Biological Aging, Cognitive Aging, and Dementia Risk in a Community-Based Cohort: The Atherosclerosis Risk in Communities Study

Biological aging, defined as the progressive deterioration of physiological integrity across multiple organ systems, has emerged as a fundamental determinant of age-related chronic diseases. Within the geroscience framework, cognitive aging and dementia are conceptualized as brain-specific manifestations of systemic biological aging. However, existing studies frequently relied on cross-sectional designs and single-tissue aging metrics, and the long-term relationship between biological aging and cognitive outcomes and multimodal neuropathological biomarkers remains insufficiently investigated. This dissertation leveraged data from the Atherosclerosis Risk in Communities (ARIC) Study. Biological aging was operationalized using Cohen’s homeostatic dysregulation, based on 19 clinical biomarkers across organ systems. Two complementary aims were pursued. First, associations of midlife biological aging with incident dementia and cognitive trajectories over 33 years of follow-up among 14,024 participants were evaluated using Cox proportional hazards models and linear mixed-effects models. Second, associations with neuroimaging and plasma biomarkers of Alzheimer’s disease (AD) pathology, cerebrovascular injury, and neurodegeneration over 21 years of follow-up were examined in a subsample of 1,715 participants using linear and logistic models. Multiple imputation and inverse-probability weighting were applied to address missing data and selection bias. In Aim 1, more advanced midlife biological aging was associated with increased risk of dementia, lower baseline cognitive function, and accelerated cognitive decline. The associations were independent of demographic and lifestyle factors and exhibited a dose-response pattern for dementia risk, with evidence of threshold patterns for cognitive outcomes. In Aim 2, higher biological aging scores were associated with smaller global and AD-related brain volumes and cortical thicknesses, greater white matter hyperintensity burden, higher risk of subcortical infarctions, and higher plasma concentrations of neurofilament light chain and phosphorylated tau-181, but not with plasma amyloid. Overall, this work comprehensively links systemic physiological dysregulation in midlife to later-life brain aging by integrating clinical outcomes with multimodal biomarkers. The results identify biological aging as an important determinant of mixed neurodegenerative and small vessel-related cerebrovascular pathologies underlying cognitive decline and dementia. This dissertation highlights the potential utility of scalable biological aging measures for early risk stratification and underscores the importance of targeting systemic aging processes in prevention strategies for cognitive impairment and dementia.