Examining sex-differences in puberty and brain development in carriers of autosomal dominant Alzheimer's disease

Massachusetts General Hospital, Boston MA

Investigators

Abstract

Research suggests that shorter reproductive span and early menopause are associated with increased dementia risk. Mechanisms associated with the impact of sex steroid hormones on Alzheimer’s disease (AD) need to be further clarified. Rare families with autosomal dominant Alzheimer’s Disease (ADAD) offer a unique opportunity to characterize the earliest biological mechanisms associated with predisposition to develop AD later in life. Findings from these families can help guide research on the sporadic late-onset AD; the common form of the disease leading to dementia. ADAD carriers develop early-onset dementia with near 100% certainty, while non-carriers from the same families are virtually free from AD, especially at younger ages. We propose to study Presenilin-1 (PSEN1) E280A carriers from the world-wide largest known ADAD kindred, which includes over 6,000 living relatives with over 1,200 mutation carriers. Carriers from these kindred have a median age of 49 years at dementia onset. In a pioneering examination of the earliest sex differences in children with the E280A mutation, we studied general intellectual abilities (using the WISC-IV) and found that male carriers had worse working memory compared to female carriers, suggesting sex-dependent vulnerability in cognition starting at earlier ages than in the general population. These original findings motivate the current examination of the impact of puberty on cognition and cerebral microstructure in AD. More research is needed to clarify the effect of sex differences and related hormonal differences on brain development and cognition across puberty in individuals at the highest risk of dementia. Understanding the early development of these individuals is sine qua none to elucidate the mechanisms underlying early sex-dependent risks and resilience to AD. This investigation is unique and fundamental to guide future research and treatments in both early and late-onset AD. Here we aim to test the novel hypothesis that children carrying the PSEN1 E280A mutation have distinct functional brain development consequences around puberty, and that those differences are sex-specific and set the foundation for future sex-differences in their risk and resilience to AD. To test this hypothesis, we will examine relevant physical and biochemical markers of puberty in relation to brain function and microstructure, using advanced MRI brain maturation methods and graph-based network analyses in 200 children from the Colombian kindred with the PSEN1 E280A mutation aged 7-16 years. Aims are: 1) Examine the role of puberty in carriers’ cognitive and socio-emotional abilities; 2) Examine associations between carriers’ pubertal status and brain microstructure and composition using whole brain myelin water fraction and axonal density imaging, and 3) Determine the association between carriers’ pubertal status and organization of functional connections in the brain. This project is a unique opportunity to advance our understanding of the neurobiology driving sex differences in AD risk and resilience at early life.