Acetate supplementation rescued learning in an ACSS2-dependent manner and restored gene expression linked to cognition.<h4>Discussion</h4>ACSS2 acts as a neuroprotective metabolic enzyme in vulnerable hippocampal neurons, and targeting this pathway through dietary supplementation may offer therapeutic potential for AD and related tauopathies.<h4>Highlights</h4>We combine tau seeding with deletion of acetyl-CoA synthetase 2 (ACSS2) to test this enzyme in an Alzheimer's disease model. This evidence concerns the gene ACSS2 and early-onset autosomal dominant Alzheimer disease.