Sex Differences in Education and Cerebrovascular Contributions to Cognitive Aging
Authors: DuBose Lyndsey , Ponto Laura , Moser David , Fiedorowicz Jess , Magnotta Vincent , Harlynn Emily , Pierce Gary 
Published: April 2020

IntroductionAlzheimer’s disease (AD) manifests through complex interactions of modifiable (blood pressure, education) and non‐modifiable (age, female sex) risk factors. While women are initially protected against cognitive decline, they are diagnosed with AD at more advanced disease states compared with men however, the mechanism by which this occurs remains unclear. Recently, we demonstrated that education attenuates the adverse effects of vascular pulse pressure (PP), a novel risk factor for cerebrovascular dysfunction in AD, on cognitive performance but this relation differed by sex. Cerebrovascular dysfunction uncouples cerebral blood flow (CBF) supply from metabolic demand contributing to acidosis and lower cognition in AD. Therefore, we explored differences in the contribution of education, PP and cerebrovascular dysfunction on cognitive performance in older adults stratified by sex. We hypothesized that 1) education would differentially moderate the relation between PP and global cognition; 2) relations between lower global cognitive performance, CBF dysfunction, cerebral acidosis and amyloid deposition would differ in men and women without AD.MethodsIn the entire cohort, brachial PP and global cognitive performance (RBANS Total Scale Score) were measured in 113 adults (50–84 years, 50% female). In a subset, CBF ([15O]water PET imaging, n=27), amyloid deposition (Pittsburgh Compound‐B, n=24) and cerebral pH (T1rho MRI, n=19) were measured. Global CBF was quantified under basal and memory recall of a learned word list to calculate the absolute change in CBF between memory and basal conditions (ΔCBF). Global cerebrovascular reserve (CVR%) to a pharmacological stimulus (acetazolamide) was measured as an index of cerebrovascular function independent of neuronal activity.ResultsIn the entire cohort, global cognitive performance was one standard deviation lower in men compared with women (p=0.01) despite no differences in education (p=0.11). Education attenuated the detrimental effects of PP (education*PP, B=0.06±0.02, p=0.01, F=11.3, p<0.001, R2=0.53) on global cognitive performance in men only. In the subset, CVR% was higher in women compared with men (50±6 vs. 25±3%, p<0.001); however, basal CBF, ΔCBF, brain pH and amyloid burden did not differ by sex (p>0.39). Higher PP was associated with lower CVR% in men (r= −0.70, p=0.001, covariate: age) but not women (r=0.40, p=0.29). CVR% was correlated with a greater increase in CBF during the memory condition (ΔCBF) in women (r=0.75, p=0.01, age) but not men (r=0.39, p=0.49). A larger reduction in CBF during the memory condition (ΔCBF) was associated with elevated cerebral acidosis in men (r=‐0.80, p=0.01, age) but not women (r= −0.48, p=0.19). Finally, higher RBANs performance was correlated with a greater ΔCBF in response to the memory stimulus in women (r=0.83, p=0.02, education) but not men (r=0.34, p=0.31).ConclusionEducation moderates the effects of PP on cognitive performance in men only. However, greater cerebrovascular responsiveness to a pharmacological or memory stimulus is associated with higher cognitive performance in women only. These data suggest mechanisms contributing to cognitive decline may differ between men and women.Support or Funding InformationNIH1R03AG047306, 1S10OD025025‐01