Cerebrovascular response to exercise interacts with individual genotype and amyloid-beta deposition to influence response inhibition with aging

Abstract

The etiology of cognitive dysfunction associated with Alzheimer's disease (AD) and dementia is multifactorial. Yet, mechanistic interactions among key neurobiological factors linked to AD pathology are unclear. This study tested the effect of interactions between cerebrovascular function, individual genotype, and structural brain pathology on response inhibition performance, an early and sensitive indicator of cognitive executive dysfunction with aging. We quantified cerebrovascular response (CVR) to moderate-intensity aerobic exercise using transcranial doppler ultrasound and global amyloid-beta (Aβ) deposition using positron emission tomography in a group of cognitively normal older adults genotyped as APOE4 carriers and noncarriers. We quantified response inhibition during a cognitive Stroop test. Individuals with blunted CVR possessed greater Aβ deposition. There was CVR-by-carrier status-by-Aβ interaction on response inhibition. Blunted CVR was associated with impaired response inhibition specifically in APOE4 carriers. Despite having greater Aβ deposition, APOE4 carriers with higher CVR demonstrated better response inhibition. Cerebrovascular interactions with individual genotype and structural brain pathology may provide a physiologically-informed target for precision-medicine approaches for early treatment and prevention of cognitive dysfunction with aging.

Keywords: APOE; Alzheimer's disease; Amyloid plaque; Cardiovascular; Cognition; Executive function; Stroop; Transcranial Doppler.

Figure 1.

Relationship between cerebrovascular response to moderate-intensity exercise and global amyloid-beta (Aβ) burden. A higher CVR predicted lower Aβ deposition across all participants (p=.013) (A). In APOE4 carriers, individuals classified as having elevated Aβ (solid line) demonstrated a stronger negative effect of CVR on Aβ deposition compared to APOE4 carriers classified as nonelevated Aβ (broken line) (p=.032) (B). In APOE4 noncarriers, there were no significant differences in the effect of CVR on Aβ deposition between individuals with elevated versus nonelevated Aβ deposition (p=.272) (C).

Figure 2.

Association between cerebrovascular response to moderate-intensity aerobic exercise and response inhibition performance predicted from the regression model in APOE4 carriers (n=20) (solid line) and noncarriers (n=50) (broken line). In APOE4 carriers, greater cerebrovascular response to exercise was associated with better performance on the Stroop response inhibition task (p<.001). In noncarriers, no relationship was observed (p=.112). Results for this regression model are detailed in Table 3.

Figure 3.

Association between Aβ deposition and response inhibition performance illustrated as a function of cerebrovascular response (CVR) to moderate-intensity aerobic exercise in APOE4 carriers (black color) (n=20) (A) and noncarriers (grey color) (n=50) (B). APOE4 carriers with high CVR (≥ 5.7cm/s) (solid line) showed a positive relationship between Aβ deposition and response inhibition performance, while APOE4 carriers with low CVR (< 5.7cm/s) (broken line) showed no positive effect. CVR also showed a lower effect on response inhibition in noncarriers. Results for this regression model are detailed in Table 3. (C) Response inhibition performance in APOE4 carriers and noncarriers with low and high CVR. There was a significant APOE4 carrier group × CVR interaction. APOE4 carriers with high CVR had higher response inhibition performance compared to APOE4 carriers with low CVR (p=.005) and noncarriers (p=.017). Among individuals with low CVR, APOE4 carriers had lower response inhibition performance compared to noncarriers (p=.013). Within the noncarrier group, noncarriers with low CVR had higher response inhibition performance compared to those with high CVR (p=.034). *p<.05, **p<.01. CVR is illustrated as a median (5.7cm/s) split of the group, where High CVR ≥ 5.7cm/s; Low CVR < 5.7cm/s.