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TMEM106B pathology occurs in normal aging and is increased in TDP-43 proteinopathy but its role in dementia remains unclear. Cerebrovascular disease (CVD) is a driver and co-pathology of dementia, yet its contribution to TMEM106B accumulation in the context of TDP-43 and ad neuropathological changes (ADNC) has not been explored. We analyzed post-mortem human hippocampal sections spanning not-, low-, intermediate-, and high-ADNC. In secondary analyses, cases \u226565\u2009years were stratified by TDP-43 immunopositivity and CVD severity; cases &amp;lt;65\u2009years were included to contextualize age-associated effects. TMEM106B immunoreactivity was quantified using digital pathology. Linear regression models demonstrated that age and sex (higher in females) were independent predictors of TMEM106B immunopositivity whereas Braak stage, CERAD-NP score, and Thal phase were not. The positive TDP-43-TMEM106B association was attenuated with increased CVD pathology severity, suggesting that vascular burden modifies this relationship. Sensitivity analyses restricted to LATE-NC attenuated several associations, indicating that pooled TDP-43 findings should be interpreted cautiously given possible disease heterogeneity. TMEM106B immunoreactivity was most strongly associated with age and sex, while vascular burden, rather than ADNC level, modified its relationship with TDP-43 proteinopathy.<\/jats:p>","DOI":"10.1093\/jnen\/nlag031","type":"journal-article","created":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T12:35:51Z","timestamp":1774096551000},"page":"963-974","source":"Crossref","is-referenced-by-count":0,"title":["Vascular burden attenuates the TDP-43-TMEM106B pathological relationship in neurodegenerative disease with and without Alzheimer disease neuropathological change"],"prefix":"10.1093","volume":"85","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-2305-7281","authenticated-orcid":false,"given":"Matthew B","family":"Dopler","sequence":"first","affiliation":[{"name":"Glenn Biggs Institute for Alzheimer\u2019s and Neurodegenerative Diseases, University of Texas Health Science Center at San Antonio , San Antonio, TX,","place":["United 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and Laboratory Medicine, University of Texas Health Science Center at San Antonio , San Antonio, TX,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gladys","family":"Maestre","sequence":"additional","affiliation":[{"name":"Institute of Neurosciences, School of Medicine, University of Texas Rio Grande Valley , Harlingen, TX,","place":["United States"]},{"name":"Rio Grande Valley Alzheimer\u2019s Disease Resource Center for Minority Aging Research (RGV AD-RCMAR), University of Texas Rio Grande Valley , Brownsville, TX,","place":["United States"]},{"name":"Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley , Brownsville, TX,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudha","family":"Seshadri","sequence":"additional","affiliation":[{"name":"Glenn Biggs Institute for Alzheimer\u2019s and Neurodegenerative Diseases, University of Texas Health Science Center at San 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