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.

Highlights Low baseline default-mode integrity and high amyloid presage future network atrophy. The high amyloid group drives the within-network atrophy effect. Alzheimer’s disease-related biomarkers didn’t explain the high amyloid group’s effect. Results support links between functional and cortical integrity and connectivity as a protective factor.

A functional gradient has been proposed across the medial temporal lobes (MTL) such that the anterior MTL is thought to support processing of individual items (e.g., item memory and complex object perception), whereas the posterior MTL is thought to support item-context retrieval (e.g., source memory). Whereas functional imaging studies have provided evidence supporting this anatomical organization, results from structural analyses remain inconclusive. The current study examined the relationship between volume of MTL regions of interest (ROIs), and performance on a source memory task and a fine-grain complex object perception task, in healthy young adults (mean age = 21.5, range = 18-29). Using a semiautomated procedure, we segmented the parahippocampal and perirhinal cortices (PHC, PRC), posteromedial and anterolateral entorhinal cortices (pmERC, alERC), and posterior and anterior hippocampus (postHC, antHC) on high-resolution T2-weighted MRIs. Regional volumes were computed as proportions of intracranial volume, and as posterior-anterior volumetric ratios (PHC: PRC, pmERC:alERC, postHC:antHC). Partial-least squares regressions were applied to predict source and item memory, and perceptual discrimination accuracy, based on ROI and ratio volumes. In our ROI regressions, we found that postHC volume was positively correlated with a latent factor predicting source memory, and PRC and antHC volumes were negatively correlated to this latent factor. In our ratio regressions, we observed an effect relating the posterior-anterior distribution of gray matter across the MTL with source memory. Our results demonstrate differential associations between anterior and posterior MTL and source memory performance. Findings from this study highlight the importance of considering patterns of structure-behavior associations in the neurobiology of episodic memory.

Background Clinically normal females exhibit greater [18]F‐flortaucipir (FTP) PET signal than males in both temporal and neocortices. It remains unclear whether sex differences in neocortical regions are primarily explained by technical variability issues. We aimed to investigate the contribution of signal spillover/off‐target skull binding to sex differences in FTP‐PET. Next, we explored partial volume effects (PVE) by simulating sex differences in smoothed FTP‐PET signal. Discerning sex differences in tau signal versus noise is pivotal to understanding sex differences in the pathology of Alzheimer’s disease and associated tauopathies. Method 343 clinically normal (female=58%; mean[SD]=73.8[8.5] years) (female=38%; mean[SD]=76.9[7.3] years) participants from the Harvard Aging Brain Study and the Alzheimer’s Disease Neuroimaging Initiative underwent cross‐sectional FTP‐PET (standardized uptake value ratios [SUVrs]). For skull analyses, we created skull ROIs based on signal 12mm from the outer perimeter of voxels in FreeSurfer‐defined tau ROIs. Linear regression models estimated the main effects of sex across cortical tau ROIs while correcting for local skull binding. We simulated PVE by convolving group‐level SUVr means in each ROI with 6mm Gaussian kernels, and then compared the sexes with linear regression models post‐smoothing. Result Widespread sex differences in skull binding were observed (Table 1). Covarying for skull binding ameliorated weaker sex differences in cortical FTP signal but did not impact the largest effects. Sex differences in PVE were observed in both female and male directions; no clear sex‐related biases in PVE were found to impact cortical tau sex differences except for the rostral middle frontal region (Figure 1). Conclusion Our findings suggest that sex differences in FTP‐PET are not solely attributed to skull ‘clouding’ or PVE, but rather support hypotheses of female‐related tau vulnerability. Nevertheless, as only two potential confounds were investigated, and gross morphology/volumetric issues remain a key concern, further investigation is needed to fully elucidate this phenomenon. Investigations of sex differences in longitudinal tau accumulation (a few preliminary reports already suggest faster rates in females) will add further support to the argument that noise properties inherent in FTP‐PET do not significantly contribute to sex differences in cortical tau signal.