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

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 (CVRmimic) using sex-stratified linear mixed efefcts (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; CVRmimic in none of the six. HVR - cognitive coupling held in four of six FRS and four of six CVRmimic models. Indirect effects reached significance in four of six FRS and none of the six CVRmimic models. LME 3-way interactions (years x risk x HVR) survived FDR correction in all six FRS versus none of the six CVRmimic models. DISCUSSION: FRS "effects" on hippocampal-cognitive decline largely reflect age-related variance. Age adjusted measures complement FRS by isolating cardiovascular effects from aging.