Stress, exercise, and Alzheimer's disease: A neurovascular pathway

University of California San Diego, School of Medicine, Department of Psychiatry, San Diego, CA, USA.
Medical Hypotheses (Impact Factor: 1.07). 03/2011; 76(6):847-54. DOI: 10.1016/j.mehy.2011.02.034
Source: PubMed


Genetic factors are known to play a role in Alzheimer's disease (AD) vulnerability, yet less than 1% of incident AD cases are directly linked to genetic causes, suggesting that environmental variables likely play a role in the majority of cases. Several recent human and animal studies have examined the effects of behavioral factors, specifically psychological stress and exercise, on AD vulnerability. Numerous animal studies have found that, while stress exacerbates neuropathological changes associated with AD, exercise reduces these changes. Some human studies suggest that psychological stress can increase the risk of developing AD, while other studies suggest that exercise can significantly reduce AD risk. Most animal studies investigating the mechanisms responsible for the effects of these behavioral factors have focused on neuronal processes, including the effects of stress hormones and neurotrophic factors on the neuropathological hallmarks of AD, namely amyloid-beta (Aβ) deposition and tau-phosphorylation. However, cumulative evidence indicates that, in humans, AD is associated with the presence of cerebrovascular disease, and cardiovascular risk factors are associated with increased risk of developing AD. There is an extensive literature demonstrating that behavioral factors, particularly stress and exercise, can powerfully modulate the pathophysiology of vascular disease. Thus, the following model proposes that the influence of stress and exercise on AD risk may be partially due to the effects of these behavioral factors on vascular homeostasis and pathology. These effects are likely due to both indirect modification of AD risk through alterations in vascular risk factors, such as hypertension, diabetes, and aortic stiffening, as well as direct influence on the cerebrovasculature, including changes in cerebral blood flow, angiogenesis, and vascular disease. Future studies examining the effects of behavioral factors on AD risk should incorporate measures of both peripheral and cerebral vascular function to further our understanding of the mechanisms by which behavior can modify AD susceptibility. Greater knowledge of the molecular mechanisms behind these behavioral effects would further our understanding of the disease and lead to innovative treatment and preventive approaches.

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    • "Indeed, because the vast majority of older adults have Ab accumulation in brain to some degree, our results provide a possible explanation for how known environmental toxicants to the dopaminergic system could promote cognitive decline with advancing age. Alternatively, our data may help explain why behaviors such as exercise and social activity, both known to increase dopaminergic activity, may be protective against AD dementia despite no apparent effect on cerebral amyloid burden (Nation et al., 2011). Finally, our results provide some support to the possibility that D 2 receptor agonists might delay clinical presentation or, perhaps, even act as neuroprotectants in individuals with striatal Ab accumulation. "
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    • "This may predispose the anterior hippocampus to exhibit the most volume loss when HPA function is disrupted. Dysregulation of such neuroendocrine function has long been linked with advancing age [57] [58] [59], and has also been implicated in other disorders such as AD [60] [61], clinical depression [62], and chronic stress [63]. Coupled with knowledge about hippocampal projections to surrounding tissue, examining the subdivisions of the hippocampus may provide a richer understanding of these conditions. "
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