Sex differences in the association between AD biomarkers and cognitive decline

Abstract

Women are disproportionately affected by Alzheimer's disease (AD) in terms of both disease prevalence and severity. Previous autopsy work has suggested that, in the presence of AD neuropathology, females are more susceptible to the clinical manifestation of AD. This manuscript extends that work by evaluating whether sex alters the established associations between cerebrospinal fluid (CSF) biomarker levels and brain aging outcomes (hippocampal volume, cognition). Participants were drawn from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and included individuals with normal cognition (n = 348), mild cognitive impairment (n = 565), and AD (n = 185). We leveraged mixed effects regression models to assess the interaction between sex and baseline cerebrospinal fluid biomarker levels of amyloid-β42 (Aβ-42) and total tau on cross-sectional and longitudinal brain aging outcomes. We found a significant interaction between sex and Aβ-42 on longitudinal hippocampal atrophy (p = 0.002), and longitudinal decline in memory (p = 0.017) and executive function (p = 0.025). Similarly, we observed an interaction between sex and total tau level on longitudinal hippocampal atrophy (p = 0.008), and longitudinal decline in executive function (p = 0.034). Women with Aβ-42 and total tau levels indicative of worse pathological changes showed more rapid hippocampal atrophy and cognitive decline. The sex difference was particularly pronounced among individuals with MCI, with lower education, and varied by APOE ε4 allele. These results suggest females may be more susceptible to the clinical manifestation of AD.

Keywords: Alzheimer’s disease; Biomarkers; Cognition; Hippocampus; Sex differences.

Figure 1. Females show a faster rate of hippocampal atrophy in the presence of enhanced (low levels) of CSF Aβ-42. (IMAGE FOR REVIEW PURPOSES ONLY)

CSF Aβ-42 levels are along the x-axis. Annual change in left hippocampal volume is along the y axis. Sex is differentiated by color with males in red and females in blue. The gray shading around the regression line represents the standard error.

Figure 2. Females show a faster rate of hippocampal atrophy in the presence of enhanced CSF tau levels

CSF Aβ-42 levels are along the x-axis. Annual change in right hippocampal volume is along the y axis. Sex is differentiated by color with males in red and females in blue. The gray shading around the regression line represents the standard error.