Sex Mediates Relationships Between Regional Tau Pathology and Cognitive Decline

Abstract

Objective: The goal of this study was to examine sex differences in tau distribution across the brain of older adults, using positron emission tomography (PET), and investigate how these differences might associate with cognitive trajectories.

Methods: Participants were 343 clinically normal individuals (women, 58%; 73.8 [8.5] years) and 55 individuals with mild cognitive impairment (MCI; women, 38%; 76.9 [7.3] years) from the Harvard Aging Brain Study and the Alzheimer's Disease Neuroimaging Initiative. We examined ¹⁸ F-Flortaucipir (FTP)-positron emission tomography (PET) signal across 41 cortical and subcortical regions of interest (ROIs). Linear regression models estimated the effect of sex on FTP-signal for each ROI after adjusting for age and cohort. We also examined interactions between sex*Aβ-PET positive / negative (+ / -) and sex*apolipoprotein ε4 (APOEε4) status. Linear mixed models estimated the moderating effect of sex on the relationship between a composite of sex-differentiated tau ROIs and cognitive decline.

Results: Women showed significantly higher FTP-signals than men across multiple regions of the cortical mantle (p < 0.007). β-amyloid (Aβ)-moderated sex differences in tau signal were localized to medial and inferio-lateral temporal regions (p < 0.007); Aβ + women exhibited greater FTP-signal than other groups. APOEε4-moderated sex differences in FTP-signal were only found in the lateral occipital lobe. Women with higher FTP-signals in composite ROI exhibited faster cognitive decline than men (p = 0.04).

Interpretation: Tau vulnerability in women is not just limited to the medial temporal lobe and significantly contributed to greater risk of faster cognitive decline. Interactive effects of sex and Aβ were predominantly localized in the temporal lobe, however, sex differences in extra-temporal tau highlights the possibility of accelerated tau proliferation in women with the onset of clinical symptomatology. ANN NEUROL 2020;88:921-932.

FIGURE 1:

Main effects of sex on ¹⁸F-Flortaucipir (FTP) standardized uptake value ratios (SUVrs) after adjusting for age and cohort (A) with region of interest (ROI)-based analyses across all participants (corrected p < 0.007), (B) showing vertex-wise (false discovery rate [FDR] corrected p = 0.016), and (C) showing beta weights and standard errors for each ROI with corresponding model R² (bars to the right denoting female > male [F > M]). ns = not significant; PET = positron emission tomography; PVC = partial volume corrected; STS = superior temporal sulcus.

FIGURE 2:

Interactive effects of sex and β-amyloid (Aβ) positive / negative (+ / −)on ¹⁸F-Flortaucipir (FTP) standardized uptake value ratios (SUVrs) after adjusting for age and cohort (A) with region of interest (ROI)-based analyses within Aβ + participants only (n = 129; corrected p < 0.007), (B) β standardized and standard error for each ROI with corresponding model R² (bars to the right denoting female > male [F > M]), and (C) model estimates of FTP SUVrs in the inferior temporal cortex (with 95% confidence intervals) in men and women with Aβ-positron emission tomography (PET) +/−. ns = not significant; PVC = partial volume corrected; STS = superior temporal sulcus.

FIGURE 3:

Density maps depicting the distributions of ¹⁸F-Flortaucipir (FTP)-signal in regions that are differentiated by a sex*Aβ interaction. Aβ = β-amyloid; PET = positron emission tomography; SUVr = standardized uptake value ratio.

FIGURE 4:

Interactive effects of sex and apolipoprotein ε4 (APOEε4) on ¹⁸F-Flortaucipir (FTP) standardized uptake value ratio (SUVr) after adjusting for age and cohort (A) with region of interest (ROI)-based analyses within APOEε4 carriers only (n = 109; corrected p < 0.007), (B) β standardized and standard error for each ROI with corresponding model R² (bars to the right denoting female > male [F > M]), and (C) model estimates (with 95% confidence interval) of FTP SUVr in men and women with and without APOEε4 carriage. ns = not significant; PET = positron emission tomography; PVC = partial volume corrected; STS = superior temporal sulcus.

FIGURE 5:

Spaghetti plot of cognitive trajectories over time in clinically normal individuals (0th time represents the first ¹⁸F-Flortaucipir [FTP]-positron emission tomography [PET] scan) and faceted by a tertile split of composite FTP-PET signal (top = meta-region of interest [ROI], middle = meta temporal ROI, and bottom = reference-ROI) with quadratic fit curves stratified by sex. PACC = Preclinical Alzheimer’s Cognitive Composite.

FIGURE 6:

Main effects of sex on ¹⁸F-Flortaucipir (FTP) standardized uptake value ratio (SUVr) signal in clinically normal individuals only, showing beta weights and standard errors for each region of interest (ROI) with corresponding model R² (bars to the right denoting female > male [F > M]). Red indicates multiple comparison significance p < 0.007, purple indicates p < 0.05, and blue indicates subthreshold estimates. PET = positron emission tomography; PVC = partial volume corrected; STS = superior temporal sulcus.

FIGURE 7:

Main effect of sex on ¹⁸F-Flortaucipir (FTP) standardized uptake value ratio (SUVr) after adjusting for age and cohort (region of interest [ROI]-based analyses): (A) Alzheimer’s Disease Neuroimaging Initiative (ADNI) uncorrected, (B) ADNI corrected, (C) Harvard Aging Brain Study (HABS) uncorrected, and (D) HABS corrected.