RF1AG079519

Cerebrovascular Contributions to Alzheimer's Disease in Adults with Down Syndrome - 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 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.

(3) To characterize postmortem cerebrovascular neuropathology, its 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.

The Trustees Of Columbia University In The City Of New York

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.310 - Trans-NIH Research Support

National Institute on Aging (NIA) [HHS - NIH]

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

New York United States

State-Wide

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the End Date has been extended from 08/31/25 to 08/31/26.