Sex Differences in Resilience and Resistance to Brain Pathology and Dysfunction Moderated by Cerebrovascular Response to Exercise and Genetic Risk for Alzheimer's Disease

Abstract

Sex as a biological variable appears to contribute to the multifactorial etiology of Alzheimer's disease. We tested sex-based interactions between cerebrovascular function and APOE4 genotype on resistance and resilience to brain pathology and cognitive executive dysfunction in cognitively-normal older adults. Female APOE4 carriers had higher amyloid-β deposition yet achieved similar cognitive performance to males and female noncarriers. Further, female APOE4 carriers with robust cerebrovascular responses to exercise possessed lower amyloid-β. These results suggest a unique cognitive resilience and identify cerebrovascular function as a key mechanism for resistance to age-related brain pathology in females with high genetic vulnerability to Alzheimer's disease.

Keywords: Aging; Apolipoproteins E; amyloid; cardiovascular system; cerebrovascular circulation; cognition; female; hemodynamics; ultrasound.

Figure 1.

Global amyloid-β (Aβ) deposition (A) and cognitive executive function performance (B) in male and female APOE4 carriers and noncarriers. A sex-by-genotype interaction revealed that female APOE4 carriers possessed higher levels of Aβ compared to males (p=.037) and female noncarriers (p=.006) (A). There were no interactive effects or group differences in Stroop ratio, in which all older adult subgroups achieved similar levels of cognitive performance (B).

Figure 2.

Association between cerebrovascular response to exercise (CVR) and amyloid-β (Aβ) deposition in APOE4 carriers (A) and noncarriers (B). Higher CVR was associated with lower levels of Aβ deposition in female APOE4 carriers (r=−.54, p=.048), while showing no relationship in male APOE4 carriers (r=−.17, p=.716) (A). Similarly, CVR and Aβ were negatively associated in male noncarriers (r=−.64, p=.008), and showed a similar pattern in female noncarriers (r=−.29, p=.09) (B).