Alzheimer's disease (AD) is the most common type of dementia in the elderly and poses a heavy health burden to the patients and the society. Women have a higher prevalence of AD than men, and a faster decline and deterioration of cognitive functions. The entorhinal cortex (EC) is one of the earliest structures affected in AD. In recent postmortem human brain research, the team led by Prof Ai-Min Bao, from the School of Brain Science and BrainMedicine of Zhejiang University in close collaboration with Prof. Dick Swaab in Amsterdam observed in donorswith intact cognition higher levels of hyperphosphorylated Tau (pTau) in the EC of elderly women than well-matched men (Hu et al., Neuropathol Appl Neurobiol. 2021; 47:958-966). This implied that the EC was an excellent structure to further study the mechanisms underlying the remarkable susceptibility of the EC for AD in women.

Fig 1: Distribution of the neuropathological Braak and Amyloid staging of AD over the brain and the accumulation of AD neuropathological proteins in relation to these neuropathological staging in the EC of cognitively intact elderly.

On March 24, 2023. Prof BAO Aimin's team from Zhejiang University School of Medicine subsequently published an article titled “Sexually dimorphic age-related molecular differences in the entorhinal cortex of cognitively intact elderly: Relation to early Alzheimer's changes” in the Journal Alzheimer’s & Dementia.

Researchers measured the changes in 12 characteristic molecules in relation to age by quantitative immunohistochemistry or in situ hybridization in the postmortem EC of cognitively intact elderly women and well-matched men (46-93 years of age). The molecules were arbitrarily grouped into sex steroid-related molecules, markers of neuronal activity, neurotransmitter-related molecules, and cholinergic activity-related molecules. Impressively, the molecular changes in relation to age indicated increasing local estrogenic and neuronal activity, accompanied by a higher and faster hyperphosphorylated Tau accumulation in women’s EC, versus a mainly stable local estrogenic/androgenic and neuronal activity in men’s EC. This indicated that EC employs a different neurobiological strategy in women and men to maintain cognitive function, which seems to be accompanied by an earlier start of AD in women. In other words, the activation in the elderly women’s EC may not only be a compensatory response to the altered brain functions related to age but also be ‘the beginning of the end’ in terms of the start of AD.

Fig 2. Sex differences in the alterations of sex steroid-related molecules and neuronal activity-related molecules in relation to age in the EC of cognitively intact elderly.

Dead brains can tell the truths, said Prof BAO Aimin. These findings from human postmortem brains are novel and inspiring, especially in relation to the sex difference in vulnerability for AD.

Source: School of Medicine,Zhejiang University