R01AG076566

Precision Medicine in Alzheimer's Disease: A Smart Trial of Adaptive Exercises and Their Mechanisms of Action Using AT(N) Biomarkers to Optimize Aerobic-Fitness Responses - Abstract

Aerobic exercise is a promising treatment for Alzheimer's disease (AD) and AD-related dementia (ADRD), but exercise trials have shown mixed effects on cognition, physical function, behavioral and psychological symptoms of dementia (BPSD), quality of life (QOL), and caregiver burden. These findings are likely due to individual differences in aerobic-fitness responses, long established in adults using peak oxygen consumption (VO2PEAK) and first reported in older adults with ADRD by our team.

AD/ADRD exercise trials report large variance in VO2PEAK changes from moderate-intensity continuous training (MICT). Mechanistically, animal studies support aerobic exercise modifying AD's AT(N) biomarkers (amyloid-beta [ASS], tau, and neurodegeneration), but similar human studies are rare. Hence, precision exercise is critical to identify MICT non-response early to initiate alternative interventions (high intensity interval training [HIIT] or combined aerobic and resistance exercise [CARE]).

Because VO2PEAK can improve and peak from 3-month MICT, it is logical to use VO2PEAK at 3 months to identify non-response and initiate HIIT or CARE. This phase II, pilot trial will be a sequential, multiple assignment, randomized trial. Its purpose is to test the effects of 6-month aerobic exercise on aerobic fitness and its mechanisms of action in community-dwelling older adults with mild AD dementia.

Our central hypothesis is that MICT augmented with HIIT or CARE will improve aerobic fitness, white matter hyperintensity (WMH), and plasma biomarkers, which underlie exercise's cognitive effects. This trial builds on our previous work showing: successful recruitment, retention, adherence, and safety; 6-month MICT maintained memory and reduced WMH; individual differences in VO2PEAK and cognitive responses to MICT; MICT improved physical function, QOL, and caregiver distress; plasma neurofilament light chain (NFL) predicted cognition; and MICT affected plasma P-TAU181.

It will randomize 108 participants 2:1 to 3-month MICT or 6-month stretching control after baseline. VO2PEAK will be assessed after 3-month MICT to identify non-responders (<5% increase) and re-randomize them 1:1 to HIIT or CARE for 3 months. Responders will continue MICT for 3 months. Participants will be followed for another 6 months.

Primary outcomes are aerobic fitness measured at 0, 3, 6, 9, and 12 months and WMH volume at 0, 6, and 12 months. Secondary outcomes (memory, physical function, BPSD, QOL, caregiver burden) and plasma ASS42/40, P-TAU181, T-TAU, and NFL will be assessed at 0, 3, 6, 9, and 12 months. This trial has 80% power for all primary hypotheses, assuming 18% and 25% attrition at 6 and 12 months, respectively.

The specific aims are to: I) test the effects of aerobic exercise on aerobic fitness, WMH volume, and patient-centered outcomes in older adults with mild AD dementia; II) determine the best exercise to improve aerobic fitness and reduce non-responses over 6 months in older adults with mild AD dementia; and III) examine the mechanisms of aerobic exercise's action on memory in mild AD dementia.

This trial is the first precision-exercise trial in AD and will utilize MRI/blood biomarkers, which are scalable.

Arizona State 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]

Tempe, Arizona 852876011 United States

Single Zip Code

Early and Late Stage Clinical Trials for the Spectrum of Alzheimers Disease/Alzheimers Related Dementias and Age-Related Cognitive Decline (R01 Clinical Trial Optional) (PAR-21-359)

Amendment Since initial award the total obligations have increased 93% from $1,945,746 to $3,754,609.