Age-related cognitive decline is linked to numerous molecular, structural, and functional changes in the brain. However, physical activity is a promising method of reducing unfavorable age-related changes. Physical activity exerts its effects on the brain through many molecular pathways, some of which are regulated by genetic variants in humans. In this paper, we highlight genes including apolipoprotein E (APOE), brain derived neurotrophic factor (BDNF), and catechol-O-methyltransferase (COMT) along with dietary omega-3 fatty acid, docosahexaenoic acid (DHA), as potential moderators of the effect of physical activity on brain health. There are a growing number of studies indicating that physical activity might mitigate the genetic risks for disease and brain dysfunction and that the combination of greater amounts of DHA intake with physical activity might promote better brain function than either treatment alone. Understanding whether genes or other lifestyles moderate the effects of physical activity on neurocognitive health is necessary for delineating the pathways by which brain health can be enhanced and for grasping the individual variation in the effectiveness of physical activity interventions on the brain and cognition. There is a need for future research to continue to assess the factors that moderate the effects of physical activity on neurocognitive function. 1. Introduction One in every eight US seniors over the age of 65 has been diagnosed with Alzheimer’s disease (AD), amounting to more than 5.4 million people. With the aging baby boomers, this number is predicted to double by 2050 [1]. Unfortunately, pharmaceuticals have had limited success in preventing or treating age-related cognitive dysfunction, such as AD or even normal cognitive aging. Fortunately, physical activity appears to be a promising nonpharmaceutical method to attenuate cognitive dysfunction in late life [2, 3]. Yet, there remain many unanswered questions about the effectiveness of physical activity to improve brain health, prevent dementia, and reduce age-related cognitive decline. “Physical activity” is an umbrella term defined by the Center for Disease Control (CDC) as any activity that increases heart rate and energy expenditure from one’s basal level [4]. Examples of physical activities are walking, gardening, or even household chores such as cleaning. In turn, “exercise” is defined as a subcategory of physical activity, being any structured or repetitive activity that aims to improve fitness, endurance, or health such as strength training, purposefully running, or
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