Cardiovascular risk and hippocampal-cognitive coupling in Alzheimer’s disease

Abstract INTRODUCTION The Framingham Risk Score (FRS) indexes cardiovascular risk (CVR), but age-weighting may confound associations with brain and cognitive outcomes. METHODS In 923 amyloid-positive ADNI participants, we compared FRS against a Multiple Indicators Multiple Causes (MIMIC)-derived age-adjusted measure (CVR mimic ) using sex-stratified linear mixed-effects (LME) and latent growth curve mediation (LGCM) models of hippocampal-to-ventricle ratio (HVR)– cognitive coupling. RESULTS FRS predicted hippocampal atrophy in all six LGCM models; CVR mimic in none of the six. HVR–cognitive coupling held in four of six FRS and four of six CVR mimic models. Indirect effects reached significance in four of six FRS and none of the six CVR mimic models. LME 3-way interactions (years × risk × HVR) survived FDR correction in all six FRS versus none of the six CVR mimic models. DISCUSSION FRS “effects” on hippocampal-cognitive decline largely reflect age-related variance. Age-adjusted measures complement FRS by isolating cardiovascular effects from aging. Research in Context Systematic Review The Framingham Risk Score (FRS) predicts brain atrophy and cognitive decline across cohorts [1–4]. Yet age dominates the FRS [5,6] and accounts for most of its predictive value in older adults [7,8], suggesting these associations may reflect age confounding. No prior study has compared FRS against an age-adjusted latent measure. Interpretation FRS indirect effects on cognitive decline via hippocampal atrophy primarily reflect age-weighting; age is itself a legitimate vascular proxy [9]. Partialling out age (CVR mimic ) nullified the cardiovascular-risk-to-hippocampal pathway, while HVR-cognitive coupling persisted, indicating coupling reflects neurodegeneration. Prior FRS-brain reports likely conflate age-driven and cardiovascular effects. Future Directions Replication in independent aging cohorts with longitudinal cardiovascular measurement is needed. The MIMIC age-adjustment framework can be applied to any composite risk score where age confounding is a concern. Intervention trials should test whether cardiovascular management preserves hippocampal-cognitive coupling using age-adjusted endpoints rather than FRS. Highlights Age-adjusted cardiovascular risk does not accelerate hippocampal atrophy Hippocampal-cognitive coupling persists regardless of how risk is measured FRS-brain associations in elderly samples primarily reflect age-weighting A reverse pattern in amyloid-negative controls supports a cognitive reserve effect MIMIC-based age-adjustment generalizes to any age-confounded composite score