Women can bear a bigger burden: ante- and post-mortem evidence for reserve in the face of tau

Abstract

In this study, we aimed to assess whether women are able to withstand more tau before exhibiting verbal memory impairment. Using data from 121 amyloid-β-positive Alzheimer's Disease Neuroimaging Initiative participants, we fit a linear model with Rey Auditory Verbal Learning Test score as the response variable and tau-PET standard uptake value ratio as the predictor and took the residuals as an estimate of verbal memory reserve for each subject. Women demonstrated higher reserve (i.e. residuals), whether the Learning (t = 2.78, P = 0.006) or Delay (t = 2.14, P = 0.03) score from the Rey Auditory Verbal Learning Test was used as a measure of verbal memory ability. To validate these findings, we examined 662 National Alzheimer's Coordinating Center participants with a C2/C3 score (Consortium to Establish a Registry for Alzheimer's Disease) at autopsy. We stratified our National Alzheimer's Coordinating Center sample into Braak 1/2, Braak 3/4 and Braak 5/6 subgroups. Within each subgroup, we compared Logical Memory scores between men and women. Men had worse verbal memory scores within the Braak 1/2 (Logical Memory Immediate: β = -5.960 ± 1.517, P < 0.001, Logical Memory Delay: β = -5.703 ± 1.677, P = 0.002) and Braak 3/4 (Logical Memory Immediate: β = -2.900 ± 0.938, P = 0.002, Logical Memory Delay: β = -2.672 ± 0.955, P = 0.006) subgroups. There were no sex differences in Logical Memory performance within the Braak 5/6 subgroup (Logical Memory Immediate: β = -0.314 ± 0.328, P = 0.34, Logical Memory Delay: β = -0.195 ± 0.287, P = 0.50). Taken together, our results point to a sex-related verbal memory reserve.

Keywords: Alzheimer’s disease; sex differences; tau; verbal memory.

Graphical Abstract

Figure 1

Women demonstrate higher reserve to tau than men. Scatter plots (A) between RAVLT Learning and tau load or (C) between RAVLT Delay and tau load. RAVLT Learning, RAVLT Delay and tau load were regressed onto age, years of education and ε4 status before plotting. Here, tau load is the average of regional SUVRs from a set of Alzheimer's disease-vulnerable regions in temporal cortex. The boxplots with swarm plot overlays are residuals from a linear model predicting (B) RAVLT Learning or (D) RAVLT Delay from tau load, age, years of education and ε4 status. Women have significantly higher residuals than men. SUVRs = Standard uptake value ratios.

Figure 2

Among participants with similar levels of Alzheimer's disease-related pathology, women perform better on verbal memory tests. On the y-axis are raw scores for (A–C) LM Immediate and (D–F) LM Delay. Within the Braak 1/2 group and within the Braak 3/4 group, women had significantly higher scores on both LM Immediate and LM Delay. We observed no significant differences in LM score in the Braak 5/6 group.