Reproductive history and later-life brain health: The Bogalusa Heart Study

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Even after accounting for longevity, women are at higher risk for Alzheimer's Disease and Related Dementias (AD/ADRD), and disease progression and underlying molecular mechanisms differ by sex. The metabolic exposures of reproduction are one potential biological driver of sex differences. Pregnancy has strong effects on metabolism: high parity is associated with later-life diabetes risk, due possibly to persistent alterations in glucose homeostasis and activity, while breastfeeding is protective against metabolic risk. Because insulin resistance and type 2 diabetes mellitus are risk factors for AD, it is plausible that these reproduction-related metabolic exposures contribute to AD risk among women. However, it is unknown whether these exposures are important predicters or modifiers of risk of cognitive decline and AD and whether such cognitive changes are driven by AD-related neurobiological substrates including cerebral amyloid. The Bogalusa Heart Study is a study of cardiovascular health starting in childhood in a biracial (65% white, 35% black) cohort. Substudies include Bogalusa Babies, which interviewed 1803 women about their reproductive histories, and an ongoing study of childhood and early adulthood glycemic control and midlife cognition, brain structure, and brain function. In this project, we build on this protocol, providing a combined sample of 950 women with cognitive measures, 450 with MRI and 275 with PET scans. The overall objective is to assess the relationship among reproductive history, lifetime metabolic exposures, and midlife cognition and brain function, as measured by AD-relevant instruments and markers. The overall hypothesis is that pregnancy-related metabolic exposures will be associated with later-life brain health even after control for pre-pregnancy metabolic exposures (glucose and insulin resistance), and that these effects will be partially mediated by metabolic exposures post- pregnancy. The hypothesis will be tested through the following specific aims: 1) Examine reproductive history as a predictor of midlife cognition and cognitive decline; 2) Examine reproductive history as a predictor of brain structural and functional outcomes; and 3) Examine reproductive history as a predictor of AD- and metabolism- related molecular substrates of cognition. Preliminary data showed worse cognition associated with nulliparity, lack of history of breastfeeding, and worse early-life glucose levels, especially among women. Therefore, the hypotheses are that nulliparity, shorter/no history of lactation, higher birthweight, and higher gestational weight gain will be associated with worse scores on a standardized neurocognitive battery and greater cognitive decline; lower gray matter volume and greater white matter hyperintensity volume on 3T brain MRI, and lower fMRI activation to a Stroop task; and higher burden of cerebral amyloid on 18F-florbetapir PET and cerebral glucose hypermetabolism on 18F-fluorodeoxyglucose PET. This study is uniquely situated to provide critical new information that could help identify treatments and interventions that may block the effects of metabolic or endocrine dysfunction on the brain, and add impetus to improving health in early adulthood to prevent AD.