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

## TL;DR

A protein linked to cellular aging, called TBCA, is strongly connected to dementia risk, suggesting it could be a target for new treatments.

## Contribution

The study identifies TBCA as a causally linked protein to dementia using SASP scores and Mendelian randomization.

## Key findings

- SASP protein scores predicted dementia risk with stronger associations in late-life participants.
- Tubulin folding cofactor A (TBCA) was the only protein with a causal link to dementia.
- Minimal SASP protein panels are effective biomarkers for dementia prediction.

## Abstract

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.