Full-compartmental Modeling of [18F]FDG PET Suggests Divergent Brain Metabolism Trajectories from Healthy Aging to Early Alzheimer Disease

Within the Alzheimer disease (AD) spectrum, metabolic alterations occur in addition to proteinopathies. While hypometabolism is frequently observed in the late symptomatic stages, characterizing the metabolic changes during early AD stages might aid in both understanding its pathophysiology and in patient selection for future treatments. In this study, we conduct an exploratory, data-driven analysis aimed at better understanding the timing and specificity of the metabolic changes in early AD. Using kinetic analysis of [18F]FDG PET brain imaging data coming from 223 individuals, including 33 preclinical individuals and 19 symptomatic individuals, we find new evidence of a more complex spatiotemporal trajectory of glucose metabolism in early AD, which includes a paradoxical regional increase in glucose phosphorylation during preclinical AD. These findings suggest that the pathologic phases of AD parallel changes in brain glucose metabolism, which is readily assessable with [18F]FDG PET imaging. Moreover, they may indicate that metabolic interventions may work differently during preclinical AD as compared to the early symptomatic phase.