Brain fuel metabolism, aging, and Alzheimer’s disease

Abstract

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.

Introduction

Alzheimer’s disease (AD) is the product of slow, progressive degenerative changes that develop in the adult brain and can remain asymptomatic for a considerable time before cognitive decline becomes clinically evident. The challenge is to identify early markers of this degenerative process before it advances to clinically overt dementia because, at that point, it is probably too late to correct the existing damage or prevent further cognitive deterioration [1].

Progress in understanding changes in brain energy metabolism during aging and AD has grown rapidly in the past three decades, and it is now widely acknowledged that hypometabolism in certain brain regions accompanies AD. However, most view this hypometabolism as a consequence of the cellular and functional degeneration in AD, i.e., that lower brain functionality requires less energy substrate [2]. We present here the concept that factors impeding optimal glucose utilization can contribute to or precipitate AD neuropathology, i.e., that brain hypometabolism is a critical part of the clinically asymptomatic early development of AD.

There is an emerging body of evidence showing that significantly lower brain glucose metabolism can be present well in advance of the onset of measurable cognitive decline in AD. This evidence comes from various clinical and experimental models including studies of family history and genetic susceptibility to AD, post-mortem brain analysis, and in vitro and animal models. For instance, in carriers of the ɛ4 allele of apolipoprotein E (apo E4), small areas of cortical hypometabolism are present decades before the clinical onset of AD, making this the earliest marker thus far identified in individuals genetically at risk for AD. Therefore, a key issue is to establish whether this hypometabolism could contribute to development and/or progression of AD, or whether these metabolic changes in the brain are predominantly a consequence of even earlier neurodegenerative processes that reduce the demand for glucose in the affected brain areas. Thus, is brain hypometabolism a primary or a secondary problem in AD?

A second, equally important, issue is to establish whether brain hypometabolism in AD involves impaired brain utilization of energy substrates in general (as hypometabolism implies) or is more or less specific to glucose. With ¹⁸F-fluorodeoxyglucose (FDG) as the only positron emission tomography (PET) tracer validated for studies of brain metabolism, this important question has not yet been answered. Physiologically, ketone bodies (ketones) are a key replacement fuel preserving brain function during periods of low glucose availability, and the brain has a transport system for ketones independent of glucose transport. The recent development of ¹¹C-acetoacetate as a ketone tracer for PET studies opens a new window to compare brain metabolism of glucose and ketones in the same individual. If brain ketone metabolism is not lower in AD or is less affected than glucose metabolism, one potential strategy to improve brain fuel availability and reduce the risk of AD that has already been targeted in clinical studies would be to develop a way to safely and reliably provide the brain with ketones as an alternative fuel to glucose.

As proposed previously [3], [4], [5], [6], we support the concept that regional brain hypometabolism contributes to the neuropathology that precipitates clinical symptoms of AD. Brain hypometabolism can presumably be exacerbated secondary to advancing neuropathology, but it can also contribute to the development of AD when present before neuropathologic changes appear. We extend this concept by proposing that brain hypometabolism may affect glucose more than ketones. Whether it is possible to reduce the risk of AD by correcting, preventing, or bypassing deteriorating brain glucose metabolism prior to the onset of neuropathology and cognitive decline remains to be determined.