Accelerated Biological Aging, Neurodegenerative Disease, and Mortality in Cardiovascular Disease Patients: Mediation and Modification Analysis

Aims Cardiovascular disease (CVD) patients exhibit increased neurodegenerative diseases and mortality risks, implying a shared heart‐brain aging pathway. As a composite biological aging predictor, the association of Phenotypic age (PhenoAge) with mortality and the mediating role of brain health remain unclear in CVD patients. Methods In 4104 CVD patients (57.3% male, mean age 67.3 years) from the National Health and Nutrition Examination Survey (median follow‐up of 7.2 years), weighted regression models examined associations of PhenoAge and its acceleration with Alzheimer's disease (AD), Parkinson's disease (PD), and mortality. Mediation effects of the association between PhenoAge and mortality explained by AD and PD were quantified. Results The mean PhenoAge was 69.9 years, and AD and PD prevalences were 7.6% and 1.8%. Each 5‐year increment of PhenoAge acceleration independently increased risks of AD (OR = 1.24; 95% CI:1.13,1.36), PD (OR = 1.22; 95% CI:1.02,1.46), and all‐cause mortality (HR = 1.30; 95% CI:1.24,1.36). AD and PD mediated 20.46%–33.18% of the association between PhenoAge and mortality. Early‐onset CVD amplified biological aging‐related mortality risk, while a healthier lifestyle attenuated the CVD mortality risk ( P interaction < 0.05). Conclusion Accelerated biological aging was associated with adverse brain health outcomes and mortality in CVD patients, with AD and PD as significant mediators. PhenoAge assessment may identify high‐risk individuals for personalized heart‐brain aging prevention.