The middle-aged brain: biological sex and sex hormones shape memory circuitry

Over the last quarter century, a staggering number of brain imaging studies have probed the neural basis of age-related cognitive decline. Using multimodal brain imaging tools, we now have a clearer understanding of the morphological, neurochemical, and neurophysiological changes that accompany age-related declines in working memory, selective attention, inhibitory control, episodic memory and more. These studies generally target adults over the age of 65, a historical precedent rooted in the average retirement age of U.S. wage-earners. An unintended consequence of this adopted standard is that it overlooks one of the most significant neuroendocrine changes in a woman's life - the transition to menopause. In this review, we summarize recent studies of the neural and cognitive changes that unfold in the middle decade of life (ages 45-60), as a function of sex, reproductive stage, and sex steroid hormones. As the 'cognitive neuroscience of aging' field evolves, applying a women's health lens to the study of the aging brain will enhance the translation of these findings for both sexes and ensure that men and women get the full benefit of our research efforts. By ignoring the midlife window, we risk missing critical clues that could reveal sex-dependent risk factors of future neurodegenerative disease.