEM106B-mediated entry 1. In neurodegenerative disease, TMEM106B serves as a critical genetic modifier of frontotemporal lobar degeneration (FTLD) pathology. The rs1990622 minor allele associates with reduced FTD risk and greater gray matter volume in GRN pathogenic variant carriers, particularly in the thalamus, with effects detectable in presymptomatic stages 2. The rs3173615 protective genotype correlates with slower disease progression in FTLD-TDP patients, linked to reduced TMEM106B core accumulation and preserved dimeric TMEM106B 3. TMEM106B aggregation appears mechanistically important, with core filaments implicated in impaired RNA transport and endolysosomal dysfunction 3. TMEM106B also represents a significant Alzheimer's disease genetic risk variant 45, contributing to microglial phagocytosis dysregulation. Its role in Alzheimer's disease involves divergent effects on amyloid-β clearance and neuroinflammation 5. TMEM106B pathology demonstrates convergent associations with TDP-43 and tau pathologies across multiple neurodegenerative disease models 6.