RF1AG091410

CLARIFYING THE INTERPLAY BETWEEN HERPESVIRUS INFECTION AND REACTIVATION, IMMUNE RESPONSES, APOE GENOTYPE, AND DEVELOPMENT OF TAU-PATHOLOGY - PROJECT SUMMARY/ABSTRACT THE ROLE OF MICROBIAL INFECTIONS IN TRIGGERING ALZHEIMER'S DISEASE (AD) HAS GAINED INCREASING SUPPORT. IN SEVERAL STUDIES, SPECIFIC VIRUSES AND BACTERIA CAPABLE OF INFECTING THE CENTRAL NERVOUS SYSTEM (CNS) WERE FOUND MORE FREQUENTLY IN AD PATIENTS, AND RECENT DISCOVERIES LINK INFECTIONS TO KEY ASPECTS OF AD PATHOLOGY. RECENT FINDINGS SUGGEST THAT ANTIVIRAL DRUGS FOR HERPES SIMPLEX VIRUS 1 AND VACCINES FOR HERPES ZOSTER (SHINGLES) MAY REDUCE THE RISK OF AD, WITH STUDIES SHOWING UP TO 20% RISK REDUCTION. WHILE THESE FINDINGS ARE INTRIGUING, THEY HAVE IMPORTANT LIMITATIONS. MOST NOTABLY, THEY ARE PRONE TO REVERSE CAUSATION, AS BEHAVIORAL AND PATHOLOGICAL CHANGES RELATED TO AD MAY INCREASE SUSCEPTIBILITY TO CNS INFECTIONS. FURTHERMORE, MOST STUDIES USED TRADITIONAL CASE-CONTROL DESIGNS, WHICH ARE PRONE TO BIAS DUE TO CONVENIENCE SAMPLING OF CONTROLS, AND HAD INSUFFICIENT FOLLOW-UP TO ACCOUNT FOR THE LONG PRECLINICAL PHASE OF AD. MOST STUDIES ALSO USED LABORATORY ASSAYS THAT CANNOT DISTINGUISH BETWEEN IMPORTANT VIRUSES OR MEASURE IMMUNE RESPONSES AGAINST THESE VIRUSES. WE WILL USE A UNIQUE RESOURCE, THE NURSES’ HEALTH STUDY, A LONGITUDINAL COHORT FOLLOWING OVER 100,000 WOMEN SINCE 1976. IT FEATURES DETAILED INFORMATION ON DIETARY AND BEHAVIORAL HABITS COLLECTED BIENNIALLY DURING FOLLOW-UP, CRITICAL FOR ASSESSING AND CONTROLLING POTENTIAL SOURCES OF CONFOUNDING. IN OUR PROPOSED STUDY, WE WILL ANALYZE ARCHIVED SAMPLES FROM 1,800 WOMEN, ENRICHED FOR THOSE WITH HIGH-RISK APOE GENOTYPES AND LOW COGNITIVE SCORES, FOR TAU-PATHOLOGY USING PHOSPHORYLATED TAU 217 (PTAU-217), A BIOMARKER WHOSE ABNORMAL RESULTS ARE NOW DEEMED SUFFICIENT TO ESTABLISH AN AD DIAGNOSIS. IN 300 WOMEN WITH THE HIGHEST AND 300 WITH THE LOWEST LEVELS OF TAU-PATHOLOGY, WE WILL ANALYZE IMMUNE RESPONSES IN SAMPLES COLLECTED 10 YEARS EARLIER USING THE LUCIFERASE IMMUNOPRECIPITATION SYSTEM (LIPS) AND NUCLEIC ACID PROGRAMMABLE PROTEIN ARRAY (NAPPA). THIS WILL ENABLE A LONGITUDINAL ASSESSMENT OF HUMORAL IMMUNITY AGAINST 1,800 PROTEINS MAPPING TO 158 VIRUSES AND BACTERIA, INCLUDING ALL HERPESVIRUSES, AND SUBSEQUENT DEVELOPMENT OF TAU-PATHOLOGY. WE WILL ALSO ASSESS THE INTERPLAY BETWEEN INFECTIONS, APOE GENOTYPE, AGING, AND AD RISK FACTORS, WHICH MAY INFORM UNDERLYING MECHANISMS. WITH OUR PROPOSED PROJECT, WE SEEK TO TRANSFORM OUR UNDERSTANDING OF AD AND CONTRIBUTE TO THE DEVELOPMENT OF NEW TREATMENT AND PREVENTION STRATEGIES. OUR STUDY REPRESENTS THE FIRST COMPREHENSIVE LONGITUDINAL INVESTIGATION COMBINING STATE-OF-THE-ART BIOMARKERS OF INFECTION EXPOSURE AND AD PATHOLOGY TO DETERMINE WHETHER AND HOW INFECTIONS TRIGGER AD PATHOLOGY BEFORE SYMPTOM ONSET. WITH OUR PROPOSED PROJECT, WE SEEK TO TRANSFORM OUR UNDERSTANDING OF AD AND CONTRIBUTE TO THE DEVELOPMENT OF NEW TREATMENT AND PREVENTION STRATEGIES.

President And Fellows Of Harvard College

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]

Massachusetts United States

State-Wide

Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional) (PAR-22-093)