The Association Between Tau Burden and TIMP3 Varies by APOE4 Status

Abstract Background Tissue inhibitor of metalloproteinases‐3 (TIMP3) regulates extracellular matrix integrity, neuroinflammation, and blood‐brain barrier (BBB) function, all of which have bidirectional relationships with tau pathology in Alzheimer's disease (AD). Tau burden in medial temporal regions is a key marker of AD progression, yet its relationship with TIMP3 remains unclear. Given APOE4 's role in exacerbating tau pathology and BBB dysfunction, this study examines whether tau burden is associated with TIMP3 levels in older women with mild cognitive impairment (MCI) and whether APOE4 moderates this relationship. Method Data were collected from 50 older women (aged:72.4±4.2 years; 47.5% APOE4 carriers) participating in the Women Inflammation and Tau Study at the University of California, San Diego. All women were at higher risk for AD, defined as a polygenic hazard score in the upper 50 th percentile and a score on the Telephone Montreal Cognitive Assessment suggestive of mild cognitive impairment (i.e., scores=13‐20/22). Tau burden was assessed using MK‐6240 standardized uptake value ratio from a composite region corresponding to BRAAK stages 3/4 and TIMP3 levels were measured in cerebrospinal fluid. Moderated linear regression was used to analyze tau burden in BRAAK 3/4 in relation to TIMP3 levels, and the moderating role of APOE4 . The model adjusted for age and body mass index. Result The overall model was statistically significant and explained 27% of the variance in TIMP3 levels, F(5, 44) = 2.43, p = .012. Results revealed a significant moderating effect of APOE4 on the relationship between tau burden and TIMP3 levels, b = 5.54, p = .006. Specifically, greater tau burden was associated with higher TIMP3 levels, b=2.62, p = .049, among APOE4 carriers; whereas greater tau burden was related to lower TIMP3 levels in non‐carriers, b = ‐2.91, p = .048. Conclusion Our findings suggest a complex relationship between TIMP3 and tau pathology, potentially modulated by APOE4 status. Specifically, higher tau burden was associated with increased TIMP3 levels in APOE4 carriers but decreased TIMP3 levels in non‐carriers. Further research is warranted to clarify the mechanisms underlying TIMP3 regulation in AD, including its interactions with APOE genotype, tau pathology, and cerebrovascular integrity.