Hypertension and Hypercholesterolemia Modify Dementia Risk in Relation to APOE ε4 Status

Background: There is significant interest in understanding the role of modifiable vascular risk factors contributing to dementia risk across age groups. Objective: Risk of dementia onset was assessed in relation to vascular risk factors of hypertension and hypercholesterolemia among cognitively normal APOE epsilon 4 carriers and non-carriers. Methods: In a sample of prospectively characterized longitudinal cohort from the National Alzheimer's Coordinating Center database, 9,349 participants met criteria for normal cognition at baseline, had a CDR-Global (CDR-G) score of zero, and had concomitant data on APOE epsilon 4 status and medical co-morbidities including histories of hypertension and hypercholesterolemia. Multivariable Cox proportional hazards models adjusted for well-known potential confounders were used to compare dementia onset among APOE epsilon 4 carriers and non-carriers by young (<= 65 years) and old (> 65 year) age groups. Results: 519 participants converted to dementia within an average follow up of 5.97 years. Among older APOE epsilon 4 carriers, hypercholesterolemia was related to lower risk of dementia (HR (95% CI), 0.68 (0.49-0.94), p = 0.02). Among older APOE epsilon 4 non-carriers, hypertension was related to higher risk of dementia (HR (95% CI), 1.44 (1.13-1.82), p = 0.003). These results were corroborated among a subset with autopsy data characterizing underlying neuropathology. Among younger participants, vascular risk factors did not impact dementia risk, likely from a lower frequency of vascular and Alzheimer's as etiologies of dementia among this cohort. Conclusion: A history of hypercholesterolemia related to a lower risk of dementia among older APOE epsilon 4 carriers, while hypertension related to a higher risk of dementia among older APOE epsilon 4 non-carriers.