Sex Differences in the Clinical Expression of Alzheimer's Disease Neuropathology and Their Underlying Biological Mechanisms

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PROJECT SUMMARY/ABSTRACT Sex differences in the risk of Alzheimer’s disease (AD) and AD pathology burden have been extensively studied; however, little is known about how AD pathology burden relates to clinical symptoms in women versus men. Evidence of a cognitive advantage in the preclinical stage of AD, yet a two-times steeper cognitive decline thereafter indicate that the question of sex differences in the clinical manifestation of AD pathology is an important one. These sex differences have clinical implications in that our established thresholds for AD clinical and biological markers used to diagnose and track disease were typically generated without consideration for sex disparities. If women are better able to maintain what our current cognitive thresholds consider “normal” cognition until a more advanced pathology state than men, then diagnosis of MCI could be delayed, thus limiting the opportunity for early intervention. We hypothesize that sex differences in the clinical translation of AD pathology results from a sex-specific balance of brain-related resilience/risk factors that change with disease stage. Our proposal is particularly innovative in that we will first characterize sex differences in how AD pathology relates to clinical symptoms by disease stage and then examine its neurobiological underpinnings and clinical implications. We will leverage both in-vivo, longitudinal biomarker data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and prospective neuropathological data in brain tissue from multiple Alzheimer’s Disease Research Centers (ADRCs). Given their strong ties to AD pathology and the sex differences that our earlier data show, we will examine the brain resilience/risk mechanisms of (1) PET-measured brain glucose metabolism, (2) NMDAR density, a marker of glutamate neurotransmission, and (3) translocator protein 18kDA (TSPO) levels, a marker of microglial activation. Specifically, Aim 1 will utilize ADNI data to examine sex differences in trajectories of cognitive function and their relationship to longitudinal variation in AD pathology (Aβ and Tau) and brain metabolism by AD stage. In Aim 2, we will conduct in vitro autoradiography in hippocampal and cortical brain tissue of 60 normal control, 60 mild cognitive impairment and 60 AD dementia autopsy cases to determine sex differences in plaque, tangle, NMDAR and TSPO density and how they relate to each other and to antemortem cognitive function in each of the three diagnostic groups. In Aim 3, we will take action on these sex differences by generating sex-specific cut-scores for cognitive tests commonly used in MCI/AD diagnostic criteria with the optimal balance of sensitivity/specificity in detecting the presence of clinically-significant levels of AD biomarkers/pathology. The public health benefits of our project would be significant in that by understanding and accounting for sex disparities in our clinical and biomarker approaches to AD diagnosis, we will improve clinical and biomarker approaches to disease diagnosis and tracking in both sexes and possibly identify sex-specific therapeutic targets.