Sex/gender differences in the clinical trajectory of Alzheimer’s disease: Insights into diagnosis and cognitive reserve

Abstract

• Females show a cognitive advantage in early AD followed by more rapid decline. • Females’ verbal memory strengths may delay MCI detection. • Non sex-adjusted verbal memory norms result in about 20% MCI diagnostic errors. • We need to identify cognitive assessments sensitive to early decline in females. • Tailored diagnostics are essential for equitable AD intervention. The two-times higher prevalence of Alzheimer’s disease (AD) in females versus males is well-known; however, there are also sex/gender differences in clinical presentation and diagnostic accuracy that are less examined but equally important to understand in terms of improving early detection, intervention and disease tracking in each sex/gender. This review explores how these disparities in clinical presentation manifest across the AD continuum, with a focus on the earlier stages of preclinical AD and mild cognitive impairment (MCI). We summarize evidence indicating that female’s verbal memory advantage may mask early cognitive decline, leading to delayed MCI diagnosis and limiting opportunities for early intervention. Conversely, females demonstrate steeper cognitive decline at later disease stages compared to males. These patterns align with the cognitive reserve theory, suggesting female’s verbal memory strength may act as a domain-specific resilience factor. Lastly, this review emphasizes the need for sex-sensitive diagnostic tools to improve early detection accuracy and equity in clinical practice.

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