R01AG072644

Brain Effects of Lifetime Racial/Ethnic Discrimination on the LC-NE Function and the Risk for Alzheimer's Disease - Project Summary

Alzheimer's Disease (AD) is a global crisis facing the aging population and society as a whole. Despite studies suggesting that blacks may be at greater risk of developing AD, with 2-3 times higher prevalence rate of cognitive impairment than whites, there have been few studies investigating health disparities, and blacks have been underrepresented in many prominent U.S. AD biomarker studies and clinical trials.

The current biomarker classification system (i.e., the ATN model) does not fully account for health disparities and can't explain the increased prevalence among blacks of both AD and vascular risk factors for AD such as diabetes and hypertension when compared to whites.

Research on cognitive aging has traditionally focused on how decline in various cortical and hippocampal regions influences cognition. However, tau pathology emerges decades before amyloid pathology, appearing first in the brainstem; particularly in the locus coeruleus (LC), the source of brain's norepinephrine (NE).

Our decade-long studies in humans using a norepinephrine transporter (NET)-selective radiotracer ([11C]MRB) have demonstrated a special vulnerability of LC to aging and stress. Our preliminary data reveals that the decline rate of NET, normally associated with aging due to loss in NET availability and cell death, is much faster among blacks starting in the mid-30s, particularly in black males (e.g., 2-3%/yr vs. 0.14-0.23%/yr in thalamus and brainstem for black males vs. white males (p<0.00001)).

As the LC plays a central role in the integration and orchestration of the adaptive CNS response to various stressors or challenges, we hypothesize that cumulative exposure to socioeconomic disadvantage and racial discrimination may cause long-lasting changes in LC function followed by LC neuronal loss, which would explain the different AD phenotypical clinical presentation among blacks (i.e., less tau burden but more LC loss and vascular damage).

Our hypothesis is also supported by the broad evidence that the LC is an early site of AD neurodegeneration and LC cell density is more strongly associated with cognitive decline than other nuclei.

We propose to test this hypothesis by demonstrating that there will be age and race/ethnic differences on NET availability (measured with [11C]MRB) across midlife and late-life in the LC and its target brain regions (AIM 1), and that decreased NET availability is associated with stress levels and impaired cognition (AIM 2), as well as the predictive value of NET availability on longitudinal change in cognition (AIM 3).

There is the potential to determine if dysfunction of the LC is: i) a potential marker for the increased AD pathology that is observed in normal aging; ii) a key contributor to the development of metabolic syndrome, vascular dysfunction, and cognitive decline, as result of chronic stress; iii) associated with increased prevalence of both AD and vascular risk factors for AD in blacks when compared to whites; iv) associated with everyday stress levels and cumulative stress burden; v) a key mechanism that contributes to the health disparities in AD expression.

New York University

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.

93.866 - Aging Research

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

New York United States

State-Wide

Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional) (PAR-19-070)

Amendment Since initial award the End Date has been extended from 06/30/26 to 06/30/27 and the total obligations have increased 291% from $847,141 to $3,312,473.