Neurobiology of Disease June 30, 2012 [epub] Karlie A. Intlekofer, Carl W. Cotman Institute for Memory Impairments and Neurological Disorders, University of California Irvine KEY POINTS FROM THIS ARTICLE: 1) Alzheimer’s disease (AD) afflicts more than 5.4 million Americans and is themost common type of dementia, yet effective drug treatments have not beenidentified. 2) Alzheimer’s disease (AD) affects more than one in eight Americans over theage of 65 and nearly half of those over the age of 85. 3) Today there are about 40 million people with AD (worldwide), and in 2050,AD will soar to over 100 million people. 4) Physical activity enhances learning and memory for people of all ages,including individuals that suffer from cognitive impairment. 5) Physical activity reinstates brain function by enhancing brain-derivedneurotrophic factor (BDNF) and other growth factors that promote neurogenesis,angiogenesis, and synaptic plasticity. 6) Physical activity counteracts age- and AD-associated declines in mitochondrial and immune system function. A growing body of evidence alsosuggests that exercise interventions hold the potential to reduce the pathologicalfeatures associated with AD. 7) Exercise is a powerful stimulus that can reverse the molecular changes thatunderlie the progressive loss of hippocampal function in advanced age and AD. 8) Exercise promotes dynamic changes that facilitate brain function. Exercisepromotes brain health in advancing age and AD. 9) Physical activity is a protective factor against cognitive impairment anddementia. 10) The risk of AD is inversely correlated to levels of daily exercise, even withwalking as little as one mile per day. 11) The leading modifiable risk factor for AD in the United States is physicalinactivity, which increases the relative risk of AD by almost two-fold. 12) Exercise significantly improves cognitive performance, memory and attentionin individuals with cognitive impairment. 13) Exercise slows the rate of cognitive decline. Exercise is a potent strategy toalter the trajectory of cognitive decline. 14) AD patients that undergo 5 to 12 weeks of moderate exercise showenhanced memory and improved performance on neuropsychological tests. 15) Physical activity supports brain health even when initiated after theappearance of AD pathology. 16) Exercise increases BDNF. BDNF plays an important role in synaptic plasticityby promoting long-term potentiation (LTP), a synaptic analog of learning andmemory. 17) Physical activity has been shown to enhance neuronal morphology byincreasing synaptic density and dendritic arborization in the hippocampus. 18) Exercise reverses the decline in neurogenesis that occurs with age and elicitsfavorable effects on neuroplasticity. 19) Exercise increases brain glucose utilization and enhances proliferation leadingto enhanced blood flow. 20) Exercise-induced neural activation in the hippocampus requires enhancedmitochondrial capacity to produce ATP from the oxidative phosphorylation ofglucose. Exercise enhances mitochondrial proliferation and respiration. Thismitochondrial biogenesis greatly enhances metabolic capacity and the expression ofboth nuclear and mitochondrial genes. 21) Mitochondrial DNA has a high mutation rate and limited repair mechanisms.Physical activity attenuates mitochondrial DNA (mtDNA) damage and dysfunction. 22) Exercise improves mitochondrial respiration. The tuning of mitochondrialfunction may be an example of a central mechanism by which exercise protectsagainst cognitive decline. 23) An increase in brain inflammation is a risk factor in cognitive dysfunction.Inflammation is tightly associated with memory deficits in the elderly. Regularmoderate exercise is associated with reduced systemic inflammation.Exercise may alleviate the pro-inflammatory immune responses that characterizeaging. 24) Physical activity may confer enhanced protection from infection. 25) There are three major Apolipoprotein E (APOE) alleles in humans,ε2, ε3 and ε4, but only ε4 is associated with increased risk for AD. At least someof the neural consequences of carrying the ε4 isoform may be overcome by physicalexercise. Those with genetic susceptibility to AD stand to gain the most from physical activity. 26) Exercise is an emerging therapeutic strategy that improves the function ofmitochondria, immune system, and can mitigate the neurodegeneration inherent inAD and advancing age. By inducing neurotrophins and growth factors that enhanceneuroplasticity, physical activity can significantly improve hippocampal function to a degree even with advancing age and disease. 27) Exercise has emerged as an efficacious therapeutic strategy that yields broadbenefits to cognitive function.