Reduced gene expression in neocortical and limbic brain regions in female Alzheimer's patients correlates with cognitive and neuropathological phenotypes.

Women have a higher incidence of Alzheimer's disease (AD), even after adjusting for increased longevity. Thus, there is an urgent need to identify the molecular networks that underpin the sex-associated risk of AD. Recent efforts have identified as a key regulator of tau phosphorylation signaling pathway is the only gene, to date, that when deleted can cause both tau and Aβ-related pathologies in an age-dependent manner. We analyzed multiple brain transcriptomic datasets focusing on sex differences in mRNA levels, in an aging and AD cohort, which revealed reduced levels driven by females. Then, we validated this observation in an independent dataset (ROS/MAP) which also revealed that is negatively correlated with multiregional neurofibrillary tangle density and global cognitive function, in females only. Additional analysis revealed a decrease in in subjects with mild cognitive impairment (MCI) compared with aged individuals, again, driven predominantly by female subjects. Our results show that while both male and female AD patients show decreased expression, changes occur before the onset of clinical symptoms of AD in females and correlate to early events associated with AD risk (e.g., synaptic dysfunction). These changes are specific to neurons, and may be a potential prognostic marker to assess AD risk in the aging population and even more so in AD females with increased risk of AD.