Neuroendocrine signaling as a pathological seed for the female bias of Alzheimer’s disease and the concept of estrobolome

The prevalence of Alzheimer's disease (AD) is anticipated to escalate with the global increase in life expectancy. Although sex-based differences in AD have been previously documented, doubts persist regarding the relationship between sex and pathophysiological pathways. Sex hormones may contribute to these disparities, with a heightened risk of AD-related dementia associated with oophorectomy before menopause. We cannot ascertain if estrogens alone are solely accountable for this accelerated pathological progression of the disease. Estrogens are regulated by the gut microbiota. Thus, the gut-estrogen-brain axis appears to be implicated as a potential new influencer in the pathophysiology of AD, as the female microbiome differs from the male gut microbiome. This suggests it could be a risk factor for the higher prevalence of AD in women. This review speculates on the possible mechanisms for AD prevalence in women, including both anatomical and neuroendocrinological perspectives.