TARDBP and Alzheimer disease: While it is possible that Aβ dysmetabolism prior to amyloid plaque formation or other pathophysiologies such as tau or TDP43 may underlie glucose hypometabolism in these cases, the hypometabolism-first biomarker profile pathway to preclinical AD lends strong support to a primary role for energy hypometabolism in the pathogenesis of at least a subset of sporadic AD patients.