The impact of sex on memory during aging and Alzheimer's disease progression: Epigenetic mechanisms

Alzheimer's disease (AD) is a leading cause of dementia, disability, and death in the elderly. While the etiology of AD is unknown, there are several established risk factors for the disease including, aging, female sex, and genetics. However, specific genetic mutations only account for a small percentage (1-5%) of AD cases and the much more common sporadic form of the disease has no causative genetic basis, although certain risk factor genes have been identified. While the genetic code remains static throughout the lifetime, the activation and expression levels of genes change dynamically over time via epigenetics. Recent evidence has emerged linking changes in epigenetics to the pathogenesis of AD, and epigenetic alterations also modulate cognitive changes during physiological aging. Aging is the greatest risk factor for the development of AD and two-thirds of all AD patients are women, who experience an increased rate of symptom progression compared to men of the same age. In humans and other mammalian species, males and females experience aging differently, raising the important question of whether sex differences in epigenetic regulation during aging could provide an explanation for sex differences in neurodegenerative diseases such as AD. This review explores distinct epigenetic changes that impact memory function during aging and AD, with a specific focus on sexually divergent epigenetic alterations (in particular, histone modifications) as a potential mechanistic explanation for sex differences in AD.