Sex-related differences in the relationship between β-amyloid and cognitive trajectories in older adults.

Objective: We aimed to test the hypothesis that elevated neocortical β-amyloid (Aβ), a hallmark feature of Alzheimer’s disease (AD), predicts sex-specific cognitive trajectories in clinically normal older adults, with women showing greater risk of decline than men. Method: Florbetapir Aβ positron emission tomography (PET) was acquired in 149 clinically normal older adults (52% female, M_age = 74). Participants underwent cognitive testing at baseline and during annual follow-up visits over a timespan of up to 5.14 years. Mixed-effects regression models evaluated whether relations between baseline neocortical Standardized Uptake Value Ratio (SUVR) and composite scores of episodic memory, executive functioning, and processing speed were moderated by sex (male/female) and apolipoprotein E (APOE) status (ε4 carrier/noncarrier). Results: Higher baseline SUVR was associated with longitudinal decline in episodic memory in women (b = −1.32, p < .001) but not men (b = −0.30, p = .28). Female APOE ε4 carriers with elevated SUVR showed particularly precipitous declines in episodic memory (b = −4.33, p < .001) whereas other cognitive domains were spared. SUVR did not predict changes in executive functioning or processing speed, regardless of sex (ps >.63), though there was a main effect of SUVR on processing speed (b = 2.50, p = .003). Conclusions: Clinically normal women with elevated Aβ are more vulnerable to episodic memory decline than men. Understanding sex-related differences in AD, particularly in preclinical stages, is crucial for guiding precision medicine approaches to early detection and intervention. (PsycInfo Database Record (c) 2020 APA, all rights reserved)Key Points—Question: This study evaluated whether older men and women are differentially susceptible to cognitive decline in very early, presymptomatic stages of the Alzheimer’s disease (AD) continuum. Findings: Our results indicated that clinically normal women with elevated β-amyloid (a protein associated with AD that accumulates in the brain) show significantly greater rates of memory decline over time compared with men, especially when they carry the apolipoprotein E (APOE) ε4 allele (a genetic risk factor for AD). Importance: These findings suggest that women are particularly vulnerable to memory changes in early stages of AD and may help to improve early diagnosis and intervention efforts. Next Steps: Future work should investigate biological (e.g., hormonal, immunological, and cardiovascular), sociocultural (e.g., educational and occupational disparities), and other factors that may help to explain why women are disproportionately at risk for early AD-related cognitive changes.