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)
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Special Emphasis Panel (ZAG1-ZIJ-7)
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University of California San Diego
La Jolla
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Besser, Lilah; Kukull, Walter; Knopman, David S et al. (2018) Version 3 of the National Alzheimer's Coordinating Center's Uniform Data Set. Alzheimer Dis Assoc Disord 32:351-358
Jacobs, Heidi I L; Hedden, Trey; Schultz, Aaron P et al. (2018) Structural tract alterations predict downstream tau accumulation in amyloid-positive older individuals. Nat Neurosci 21:424-431
Buckley, Rachel F; Mormino, Elizabeth C; Amariglio, Rebecca E et al. (2018) Sex, amyloid, and APOE ?4 and risk of cognitive decline in preclinical Alzheimer's disease: Findings from three well-characterized cohorts. Alzheimers Dement 14:1193-1203
Jacobs, Diane M; Ard, M Colin; Salmon, David P et al. (2017) Potential implications of practice effects in Alzheimer's disease prevention trials. Alzheimers Dement (N Y) 3:531-535
Marquié, Marta; Verwer, Eline E; Meltzer, Avery C et al. (2017) Lessons learned about [F-18]-AV-1451 off-target binding from an autopsy-confirmed Parkinson's case. Acta Neuropathol Commun 5:75
Dekhtyar, Maria; Papp, Kathryn V; Buckley, Rachel et al. (2017) Neuroimaging markers associated with maintenance of optimal memory performance in late-life. Neuropsychologia 100:164-170
Schultz, Aaron P; Chhatwal, Jasmeer P; Hedden, Trey et al. (2017) Phases of Hyperconnectivity and Hypoconnectivity in the Default Mode and Salience Networks Track with Amyloid and Tau in Clinically Normal Individuals. J Neurosci 37:4323-4331
Vannini, Patrizia; Hanseeuw, Bernard; Munro, Catherine E et al. (2017) Anosognosia for memory deficits in mild cognitive impairment: Insight into the neural mechanism using functional and molecular imaging. Neuroimage Clin 15:408-414
Donohue, Michael C; Sperling, Reisa A; Petersen, Ronald et al. (2017) Association Between Elevated Brain Amyloid and Subsequent Cognitive Decline Among Cognitively Normal Persons. JAMA 317:2305-2316
LaPoint, Molly R; Chhatwal, Jasmeer P; Sepulcre, Jorge et al. (2017) The association between tau PET and retrospective cortical thinning in clinically normal elderly. Neuroimage 157:612-622

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