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The Middle-Aged Brain: Biological sex and sex hormones shape memory circuitry.

E. Jacobs,J. Goldstein

Published 2018 in Current Opinion in Behavioral Sciences

ABSTRACT

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 (for review, see Cabeza, Nyberg & Park, 2016). 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 turn, it obscures our understanding of sex-dependent pathways that may shape the brain early in the aging process. The median age of menopause is 52.4 years (Gold et al., 2001). The time between the first clinical appearance of decreased ovarian function (i.e. shorter inter-menstrual time periods) to menstrual irregularity and final amenorrhea is variable and protracted, occurring over several years. The menopausal transition is marked by a decline in ovarian hormone production and is a time when many women report changes in memory and attention (e.g. “menopause fog”). Two decades of rodent and nonhuman primate studies have established the role of sex hormones in the synaptic organization of the hippocampus and prefrontal cortex (PFC), and their impact on memory function (Frick et al., 2017, Hara et al. 2015). A parallel literature has emerged within the human cognitive neuroscience field to identify the role of sex hormones in memory circuitry in the human brain. 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 sex dependent 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.

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