Objectives/Goals: TMEM106B forms age-dependent amyloid fibrils that are elevated in dementia patients and correlated with increased TDP-43 pathology. Cerebrovascular disease (CVD), a major dementia co-pathology, may contribute to TDP-43 dysfunction. Understanding the relationships among CVD, TMEM106B, and TDP-43 is crucial for developing targeted therapies. Methods/Study Population: We compared autopsy brains across TDP-43 pathologies and CVD to investigate potential differences in TMEM106B levels. Autopsy brain samples (N=58) were selected from the Biggs Brain Bank to include frontotemporal lobar degeneration with TDP pathology (FTLD-TDP), limbic-predominant age-related TDP-43 encephalopathy (LATE), TDP-43 negative Alzheimer’s diseases neuropathologic change (ADNC), and controls. Immunofluorescence staining using anti-TMEM106B (239-250aa) was performed on formalin-fixed posterior hippocampal sections to assess whether CVD burden had an impact on TMEM staining patterns. Quantitative digital pathology analyses were conducted on whole slide images (WSI) to quantify TMEM106B fibril accumulation. Results/Anticipated Results: Age was the strongest predictor of TMEM106B fibril accumulation (p < 0.001), and females showed higher fibril burden than males (p = 0.035). TDP-43 pathology was associated with increased TMEM106B accumulation (p = 0.03). Greater co-existing cardiovascular disease (CVD) pathology burden showed a trend toward reduced TMEM106B fibril accumulation, suggesting an attenuating, and possibly dose-dependent effect of CVD pathology on the observed TDP-43 and TMEM106B association (p = 0.058). Across ADNC (Braak tangle stage, Thal amyloid plaque phase, CERAD neuritic plaque density score), increasing CVD pathology burden did not modify TMEM106B fibril levels with increasing Braak stage (p = 0.64), Thal phase (p = 0.39), or CERAD score (p = 0.56), and TDP-43 did not increase TMEM106B in the presence of these AD lesions. Discussion/Significance of Impact: Age, sex, and TDP-43 are determinants of TMEM106B fibril. Increasing CVD pathology appears to blunt the TDP-43 and TMEM106B association, possibly due to hypoxia-driven lysosomal dysfunction. Additional co-pathologies do not appear to drive TMEM106B fibril accumulation. Future work will assess if lower TMEM106B may reflect compensatory change.
Dopler et al. (Wed,) studied this question.