Memory and Brain Aging

Over six decades of epidemiological research suggests that women have twice the risk of men for memory disorders. In fact, Alzheimer’s Disease (AD) afflicts approximately 5.4 million Americans and two-thirds of them (or 3.3 million people) are women.  Although this is in part due to the later age of mortality among women, it has been demonstrated that the increased risk exists, adjusted for chronologic age. Thus, understanding the pathophysiology of sex differences in aging of the memory circuitry has important implications for reduction of disorders of later life worldwide, particularly in women.  Most work on cognitive aging begins with study samples at >age 60. However, the risk of vulnerability for cognitive aging is expressed in the late age 40’s to 50’s, a period during which women transition into menopause.  In fact, previous work demonstrated the regulation of the memory circuitry by hormones and their implications for understanding changes in brain circuitry aging.  Animal work has demonstrated the regulation of cognitive aging genes and AD pathology by sex steroid hormones.  Women have greater pathology even in the face of similar genetic risk.  Finally, sex differences in AD risk may be due to the fact that women are at higher risk for other medical conditions that have been independently associated with risk for AD (such as depression).  Thus we believe there are shared causes resulting in sex differences across chronic diseases.  Sex differences in AD risk are expressed after the menopausal transition.  This is a curious fact, given that healthy women actually have better verbal memory performance than healthy men  – a female advantage that dissipates after menopause. Although we know this sex difference in memory decline exists, there has been little systematic focus on understanding the reasons why.   

Our team has taken a developmental approach to thinking about sex differences in brain aging... that is we are mapping out sex-dependent developmental pathways that result in sex differences in memory decline in one’s 50’s to 60’s, that we believe lay the vulnerability for why we see sex differences in AD risk in mid-life.  We believe these pathways include the impact of hormones and sex differences in genes, metabolic (e.g., insulin, glucose) and immune pathways. We have been following a prenatal cohort now in their early 50’s to investigate these developmental pathways on sex differences in memory circuitry aging.  Dr. Emily Jacobs is leading studies of sex differences in hormonal and genetic regulation of memory circuitry aging. We argue that an understanding of the sex-dependent risk for AD will be critical in the development of sex-dependent therapeutics and prevention strategies for AD. 

Taking a developmental, lifespan perspective to studying aging of the brain is an optimistic approach, since it will provide the basis for early intervention strategies. In the service of this, we initiated the creation of a healthy aging cohort between the ages of 45-65 (with a goal of 10,000) that will be used to test the development of a sex-dependent risk algorithm for AD to identify a population for early therapeutic intervention and to establish a resource for future generations to follow into older aging.