Sexual dimorphism and susceptibility to Alzheimer's disease: Understanding genetic involvement and other risk factors

Alzheimer's disease (AD) is a progressive neurodegenerative condition characterized by persistent cognitive decli ne, tau-containing intracellular neurofibrillary tangles, and β-amyloid (Aβ)-containing extracellular plaques. Early symptoms include patchy memory loss and some behavioural abnormalities. There is a plethora of studies that have reported sexual dimorphism and a higher prevalence of Alzheimer's disease in women. However, the molecular mechanisms responsible for these differences remain an enigma. The increasing aging population, as well as the decline in estrogen levels, have been attributed to increased risk in the development of AD in women. Hormone replacement therapy (HRT) has been proposed as an approach for tackling the increased AD susceptibility in women; increased AD vulnerability in men is also linked to testosterone levels. In addition to the hormonal influence as one of the causative factors for increased risk of AD, there is the involvement of genetic factors, with APOE ε4 gene documented as a risk gene leading to tau pathological changes in the brain of female AD patients. Here, we aim to systematically examine literature on the factors and molecular mechanisms responsible for sexual dimorphism in increased vulnerability and pathological features of AD, with the hope that it may provide information on the diagnosis and therapeutic interventions in AD.