Contrasting Metabolic Insufficiency in Aging and Dementia.

Metabolic insufficiency and neuronal dysfunction occur in normal aging but is exaggerated in dementia and Alzheimer's disease (AD). Metabolic insufficiency includes factors important for both substrate supply and utilization in the brain. Metabolic insufficiency occurs through a number of serial mechanisms, particularly changes in cerebrovascular supply through blood vessel abnormalities (ie, small and large vessel vasculopathy, stroke), alterations in neurovascular coupling providing dynamic blood flow supply in relation to neuronal demand, abnormalities in blood brain barrier including decreased glucose and amino acid transport, altered glymphatic flow in terms of substrate supply across the extracellular space to cells and drainage into CSF of metabolites, impaired transport into cells, and abnormal intracellular metabolism with more reliance on glycolysis and less on mitochondrial function. Recent studies have confirmed abnormal neurovascular coupling in a mouse model of AD in response to metabolic challenges, but the supply chain from the vascular system into neurons is disrupted much earlier in dementia than in equivalently aged individuals, contributing to the progressive neuronal degeneration and cognitive dysfunction associated with dementia. We discuss several metabolic treatment approaches, but these depend on characterizing patients as to who would benefit the most. Surrogate biomarkers of metabolism are being developed to include dynamic estimates of neuronal demand, sufficiency of neurovascular coupling, and glymphatic flow to supplement traditional static measurements. These surrogate biomarkers could be used to gauge efficacy of metabolic treatments in slowing down or modifying dementia time course.