Project 2 of the ADCS U01 renewal application will be a pivotal multi-site randomized controlled trial to assess whether supervised aerobic exercise is an effective therapeutic option to ameliorate cognitive decline, slow brain atrophy, and favorably alter Alzheimer pathology in older adults with mild cognitive impairment (MCI) and thus in the earliest stages of disease. Two short-term intervention studies completed . thus far provide preliminary support for a cognition-enhancing effect of exercise in MCI. The proposed trial will examine the effects of a structured and supervised 12-month moderate- to high-intensity aerobic exercise intervention versus stretching on cognition and biomarkers of AD pathology in cerebrospinal fluid (CSF) and brain structure using MRI. Sedentary older adults (60-85 yrs old) with amnestic MCI (n=300, CDR=0.5) will be enrolled. Both arms of the intervention will be carried out in community exercise facilities, and physical activity will be gradually increased over the first few weeks and then maintained at the targeted duration and heart rate intensity for the rest of the 12-month trial. Participants will benefit from close supervision using established methods from other successful multi-site exercise trials, on-going health education, and a diversified support system provided by staff, fitness trainers, and an exercise 'Buddy'for peer support. Each week, the interventionist will meet with the participant at the exercise facility to supervise the activity routine, review study goals and progress, identify and resolve issues related to continued adherence, provide encouragement and emotional support, and develop the exercise plan for the coming week. Cognitive and functional outcomes, collected at baseline, months 6 and 12, and again following a 6-month unsupervised extension of the intervention, will include the ADAS-Cog13, supplemented with other tests of executive function, a global (composite) measure of executive function and of episodic memory, the Clinical Dementia Rating scale (sum of boxes). Activities of Independent Living for MCI, and the Geriatric Depression Scale. In addition, participants will complete a brief cognitive test and questionnaire about mood and sleep each week during the supervised exercise session. Biomarkers of exercise efficacy, collected at baseline and month 12, will include measures of aging and AD pathology in CSF, and whole and regional brain volumes. Although regular exercise is widely accepted and recommended to maintain optimum physical health and prevent various medical conditions such as cardiovascular disease and diabetes, exercise is not prescribed with the same conviction to maintain optimum cognitive health or prevent diseases associated with cognitive decline. The results of this study will provide critical data regarding the efficacy of aerobic exercise to improve cognition and favorably alter markers of Alzheimer's disease pathology.

Public Health Relevance

An urgent need exists to identify effective interventions that can arrest or reverse Alzheimer's disease at its earliest stages. Our aim in the proposed study is to provide convincing evidence to practitioners and the public that physical exercise is an effective strategy to reduce cognitive, functional, and neuropathological burden associated with mild cognitive impairment (MCI). Although positive effects of aerobic exercise on brain structure and function are reported in normal aging, similar work in MCI is only beginning to garner support. The proposed pivotal trial may forever impact standard of care for this group of vulnerable adults.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-7 (02))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
La Jolla
United States
Zip Code
Mormino, Elizabeth C; Betensky, Rebecca A; Hedden, Trey et al. (2014) Amyloid and APOE ?4 interact to influence short-term decline in preclinical Alzheimer disease. Neurology 82:1760-7
Mormino, Elizabeth C; Betensky, Rebecca A; Hedden, Trey et al. (2014) Synergistic effect of ?-amyloid and neurodegeneration on cognitive decline in clinically normal individuals. JAMA Neurol 71:1379-85
Rafii, Michael S; Taylor, Curtis S; Kim, Hyun T et al. (2014) Neuropsychiatric symptoms and regional neocortical atrophy in mild cognitive impairment and Alzheimer's disease. Am J Alzheimers Dis Other Demen 29:159-65
Whitehouse, Peter J (2014) The end of Alzheimer's disease--from biochemical pharmacology to ecopsychosociology: a personal perspective. Biochem Pharmacol 88:677-81
Burstein, Aaron H; Grimes, Imogene; Galasko, Douglas R et al. (2014) Effect of TTP488 in patients with mild to moderate Alzheimer's disease. BMC Neurol 14:12
Donohue, Michael C; Jacqmin-Gadda, Hélène; Le Goff, Mélanie et al. (2014) Estimating long-term multivariate progression from short-term data. Alzheimers Dement 10:S400-10
Samieri, Cécilia; Proust-Lima, Cécile; M Glymour, Maria et al. (2014) Subjective cognitive concerns, episodic memory, and the APOE ?4 allele. Alzheimers Dement 10:752-759.e1
Galasko, Douglas; Bell, Joanne; Mancuso, Jessica Y et al. (2014) Clinical trial of an inhibitor of RAGE-A? interactions in Alzheimer disease. Neurology 82:1536-42
Sperling, Reisa A; Rentz, Dorene M; Johnson, Keith A et al. (2014) The A4 study: stopping AD before symptoms begin? Sci Transl Med 6:228fs13
Papay, Kimberly; Xie, Sharon X; Stern, Matthew et al. (2014) Naltrexone for impulse control disorders in Parkinson disease: a placebo-controlled study. Neurology 83:826-33

Showing the most recent 10 out of 14 publications