University of California San Diego, School of Medicine, Department of Psychiatry, San Diego, CA, USA.
Med Hypotheses. 2011 Jun;76(6):847-54. doi: 10.1016/j.mehy.2011.02.034. Epub 2011 Mar 12.
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.
遗传因素被认为在阿尔茨海默病（AD）易感性中起作用，但不到 1%的 AD 病例与遗传原因直接相关，这表明环境变量可能在大多数病例中起作用。最近有几项人类和动物研究检查了行为因素（特别是心理压力和运动）对 AD 易感性的影响。许多动物研究发现，虽然压力会加剧与 AD 相关的神经病理学变化，但运动可以减少这些变化。一些人类研究表明，心理压力会增加患 AD 的风险，而其他研究表明，运动可以显著降低 AD 的风险。大多数研究这些行为因素对 AD 影响的动物研究都集中在神经元过程上，包括应激激素和神经营养因子对 AD 神经病理学标志物（即淀粉样β（Aβ）沉积和 tau 磷酸化）的影响。然而，越来越多的证据表明，在人类中，AD 与脑血管疾病的存在有关，心血管危险因素与 AD 发病风险增加有关。有大量文献表明，行为因素，特别是压力和运动，可以有力地调节血管疾病的病理生理学。因此，以下模型提出，压力和运动对 AD 风险的影响可能部分归因于这些行为因素对血管稳态和病理学的影响。这些影响可能是由于通过改变高血压、糖尿病和主动脉僵硬等血管危险因素间接改变 AD 风险，以及直接影响脑血管，包括脑血流、血管生成和血管疾病的变化。未来研究检查行为因素对 AD 风险的影响时，应纳入外周和脑血管功能的测量，以进一步了解行为改变 AD 易感性的机制。对这些行为影响背后的分子机制有更多的了解将进一步了解该疾病，并导致创新的治疗和预防方法。
