CIRCULATING BDNF IS ASSOCIATED WITH ATTENUATED INFLAMMATION-RELATED NEUROAXONAL INJURY WHILE TAU-RELATED BIOMARKERS REMAIN ADDITIVE

Systemic inflammation is implicated in neurodegenerative processes, yet individual vulnerability varies. Brain-derived neurotrophic factor (BDNF) may support neuronal resilience, but whether it confers broad protection or selectively relates to specific pathways in humans remains unclear. We analyzed 3,733 community-dwelling older adults from the Health and Retirement Study (2016 Venous Blood Study). Systemic inflammation was indexed by a composite of z-standardized log(C-reactive protein) and log(interleukin-6), and plasma BDNF was measured concurrently. Using survey-weighted linear regression (svyglm) with venous-blood sampling weights and design variables, we modeled each biomarker as a function of inflammation, BDNF, and their interaction, adjusting for demographic covariates plus kidney function (cystatin C) and body mass index. Primary inference relied on prespecified model-based 2×2 marginal contrasts comparing high-inflammation (+1 SD)/low-BDNF (−1 SD) versus low-inflammation (−1 SD)/high-BDNF (+1 SD), with Benjamini–Hochberg FDR correction across biomarkers (complete-case covariates; outcome-specific samples).



Compared with the low-risk profile, the high-inflammation/low-BDNF profile showed higher pTau181 (q=0.0485), NfL (q=7.55×10^−9), GDF-15 (q=1.63×10^−18), and uPAR (q=6.11×10^−24), while Aβ42/40 and GFAP were not supported after FDR correction. Interaction tests were secondary and suggested the strongest effect modification for NfL (p=0.0174; q=0.104), consistent with a biomarker-specific, hypothesis-generating trend toward attenuation of inflammation-related neuroaxonal injury at higher BDNF. These findings support a pathway-specific resilience framework in which circulating BDNF aligns most closely with neuroaxonal injury, while pTau181 and systemic stress/immune activation markers appear elevated in the high-risk inflammatory profile, with no FDR-supported evidence of BDNF effect modification.