Genetic variation in TMEM106B alters microglial activation and cytokine responses in chronic traumatic encephalopathy

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease caused by repetitive head impacts (RHI). However, individuals with similar RHI exposure can show differing pathology, suggesting a role for genetic variation. A common Transmembrane Protein 106B (TMEM106B) risk variant is associated with greater CTE severity, though its mechanism remains unclear. To determine whether TMEM106B alters the inflammatory response to pathology in CTE, we examined associations between microglia, via immunohistochemistry, and inflammatory cytokines, via immunoassay, in brain donors with CTE with and without the risk genotype (rs3173615). We analyzed 323 RHI-exposed brain donors: 55 without pathology (controls) and 268 with CTE. Regression models tested associations between TMEM106B risk and CTE presence, CTE stage, TDP-43, and dementia in those < = 65 and > 65 years of age. Within a subset of 122 brain donors, we examined associations between microglia, cytokines, and pathology stratified by TMEM106B genotype. Among donors > 65 years old, the TMEM106B risk genotype was associated with increased CTE stage (OR = 2.748 [95% CI 1.183-6.383], p = 0.019), comparable to the effect of playing > 8 years of contact sports, and with greater odds of having TDP-43 inclusions (OR = 3.649 [95% CI 1.278-10.422], p = 0.016). In donors < = 65, TMEM106B risk was associated with higher odds of dementia (OR = 6.912 [95% CI 2.015-23.705], p = 0.002). TMEM106B gene variation had a significant effect on associations between inflammatory markers and CTE-related pathology. In the protective genotype, IL-8 and IL-6 demonstrated positive associations with CD68, TREM2, and tau pathology within the dorsolateral prefrontal cortex. In the risk genotype, IFN-γ, IL-4, TNF-α, TNF-β, and IL-10 demonstrated negative associations with TREM2 (p's < 0.05), and TNF-α was negatively associated with cortical tau (p = 0.003). These results suggest that the microglial production of TREM2-associated cytokines and their association with pathology is aberrant in the TMEM106B risk genotype in CTE. Overall, TMEM106B rs3173615 is associated with an increased risk of developing higher stage CTE and TDP-43 pathology, potentially via impaired microglial activation and aberrant cytokine production.