Exercise Improves Cognition in Older Adults at Risk for Alzheimer's Disease

Abstract & Commentary

By Sarah L. Berga, MD, James Robert McCord Professor and Chair, Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, is Associate Editor for OB/GYN Clinical Alert.

Dr. Berga reports no financial relationship to this field of study.

Synopsis: In this study of adults with memory complaints, increased physical activity improved cognition at 18 months.

Source: Lautenschlager NT, et al. Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: A randomized trial. JAMA 2008;300:1027-1037.

Older people who report memory decline or show objective evidence of cognitive impairment are more likely to develop Alzheimer's disease and other forms of dementia over time. Several clinical trials tested the efficacy of various agents alleged to forestall the onset or retard the advancement of dementia, with null effects for current therapies such as cholinesterase inhibitors, vitamin E, or cyclooxygenase-2 inhibitors. However, higher physical activity was associated with better cognition in the Nurses' Health Study1 and prospective studies have confirmed that physical activity is associated with reduced incidence of dementia, even when exercise is initiated later in life.2

These studies and observations provided the rationale for the current study, which was a randomized, controlled trial of a 24-week exercise intervention in 170 women and men older than age 49 who reported memory problems but did not meet criteria for dementia. About half of the subjects in each arm were women. The Fitness for Aging Brain Study was conducted in Australia between 2004 and 2007 at a single site. Participants were randomized to education vs a 24-week home-based program of physical activity. The cognitive section of the Alzheimer Disease Assessment Scale (ADAS-Cog) was the primary outcome variable. The scale tests 11 domains, including memory, language, and praxis. Throughout the trial, the investigators monitored Beck Depression Inventory and quality of life with the Medical Outcomes 36-Item Short-Form Health Survey. Apolipoprotein (APOE) genotype was determined. The physical activity intervention consisted of at least 150 minutes of moderate-intensity physical activity each week in three sessions of 50 minutes. All participants were asked to keep a diary of physical activity. Physical activity, cognitive function, mood, and quality of life were assessed at 6, 12, and 18 months after baseline.

By the end of the study, participants in the exercise group had better ADAS-Cog scores than those in the usual care group (P = 0.04). Participants in the physical activity group had better delayed recall. Adherence to the prescribed physical activity for 24 weeks was 78%. Women were more likely than men to drop out in both groups and those who dropped out had higher ADAS-Cog scores than those who remained. APOE e4 carriers did less well in both groups across time. The investigators interpreted the results as showing that the benefits of physical exercise were apparent after 6 months and persisted until 18 months after initiation of the exercise intervention.


Menopausal women and their physicians remain confused about the therapeutic options available for reducing the risk of dementia. This is an interesting study that offers a concrete therapy for reducing the risk of memory decline and Alzheimer's disease. The mechanisms by which physical exercise might improve cognition include improved cerebral vascular function and brain perfusion, environmental enrichment, enhanced brain plasticity via synaptogenesis, neurogenesis, and attenuation of the neural responses to stress. In humans, increased physical activity resulted in increased blood flow in regions that modulate attention.3

The study hints that exercise might be less effective for reduction of the risk of dementia for women than for men. If so, one would want to know why women fare less well than men. One possibility is that estradiol is neurotrophic. It is not well recognized, but men have higher CSF levels of estradiol than women after age 50. Most of the estradiol in the CSF of men comes from aromatization of testosterone to estradiol. Despite the age-related decline in testicular testosterone secretion, there is still plenty around for diffusion across the blood-brain barrier. Testosterone may have independent trophic effects as well. A fundamental consideration is whether there might be an interaction or synergism at work. It seems reasonable to suggest that if estradiol is neurotrophic and exercise is neurotrophic, then the two together might be at least additive, if not synergistic, in reducing or delaying the onset of dementia. Therefore, the looming question is whether older women might benefit from a combination of exercise and estradiol as a means to forestall if not prevent the inexorable decline of mind that accompanies aging.

Only future studies designed to look for synergism will allow us to move beyond paradigms in which we test only for independent effects. Further, we need to look for ways to discern sex-specific recommendations for safeguarding our health as we age.


  1. Weuve J, et al. Physical activity, including walking, and cognitive function in older women. JAMA 2004;292:1454-1461.
  2. van Gelder BM, et al. Physical activity in relation to cognitive decline in elderly men: The FINE Study. Neurology 2004;63:2316-2321.
  3. Colcombe SJ, et al. Cardiovascular fitness, cortical plasticity, and aging. Proc Natl Acad Sci U S A 2004;101:3316-3321.