Senescence protein signatures predict dementia risk with causal implication for TBCA: a two-cohort study

Senescence, a key aging mechanism, is linked to disease via the senescence-associated secretory phenotype (SASP), yet its role in dementia remains unclear. We aimed to identify a minimal circulating SASP protein panel to predict incident dementia and identify causally-associated proteins. Among midlife and late-life participants from the Atherosclerosis Risk in Communities (ARIC) study, we developed three weighted SASP protein scores via multivariable Cox proportional hazards or Lasso Cox regression. Cox proportional hazards regression estimated associations between each standardized score (mean = 0; SD = 1) and incident dementia in an independent ARIC sample and validated in the Multi-Ethnic Study of Atherosclerosis (MESA). Mendelian randomization analyses evaluated causal relationships between SASP proteins and dementia risk. Comparable significant associations were observed across scores in ARIC (per 1 SD: HRs: midlife 1.20–1.33; late-life 1.39–1.50) and MESA (midlife: 1.28–1.38; late-life 1.40–1.62), with stronger associations for late-life scores. Tubulin folding cofactor A protein was the only protein causally associated with incident dementia. SASP scores, even with few proteins, are useful dementia biomarkers, and TBCA is a promising therapeutic target.