Synergistic contributions of cerebrovascular disease and neuroinflammation to Alzheimer's disease in adults with Down syndrome

PROJECT SUMMARY Down syndrome (DS) is considered a genetic form of Alzheimer’s disease (AD). Most adults with DS have AD pathology by age 40 and progress to dementia by 60 years old. Studying AD in adults with DS is critical for two reasons. First, individuals with DS are living longer and most will experience dementia in their lifetimes, so AD represents an emerging public health crisis in this population. Second, as the pathophysiological progression of AD in adults with DS is considered similar to AD in the neurotypical population, the study of AD in DS has great potential to provide insight into pathogenesis, course, and prevention or treatment strategies for the neurotypical population as well. Despite a primary focus on the precipitating role of beta amyloid in AD, there is increasing evidence that cerebrovascular disease and neuroinflammation play a critical role in AD pathogenesis and progression. The proposed study will use a cross-disciplinary approach to understand: 1) the independent and interactive consequences of cerebrovascular lesions and neuroinflammation on AD pathology and downstream cognitive decline, 2) the relationship between cerebrovascular disease, blood-brain barrier disruption, and neuroinflammation with AD pathology, and 3) the postmortem relationships among small vessel cerebrovascular disease, neuroinflammation, and tau pathology. These aims will be examined in the Alzheimer’s Disease Biomarker Consortium – Down Syndrome, the largest longitudinal cohort study of aging in adults with DS, by examining the independent and synergistic impact of cerebrovascular and inflammatory markers on the pathophysiology and progression of AD in adults with DS. This fellowship will prepare the applicant, Natalie Edwards, for an independent, translational research career, centered on the contributions of cerebrovascular disease (CVD), neuroinflammation, blood-brain barrier (BBB) disruption, and their interactions on the pathophysiology and progression of AD in adults with DS. The comprehensive training plan focuses on an advanced methodological and biological understanding of the role of CVD and neuroinflammation in DS-AD through formal coursework, hands-on experience, mentorship, and professional development. Natalie will be supported by a mentorship team with a long history of collaboration, commitment to training, and expertise in AD and DS, including Adam Brickman at Columbia University, Elizabeth Head at University of California, Irvine, and Donna Wilcock at Indiana University. The mentorship team will provide topical training in AD, DS, neurobiology and neuropsychology of neurodegenerative diseases, vascular biology, and applied training in neuroimaging, biofluidic biomarkers, and neuropathology and strategies for career development. The training plan will help Natalie develop an in-depth knowledge in: 1) advanced neuroimaging techniques, 2) biofluidic biomarkers of AD and neuroinflammation, 3) fundamental neuropathological techniques and analytic strategies, and 4) developing a novel line of translational research. .