Grant: Operating Grant

In certain brain regions, glucose uptake decreases significantly in Alzheimer's disease (AD). Decreased brain glucose uptake can occur decades before the clinical onset of AD, making it the earliest reported pathophysiological change associated with AD. Using positron emission tomography (PET), we have preliminary evidence showing that in the healthy elderly, brain glucose uptake declines 11-13% in the same regions as in AD but that brain ketone uptake is unaffected. We have also shown that rats in mild, experimental ketonemia (MEK; 1-2 mM total plasma ketones for 2 wk) have a 2-3 fold increase in brain uptake of both ketones and glucose. If confirmed in humans, this novel finding might explain why, in short term studies, MEK improves cognition in AD. The amnestic form of mild cognitive impairment (aMCI) is the condition most likely to lead to AD. We hypothesize that - (i) aMCI predisposes to AD in part because it exacerbates the age-related trend towards lower brain uptake of glucose in brain regions affected in AD, and (ii) MEK has a beneficial effect on cognition because it bypasses or corrects lower brain glucose uptake. The objective is to better understand the link between deteriorating glucose uptake and risk of declining cognition in the adult/aging brain. Specifically, before and after inducing MEK, we will assess cognitive function and use our PET method to assess the brain uptake of ketones and glucose in human studies involving the healthy elderly and aMCI. In aged rats, we will examine mechanistic aspects of different models of MEK including brain fuel uptake, and brain glucose and ketone transporter expression. Whether gradually deteriorating brain glucose uptake with aging can be corrected is unknown. MEK is currently the only known way to raise brain glucose uptake so it has important implications for nutritional strategies to reduce the risk of developing aMCI or, potentially, its conversion to AD.