R01AG070866

Investigating the Temperature Dependence of Age-Related Tau Pathology Relevant to Early Alzheimer's Disease - Project Summary Abstract

Alzheimer's disease is a common neurodegenerative disease that is increasing in prevalence with the aging population, characterized by the accumulation of amyloid-beta (Aβ) peptide associated plaques and hyperphosphorylated tau protein associated neurofibrillary tangles (NFTs). This proposal seeks to link a known feature of aging, namely impaired thermoregulation and lower body and brain temperature, with this age-related increase in NFT pathology.

Older age is associated with a long (10–20 year) preclinical phase before symptom onset, in which Aβ and NFT pathology increases and can be measured with tau PET and plasma markers. Extensive and compelling preclinical (rodent and in vitro) findings show that tau phosphorylation is strongly potentiated by small decreases in temperature (decreases in molecular kinetic energy), owing to the differing dependence of regulatory kinases and phosphatases upon this property. Other molecular processes that cause NFT formation may be similarly temperature dependent.

We will build upon the results of our preliminary study in older adults that was motivated by these preclinical findings, providing, to our knowledge, their first human translation. Our preliminary results showed that lower telemetrically measured body temperature (TB) during the hours the subject was awake – but not during sleep – strongly predicted (R2 = 0.47, P < 0.005) the amount of tau NFT tangles measured with [18-F]-MK-6240 tau PET-MR in early Braak stage areas in cognitively normal (NL) older adults.

The purpose of the current project is to verify this strong relationship between lower waking TB and NFTs, using the same methods, in a larger sample of older adults (N = 100, 50 female, 60–80 years) who are NL or have mild cognitive impairment. Briefly, subjects will undergo medical screening (Visit 1), followed by 7 days of home actigraphy for sleep-wake cycle characterization and further screening, and neuropsychological evaluation in Visit 2.

In Visit 3, to take place over 48 hours, subjects will undergo TB measurement with ingestible telemetric thermometry over 48 hours, simultaneous with two nights of nocturnal polysomnography to integrate TB with the sleep-wake state and measure slow wave sleep, followed by plasma tau and p-tau sampling the following morning. Subjects will be free to return home during the day in between sleep studies.

At Visit 4, [18-F]-MK-6240 tau and amyloid PIB PET-MR scanning will be completed. We aim to 1) verify lower waking TB prediction of NFT in this sample, 2) incorporate and account for the effects of Aβ plaque load (known to increase NFTs) and older age into the model, and 3) test the extent to which the known relationship between TB and sleep plays a role in TB–NFT associations.

This cross-sectional study will lay the groundwork for future prospective studies to determine whether TB-based interventions can prevent the progression of NFT pathology toward reducing Alzheimer's disease burden.

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, New York 100165802 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 End Date has been extended from 04/30/26 to 04/30/27 and the total obligations have increased 375% from $863,945 to $4,104,231.