Examining Sex-Specific Effects on White Matter Integrity and Brain Function in Familial Alzheimer's Disease and Vascular Dementia

PROJECT SUMMARY/ABSTRACT Cerebral small vessel disease (CSVD) is a neurological condition characterized by damage to the small blood vessels in the brain. It is estimated that 20% to 30% of adults aged 65 and older may have some form of CSVD, and this prevalence increases with advancing age. In CSVD, vascular impairment can contribute to the accumulation of amyloid-beta protein, a hallmark feature of Alzheimer's disease (AD), by hindering its clearance from the brain and promoting the formation of amyloid plaques. Moreover, CSVD can exacerbate cognitive decline in individuals with Vascular Contributions to Cognitive Impairment and Dementia (VCID). The combination of vascular and degenerative processes in VCID can lead to more severe cognitive impairment than expected with either condition alone. Early detection of CSVD is crucial for preventing VCID and AD in older adults. The examination of underlying mechanisms of CSVD using early onset “pure” hereditary models for vascular dementia (e.g., due to Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy [CADASIL]) and AD (e.g., due to autosomal dominant mutations, ADAD) is a promising strategy for identifying diagnostic and therapeutic approaches for the more common sporadic forms of these diseases. In VCID and AD, pathology is already present in the brain for many years before the emergence of cognitive symptoms, suggesting that treatments may have the best chance of success in the preclinical stage. An important consideration is that sex differences occur in VCID and AD. Females are disproportionately affected by AD, comprising two-thirds of diagnosed individuals, whereas the prevalence of vascular dementia is about 44% higher in males than females. The mechanisms underlying these sex-specific differences remain unclear. Identifying sex-specific patterns of neurodegeneration in the early stages of cognitive impairment and dementia will enable tailored interventions, sex-specific preventative strategies, and improved diagnostic accuracy for both males and females. The overall aim of this project is to examine sex differences in VCID and AD by measuring white matter integrity, functional brain connectivity, and cognitive function in individuals genetically determined to develop early-onset VCID (CADASIL) or AD (ADAD, Presenilin-1 E280A). My overarching hypothesis is that white matter integrity and patterns of functional connectivity can be used as predictors of cognitive impairment and dementia in CADASIL and ADAD. Further, I expect that white matter integrity and functional connectivity can serve as biomarkers that predict distinct outcomes for males and females, not only in VCID but also in ADAD, the latter of which has more traditionally been characterized by measures of tau and amyloid pathology. Through this project, I will (1) gain expertise in neuroimaging analysis related to white matter disease in VCID and ADAD, (2) receive training on sex differences in dementia and sex-specific risk factors contributing to disease outcomes, and (3) establish professional relationships with research collaborators to strengthen the basis of a future career as a clinical neuroscientist.