Age-Dependent and APOE-Modified Associations Between Vascular Risk Factor Patterns and Cognitive Function

INTRODUCTION: Vascular risk factors (VRFs) are established contributors to cognitive decline, yet they often co-occur in distinct patterns. Whether VRF pattern-cognition associations are modified by age or apolipoprotein E (APOE) genotype remains unclear. METHODS: We analyzed 44,879 participants aged 60 to 90 years from the National Alzheimer's Coordinating Center (NACC) with normal cognition or mild cognitive impairment (MCI). Latent class analysis (LCA) identified VRF patterns from 7 indicators: hypertension, diabetes, hypercholesterolemia, myocardial infarction, atrial fibrillation, heart failure, and stroke. Multivariable linear regression examined associations between VRF patterns and Mini-Mental State Examination (MMSE) scores, with stratification by age and APOE ε4 status. RESULTS: Five VRF patterns were identified: Low Risk (38.4%), Metabolic Predominant (40.5%), Hypertension Predominant (16.0%), Arrhythmia-Cardiac (2.7%), and High Multimorbidity (2.4%). Each additional VRF was associated with 0.056-point lower MMSE (β=-0.056, 95% CI: -0.072 to -0.039, P<0.001). Significant age × pattern (P=0.0015) and APOE × pattern (P=0.0016) interactions emerged. In younger-old adults (60 to 74 y), Metabolic Predominant was associated with lower MMSE (β=-0.171, P<0.001), but not in older-old adults (75 to 90 y; β=0.020, P=0.53). Among APOE ε4 carriers, the Metabolic Predominant association was substantially stronger (β=-0.228, P<0.001) compared with noncarriers (β=-0.053, P=0.025), a 4.3-fold difference in magnitude. CONCLUSIONS: VRF-cognition associations show significant heterogeneity by age and APOE genotype. Attenuated associations in older-old adults may reflect survivor bias, while stronger associations in APOE ε4 carriers are consistent with gene-environment interactions.