Research Center on Aging, Health and Social Services Center-Sherbrooke University Geriatrics Institute, Université de Sherbrooke, Sherbrooke, QC, Canada; Department of Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada; Department of Physiology and Biophysics, Université de Sherbrooke, Sherbrooke, QC, Canada.
Research Center on Aging, Health and Social Services Center-Sherbrooke University Geriatrics Institute, Université de Sherbrooke, Sherbrooke, QC, Canada; Department of Physiology and Biophysics, Université de Sherbrooke, Sherbrooke, QC, Canada.
Nutrition. 2011 Jan;27(1):3-20. doi: 10.1016/j.nut.2010.07.021. Epub 2010 Oct 29.
Lower brain glucose metabolism is present before the onset of clinically measurable cognitive decline in two groups of people at risk of Alzheimer's disease--carriers of apolipoprotein E4, and in those with a maternal family history of AD. Supported by emerging evidence from in vitro and animal studies, these reports suggest that brain hypometabolism may precede and therefore contribute to the neuropathologic cascade leading to cognitive decline in AD. The reason brain hypometabolism develops is unclear but may include defects in brain glucose transport, disrupted glycolysis, and/or impaired mitochondrial function. Methodologic issues presently preclude knowing with certainty whether or not aging in the absence of cognitive impairment is necessarily associated with lower brain glucose metabolism. Nevertheless, aging appears to increase the risk of deteriorating systemic control of glucose utilization, which, in turn, may increase the risk of declining brain glucose uptake, at least in some brain regions. A contributing role of deteriorating glucose availability to or metabolism by the brain in AD does not exclude the opposite effect, i.e., that neurodegenerative processes in AD further decrease brain glucose metabolism because of reduced synaptic functionality and hence reduced energy needs, thereby completing a vicious cycle. Strategies to reduce the risk of AD by breaking this cycle should aim to (1) improve insulin sensitivity by improving systemic glucose utilization, or (2) bypass deteriorating brain glucose metabolism using approaches that safely induce mild, sustainable ketonemia.
大脑下部的葡萄糖代谢在两组有患阿尔茨海默病风险的人群中出现，这两组人群分别是载脂蛋白 E4 的携带者，以及有 AD 家族病史的人群。这些报告表明，脑代谢低下可能先于并因此导致 AD 认知能力下降的神经病理级联反应，体外和动物研究的新证据也支持这一观点。脑代谢低下发生的原因尚不清楚，但可能包括脑葡萄糖转运缺陷、糖酵解中断和/或线粒体功能受损。目前的方法学问题使得我们无法确定认知能力没有下降的衰老是否必然与大脑葡萄糖代谢降低有关。尽管如此，衰老似乎会增加全身葡萄糖利用失控的风险，而这反过来又可能增加大脑葡萄糖摄取下降的风险，至少在某些大脑区域是这样。大脑葡萄糖供应或代谢恶化在 AD 中的作用并不排除相反的效果，即 AD 中的神经退行性过程由于突触功能降低和因此能量需求降低而进一步降低大脑葡萄糖代谢，从而形成一个恶性循环。通过打破这种循环来降低 AD 风险的策略应该旨在：（1）通过改善全身葡萄糖利用来提高胰岛素敏感性，或者（2）使用安全诱导轻度、可持续酮血症的方法绕过恶化的大脑葡萄糖代谢。
