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

The etiology of cognitive dysfunction associated with Alzheimers 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 (A{beta}) 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 A{beta} deposition. There was CVR-by-carrier status-by-A{beta} interaction on response inhibition. Blunted CVR was associated with impaired response inhibition specifically in carriers. Despite having greater A{beta} deposition, 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. HighlightsO_LINeurobiological interactions between CVR, APOE genotype, and A{beta} are behaviorally significant. C_LIO_LIBlunted CVR to exercise is associated with impaired response inhibition specifically in APOE4 carriers. C_LIO_LIAPOE4 carriers with more robust CVR have higher response inhibition performance, despite having greater A{beta} deposition. C_LIO_LIAssessment of multifactorial neurobiological variables offers an early and sensitive biomarker of cognitive behavioral dysfunction with aging. C_LI