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 (AD) - carriers of apoE4, 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 contribute to the neuropathological cascade leading cognitive decline in AD. The reason for brain hypometabolism is unclear but may include defects in glucose transport at the blood-brain barrier, glycolysis, and/or mitochondrial function. Methodological 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 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 – (i) improve insulin sensitivity by improving systemic glucose utilization, or (ii) bypass deteriorating brain glucose metabolism using approaches that safely induce mild, sustainable ketonemia.

Regional brain energy substrate hypometabolism in mild AD dementia may be specific to impaired glucose uptake and/or utilization. This suggests a potential avenue for compensating brain energy deficit in AD dementia with ketones.

HighlightsWe present a robust and simple bias-adjustment scheme for neuroimaging-based brain age frameworks.The efficiency of proposed bias-adjustment scheme was assessed in the context of cognitively healthy aging and Alzheimer's disease.The proposed bias-adjustment scheme was shown efficient and statistically improved results, making it a necessary part for future brain age frameworks.

Ketones from MCT compensate for the brain glucose deficit in AD in direct proportion to the level of plasma ketones achieved.