R01AG075802

Investigating Regional and Cellular Vulnerabilities to Tau Pathology in Young-Onset Alzheimer's Disease - Project Summary/Abstract

Development of cognitive problems at any age is devastating, but development of cognitive problems in working-age people with dependents represents a major public health concern. Young-onset Alzheimer's disease (YOAD) is defined as individuals who present before age 65 and lack mutations known to cause Alzheimer's disease (AD) pathology. Neuropathology and neuroimaging studies demonstrate greater tau accumulation in YOAD who often present with atypical, non-amnestic syndromes.

Our preliminary data demonstrates that tau accumulation occurs through progressive maturity levels in tangle-bearing neurons, which disproportionately affects cortical more than limbic structures in YOAD. Moreover, we show younger age onset is associated with greater tangle accumulation and neuronal loss in nucleus basalis of Meynert (cholinergic hub) and locus coeruleus (noradrenergic hub) – two neuromodulatory hubs implicated in early stage of disease. As stereotypic amyloid-β plaque patterns are robustly observed regardless of age, and comorbid neuropathologies are less frequent in YOAD, this cohort is ideally suited for a targeted investigation of selective vulnerabilities to tangle pathology in AD.

Regional vulnerabilities to advanced tangle maturity levels in corticolimbic structures and neuromodulatory hubs are hypothesized to underlie the syndromic heterogeneity observed in YOAD. The overall goal of this grant is to uncover signatures of regional and cellular vulnerabilities underlying syndromic heterogeneity in YOAD by investigating what modifies patterns of tangle accumulation and microglial activation. Our preliminary data from single-cell RNA sequencing underscores the importance of considering disease heterogeneity and the utility of quantitative neuropathology for validating gene expression changes.

This proposal seeks to shift current research in AD by focusing on younger-aged individuals and demonstrating how regional variability can inform cellular biology even in the context of end-stage disease. To accomplish our goals and facilitate stratification by atypical and typical (amnestic) clinical syndromes, the MPI team has combined expertise and resources to amass one of the largest documented YOAD cohorts totaling 558 brains with available tissue for study.

The goal of the grant is to test the following hypotheses:
1) Modifiers of the neuropathologic patterns of tau pathology in YOAD brains differ between cases stratified by atypical vs. typical (amnestic) clinical syndromes.
2) The most vulnerable neuronal populations to AD-tau share a similar molecular signature across corticolimbic regions reflective of syndromic heterogeneity in YOAD.
3) Corticolimbic microglial activation patterns differ in the brains of YOAD cases stratified by atypical vs. typical (amnestic) clinical syndrome.

Completion of this project will identify specific cell populations vulnerable to regional AD-tau pathology and identify modifiers of microglial activation patterns corresponding to aggressive tau accumulation in YOAD.

Mayo Clinic Jacksonville (A Nonprofit Corporation)

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]

Jacksonville, Florida 322241865 United States

Single Zip Code

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

Amendment Since initial award the total obligations have increased 397% from $3,067,743 to $15,231,837.