Aerobic exercise improves hippocampal blood flow for hypertensive Apolipoprotein E4 carriers

Abstract

Cerebrovascular dysfunction likely contributes causally to Alzheimer's disease (AD). The strongest genetic risk factor for late-onset AD, Apolipoprotein E4 (APOE4), may act synergistically with vascular risk to cause dementia. Therefore, interventions that improve vascular health, such as exercise, may be particularly beneficial for APOE4 carriers. We assigned cognitively normal adults (65-87 years) to an aerobic exercise intervention or education only. Arterial spin labeling MRI measured hippocampal blood flow (HBF) before and after the 52-week intervention. We selected participants with hypertension at enrollment (n = 44). For APOE4 carriers, change in HBF (ΔHBF) was significantly (p = 0.006) higher for participants in the exercise intervention (4.09 mL/100g/min) than the control group (-2.08 mL/100g/min). There was no difference in ΔHBF between the control (-0.32 mL/100g/min) and exercise (-0.54 mL/100g/min) groups for non-carriers (p = 0.918). Additionally, a multiple regression showed an interaction between change in systolic blood pressure (ΔSBP) and APOE4 carrier status on ΔHBF (p = 0.035), with reductions in SBP increasing HBF for APOE4 carriers only. Aerobic exercise improved HBF for hypertensive APOE4 carriers only. Additionally, only APOE4 carriers exhibited an inverse relationship between ΔSBP and ΔHBF. This suggests exercise interventions, particularly those that lower SBP, may be beneficial for individuals at highest genetic risk of AD.ClinicalTrials.gov Identifier: NCT02000583.

Keywords: Alzheimer’s; aging; cerebral blood flow; exercise; hippocampus.

Figure 1.

Flowchart of Alzheimer’s Prevention through Exercise (APEx) study participants.

Figure 2.

Mean change in hippocampal blood flow (ΔHBF) from baseline to 52 weeks. (a) Among APOE4 carriers, those who underwent the exercise intervention had a significantly larger ΔHBF (increased HBF) over the 52 weeks than the control group (p = 0.006). Additionally, within the exercise intervention arm, ΔHBF was significantly larger for the APOE4 carriers than the non-carriers (p = 0.013). There were no other significant differences between groups. X = mean; horizontal line = median (b) Representative arterial spin labeling MRI (ASL-MRI) scans from a participant with high (top panel) and a participant with low (bottom panel) HBF.

Figure 3.

Relationship between change in systolic blood pressure (ΔSBP) and hippocampal blood flow (ΔHBF). Over the 52-week clinical trial period, ΔSBP was inversely associated with ΔHBF for the APOE4 carriers. There was no relationship between ΔSBP and ΔHBF for the APOE4 non-carriers. This suggests reductions in SBP in older adults with baseline hypertension may preferentially improve HBF for APOE4 carriers.