Brain Hypometabolism, Oxidative Stress, Maternal Transmission, and Risk of Late-Onset Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is an age-dependent neurodegenerative disorderassociated with progressive loss of cognitive function. Positronemission tomography (PET) imaging with2-{[}F-18]fluoro-2-deoxy-D-glucose (FDG) as the tracer has long beenused to measure resting-state cerebral metabolic rates of glucose, aproxy for neuronal activity. Several FDG-PET studies have shown thatmetabolic reductions occur decades before onset of AD symptoms,suggesting that metabolic deficits may be an upstream event in at leastsome late-onset AD cases. This review explores this possibility,initially by discussing the link between AD pathology andneurodegeneration, with a focus on the metabolic pathways involved inneuronal function and bioenergetics, and the relationship betweenglucose metabolism, oxidative stress, and AD. This will be followed by asummary of the FDG-PET method, ranging from physics to kinetic modeling,and PET findings in AD. We will then discuss recent findings ofprogressive FDG-PET hypometabolism in adult children of mothers, but notfathers, affected by late-onset AD. Given the connection between glucosemetabolism and mitochondria and the fact that mitochondrial DNA ismaternally inherited in humans, it will be argued that alteredbioenergetics may be an upstream event in individuals with a maternalfamily history of AD. Biomarkers of AD have great potential foridentifying AD endophenotypes in cognitively intact individuals at riskfor AD, which may help direct investigation of potential susceptibilitygenes.