Vascular burden attenuates the TDP-43-TMEM106B pathological relationship in neurodegenerative disease with and without Alzheimer disease neuropathological change

Authors

• Matthew B. Dopler, University of Texas Health Science Center at San Antonio
• Cole Corbett, University of Texas Health Science Center at San Antonio
• Angelique D. Gonzalez, University of Texas Health Science Center at San Antonio
• Ali Ghaseminejad-Bandpey, University of Texas Health Science Center at San Antonio
• Mallory Keating, University of Texas Health Science Center at San Antonio
• Kyra M. Clarke, University of Texas Health Science Center at San Antonio
• Oluwaseun B. Ogunbona, University of Texas Health Science Center at San Antonio
• Gladys Maestre, The University of Texas Rio Grande ValleyFollow
• Sudha Seshadri, University of Texas Health Science Center at San Antonio
• Shahroo Etemadmoghadam, University of Texas Health Science Center at San Antonio
• Margaret E. Flanagan, University of Texas Health Science Center at San Antonio

Document Type

Article

Publication Date

4-17-2026

Abstract

TMEM106B, a lysosomal transmembrane protein, is a risk factor for neurodegenerative diseases, including Alzheimer disease (ad) and TDP-43 proteinopathies. 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 ≥65 years were stratified by TDP-43 immunopositivity and CVD severity; cases < 65 years 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.

Comments

© The Author(s) 2026. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc.   This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.

Recommended Citation

Dopler, M. B., Corbett, C., Gonzalez, A. D., Ghaseminejad-Bandpey, A., Keating, M., Clarke, K. M., ... & Flanagan, M. E. (2026). Vascular burden attenuates the TDP-43-TMEM106B pathological relationship in neurodegenerative disease with and without Alzheimer disease neuropathological change. Journal of Neuropathology & Experimental Neurology, nlag031. https://doi.org/10.1093/jnen/nlag031

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License

Publication Title

Journal of Neuropathology & Experimental Neurology

DOI

10.1093/jnen/nlag031

Academic Level

faculty

Mentor/PI Department

Office of Human Genetics