PROJECT SUMMARY Adults with Down syndrome (DS) develop Alzheimer's disease (AD) pathology by 40 years of age, and many develop symptoms of dementia by 60 years of age due to the triplication of chromosome 21 where the amyloid precursor protein (APP) gene resides. Because of recent improvements in quality of life and medical advances, the average lifespan of adults with DS is increasing, making AD, which is strongly age dependent, and its cognitive and functional impacts a public health crisis in this population. Despite the field's primary focus on the amyloid, tau, and neurodegeneration (`A/T/N') pathogenic cascade in AD, there is evidence accumulating in late onset AD, other genetic forms of AD, and in our pilot data among adults with DS, of a primary role of cerebrovascular disease in AD symptom presentation and possibly disease pathogenesis. The purpose of this study is to examine neuroimaging, blood-based, and neuropathological markers of the cerebrovascular dysfunction in adults with DS. Among 550 adults with DS enrolled in the Alzheimer's Biomarker Consortium – Down Syndrome (ABC-DS; U19 AG068054) we will quantitate MRI markers of cerebrovascular disease and plasma biomarkers for vascular cognitive impairment at baseline and over longitudinal visits to examine their association with age, prevalent cognitive diagnosis, and cognitive decline over a 5-year period. In an autopsy subset (n~50), we will examine postmortem cerebrovascular markers, including cerebral amyloid angiopathy (CAA), microhemorrhages, neuroinflammation, and components of the neurovascular unit, and their association with AD pathology and clinical characteristics. The work is in line with NIH Notice of Special Interest (NOSI) NOT-OD-20-025 for R01 grant applications that focus on DS and that are programmatically aligned with the INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) Project. Our study will meet the objectives of INCLUDE by understanding the unique vascular profile in DS, which will inform medical advances for adults with DS as well as for people without DS, and by connecting existing resources (Component 2). The proposed study will transform existing knowledge of the role of cerebrovascular disease in DS and AD and point to treatment and prevention strategies. The following aims will be tested. (1) To examine MRI markers of cerebrovascular disease with respect to age, prevalent cognitive diagnosis, and incident cognitive diagnosis and cognitive decline over a 5-year period in adults with DS. (2) To examine the associations of blood-based biomarkers for vascular cognitive impairment with age, MRI markers of cerebrovascular disease, and prevalent and incident diagnoses, and cognitive decline, and (3) To characterize postmortem cerebrovascular neuropathology, relationship to AD neuropathology, downstream consequences, and antemortem diagnosis in adults with DS from a legacy autopsy series and in relation to neuroimaging and clinical outcomes from prospective ABC-DS cases.

PROJECT NARRATIVE This project will examine neuroimaging, blood-based, and neuropathological markers of the vascular contributions to cognitive impairment and Alzheimer's disease (AD) in adults with Down syndrome (DS). Adults with DS are living much longer than previously, but virtually all develop the pathology and symptoms of AD by late adulthood. By examining the cerebrovascular component of AD and cognitive decline in adults with DS, this study will identify potential targets to mitigate the emerging public health crisis in this population and inform similar interventions in the neurotypical population.