Epidemiological evidence suggests that ongoing mental or physical activity may attenuate the cognitive decline of Alzheimer's disease, or delay its onset. However, there are conflicting studies that do not show a benefit for increased cognitive activity or exercise for Alzheimer's patients. In addition, an alternate hypothesis suggests that some patients are predisposed to get Alzheimer's disease by early adulthood, and do not have the cognitive capacity or inclination to engage in mentally stimulating activity. The experiments proposed in this proposal are designed to establish cause-and-effect relationships between ongoing mental or physical activity and cognitive status in transgenic mice bearing the Swedish mutation of the amyloid precursor protein (APP). These transgenic mice develop Alzheimer-like amyloid plaques starting at approximately 10 months of age. When fed a folate-deficient diet supplemented with homocysteine for 3 months, APP transgenic mice, but not wild-type control mice, develop hippocampal-specific cell death. Thus we will be able to determine not only whether increased physical or mental activity improves cognitive performance but also whether it affects the rate of cell death or amyloid plaque formation, information that is not obtainable in human Alzheimer patients. Together, the data provided by the proposed experiments will inform us as to the potential effectiveness of cognitively stimulating activities or physical exercise as therapeutic or preventative measures in the fight against Alzheimer's disease.
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