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However, individuals with similar RHI exposure can show differing pathology, suggesting a role for genetic variation. A common\n                    <jats:italic>Transmembrane Protein 106B<\/jats:italic>\n                    (\n                    <jats:italic>TMEM106B<\/jats:italic>\n                    ) risk variant is associated with greater CTE severity, though its mechanism remains unclear. To determine whether\n                    <jats:italic>TMEM106B<\/jats:italic>\n                    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 (\n                    <jats:italic>rs3173615)<\/jats:italic>\n                    . We analyzed 323 RHI-exposed brain donors: 55 without pathology (controls) and 268 with CTE. Regression models tested associations between\n                    <jats:italic>TMEM106B<\/jats:italic>\n                    risk and CTE presence, CTE stage, TDP-43, and dementia in those\u2009&lt; =\u200965 and\u2009&gt;\u200965 years of age. Within a subset of 122 brain donors, we examined associations between microglia, cytokines, and pathology stratified by\n                    <jats:italic>TMEM106B<\/jats:italic>\n                    genotype. Among donors\u2009&gt;\u200965 years old, the\n                    <jats:italic>TMEM106B<\/jats:italic>\n                    risk genotype was associated with increased CTE stage (OR\u2009=\u20092.748 [95% CI 1.183\u20136.383],\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.019), comparable to the effect of playing\u2009&gt;\u20098 years of contact sports, and with greater odds of having TDP-43 inclusions (OR\u2009=\u20093.649 [95% CI 1.278\u201310.422],\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.016). In donors\u2009&lt; =\u200965,\n                    <jats:italic>TMEM106B<\/jats:italic>\n                    risk was associated with higher odds of dementia (OR\u2009=\u20096.912 [95% CI 2.015\u201323.705],\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.002).\n                    <jats:italic>TMEM106B<\/jats:italic>\n                    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-\u03b3, IL-4, TNF-\u03b1, TNF-\u03b2, and IL-10 demonstrated negative associations with TREM2 (\n                    <jats:italic>p<\/jats:italic>\n                    \u2019s\u2009&lt;\u20090.05), and TNF-\u03b1 was negatively associated with cortical tau (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.003). These results suggest that the microglial production of TREM2-associated cytokines and their association with pathology is aberrant in the\n                    <jats:italic>TMEM106B<\/jats:italic>\n                    risk genotype in CTE. Overall,\n                    <jats:italic>TMEM106B rs3173615<\/jats:italic>\n                    is associated with an increased risk of developing higher stage CTE and TDP-43 pathology, potentially via impaired microglial activation and aberrant cytokine production.\n                  <\/jats:p>","DOI":"10.1007\/s00401-025-02955-7","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T10:35:38Z","timestamp":1763634938000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Genetic variation in TMEM106B alters microglial activation and cytokine responses in chronic traumatic encephalopathy"],"prefix":"10.1007","volume":"150","author":[{"given":"Shahar","family":"Hartman","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nurgul","family":"Aytan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raymond","family":"Nicks","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samantha","family":"Hawkins","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Cherry","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victor E.","family":"Alvarez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gaoyuan","family":"Meng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yorghos","family":"Tripodis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brett","family":"Martin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph","family":"Palmisano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lee E.","family":"Goldstein","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Douglas I.","family":"Katz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brigid","family":"Dwyer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel H.","family":"Daneshvar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John F.","family":"Crary","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Alosco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weiming","family":"Xia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ann C.","family":"McKee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jesse","family":"Mez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thor D.","family":"Stein","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,11,20]]},"reference":[{"key":"2955_CR1","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1007\/s00401-020-02197-9","volume":"140","author":"ML Alosco","year":"2020","unstructured":"Alosco ML, Cherry JD, Huber BR, Tripodis Y, Baucom Z, Kowall NW et al (2020) Characterizing tau deposition in chronic traumatic encephalopathy (CTE): utility of the McKee CTE staging scheme. 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He also receives Royalities from Oxford University Press Inc and receive honorarium from Michael J Fox Foundation for services unrelated to this study. Yorghos Tripodis reports payment to self by the American Medical Association for editorial services. Douglas Katz receives Royalties from Demos\/Springer publishers for Textbook on TBI with chapter on CTE Daniel H. Daneshvar conducts Expert medicolegal work related to TBI and SCI, receives research and clinical support from the NFLPA, and is a Member of NFLPA Mackey-White Health and Safety Committee.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"54"}}