Senescence protein signatures predict dementia risk with causal implication for TBCA: a two-cohort study
Year: 2026
Type: preprint
Study design: Observational Study
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.
Source: Research Square
Institutions: University of Minnesota, Wake Forest University Health Sciences, Wake Forest University, National Institute on Aging, The University of Texas Southwestern Medical Center, University of Pennsylvania, Johns Hopkins University, The Lundquist Institute, Harbor–UCLA Medical Center, Baylor College of Medicine, Children's Nutrition Research Center at Baylor College of Medicine, San Francisco General Hospital, University of California, San Francisco
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Proteomics of Cardiovascular Risk: The Multiethnic Study of Atherosclerosis, MESA, Wake Forest Clinical and Translational Science Award, MESA, MESA, SUBCLINICAL CARDIOVASCULAR DISEASE STUDY--EBCT READING, MESA, Proteomic aging clock and brain structure, cognitive decline and the risk of Alzheimers Disease and related dementias, TITLE: MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA), ARIC Neurocognitive Study (ARIC-NCS) Renewal UNC 4 of 5, OPTION 3. 4/1/2014 - 3/31/2015. MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA) - READING CENTER, NHLBI, MESA, ARIC Neurocognitive Study (ARIC-NCS) Renewal 4 of 5, SUBCLINICAL CARDIOVASCULAR DISEASE STUDY-ULTRASOUND, Profiling Cardiovascular Events and Biomarkers in the Very Old to Improve Personalized Approaches for the Prevention of Cardiac and Vascular Disease, CHARGE consortium: omics discovery for CVD and aging phenotypes, Institute for Clinical and Translational Research, MESA, ARIC Neurocognitive Study (ARIC-NCS) Renewal 2 of 5, ARIC Neurocognitive Study (ARIC-NCS), MESA, Clinical and Translational Science Award, Subclinical Vascular Contributions to Alzheimer's Disease: The Multi-Ethnic Study of Atherosclerosis (MESA) Multisite Study of AD (Renewal), University of Minnesota Clinical and Translational Science Institute (UMN CTSI), ARIC Neurocognitive Study (ARIC-NCS) Renewal 2023-2028, Diabetes Research Center (DRC), UCLA Clinical and Translational Science Institute
OpenAlex ID: W7140476303