R01AG084485

Dietary protection against APOE4 phenotypes in aging and Alzheimer's - The 4 allele of apolipoprotein E (APOE4) is associated with accelerated aging and mortality as well as increased vulnerability to Alzheimer's disease (AD). Although the causal links between APOE4, aging, and AD risk remain to be fully defined, candidate mechanisms include regulation of energy metabolism and systemic and neural inflammatory tone.

Our recent findings demonstrate that nutritional approaches, including fasting mimicking diet (FMD), exhibit anti-aging and protective properties across several age-related conditions. Indeed, pathways identified to be beneficially regulated by FMD and related nutritional interventions overlap with pathways thought to underlie relationships among APOE4, aging, and AD.

In this project, we investigate the central hypothesis that the dietary intervention FMD will protect against APOE4 phenotypes that drive age-related cognitive impairment and AD pathogenesis. We will investigate this hypothesis by studying systemic and neural effects of FMD and related dietary interventions across age in mice with human APOE genotypes both in the absence and presence of AD transgenes.

Our studies will interrogate several potential mechanisms hypothesized to underlie gene x environment relationships between APOE and diet with emphases on brain energy metabolism and regulation of microglial activation profiles. We propose three aims.

Aim 1: Do dietary interventions protect against APOE4-associated aging phenotypes? We test the hypothesis that nutritional interventions will improve systemic and neural outcomes in the contexts of aging and APOE4 genotype. Studies will test the ability of diet to prevent vs treat APOE4-associated phenotypes. We will test the efficacy of low methionine or high ketone diets and assess the hypothesized abilities of a fasting-mimicking mitochondrial-derived peptide to mirror protective actions of FMD across APOE genotype.

Aim 2: Do dietary interventions provide protection against Alzheimer pathology in an APOE-dependent manner? The second aim is conceptually parallel to Aim 1 but with a focus on diet and APOE genotype in the context of AD pathology. These studies will be conducted in male and female APOE3 vs APOE4 AD mice to determine potential sex differences and at two different ages to consider efficacies for both prevention and treatment.

Aim 3: Do dietary interventions improve glial phenotypes associated with aging, APOE4, and AD? We investigate the hypothesis that the primary mechanism by which dietary interventions protect against APOE4 phenotypes is improvement in glial transcriptomic profiles and functions. We will interrogate the hypothesis that a key regulator of APOE-dependent differences is the TREM2-APOE signaling pathway, which is linked to AD risk via actions on microglial phenotype and metabolic fitness.

Completion of the proposed studies will yield preclinical data that define the interactions and underlying mechanisms among diet, APOE genotype, sex, age, and intervention timing, relationships that are essential to the effective clinical translation of dietary strategies to combat cognitive decline and AD.

University Of Southern California

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]

Los Angeles, California 900891057 United States

Single Zip Code

NIA Program Project Applications (P01 Clinical Trial Optional) (PAR-19-314)

Amendment Since initial award the total obligations have increased 301% from $996,357 to $3,995,875.