Aerobic exercise improves hippocampal blood flow for hypertensive APOE4 carriers

Background: Evidence increasingly suggests cerebrovascular dysfunction plays an early and important role in the pathogenesis of Alzheimer's disease (AD). Studies have shown the strongest known genetic risk factor for sporadic AD, Apolipoprotein E4 (APOE4), may act synergistically with vascular risk factors to promote dementia development. Aerobic exercise may attenuate cognitive decline at least partially through improvements in cerebral blood flow. Therefore, exercise interventions that improve vascular health may be particularly beneficial for APOE4 carriers. Objectives: To test the hypothesis that exercise would more effectively increase hippocampal blood flow (HBF) in hypertensive APOE4 carriers than non carriers, we performed an analysis of arterial spin labeling MRI data (ASL MRI) from a randomized controlled trial (secondary outcome). Additionally, we tested the hypothesis that changes in systolic blood pressure ({Delta}SBP) would be more negatively associated with {Delta}HBF for APOE4 carriers than non carriers. Methods: We assigned cognitively normal adults (65 to 87 years) to a 52-week aerobic exercise intervention or education only. Genotyping was performed by Taqman SNP allelic discrimination assay. ASL MRI measured HBF before and after the 52 week intervention. We selected participants with hypertension at enrollment (n {equiv} 44), defined as SBP [≥] 130mmHg or diastolic blood pressure (DBP) [≥] 80mmHg. Results: A two way ANCOVA showed a significant interaction between APOE4 carrier status and treatment group on change in HBF ({Delta}HBF) over the 52 weeks, controlling for age and sex (p = 0.040). For APOE4 carriers, {Delta}HBF was significantly (p = 0.006) higher for participants who underwent the exercise intervention (4.09 mL/100g/min) than for the control group (-2.08 mL/100g/min). There was no difference in {Delta}HBF between the control (-0.32 mL/100g/min) and exercise (-0.54 mL/100g/min) intervention groups for APOE4 non carriers (p = 0.918). Additionally, a multiple linear regression showed a significant interaction between {Delta}SBP and APOE4 carrier status on {Delta}HBF (p = 0.035), with a reduction in SBP associated with an increase in HBF for APOE4 carriers only. Conclusions: Aerobic exercise significantly improved HBF for hypertensive APOE4 carriers only. Additionally, only APOE4 carriers exhibited an inverse relationship between {Delta}SBP and {Delta}HBF. This suggests exercise interventions, particularly those that lower SBP, may be beneficial for individuals at highest genetic risk of AD.