Alzheimer’s disease (AD) is an aging-related multifactorial neurodegenerative disease characterized by unique brain pathology and cognitive syndromes. AMP-activated protein kinase (AMPK) functions as a central energy sensor at the cellular level to maintain energy homeostasis, dysregulation of which is linked to multiple neurodegenerative diseases including AD. Mammalian AMPK is a heterotrimeric complex composed of catalytic α subunit, and regulatory β and γ subunits. The kinase catalytic subunit exists in two isoforms: α1 and α2. Our group has demonstrated disruption of hippocampal AMPKα isoform expression in human AD patients and rodent models of AD. Furthermore, we showed that neuronal suppression of AMPKα1 (but not AMPKα2) restored aging-related cognitive deficits and synaptic failure in two different mouse models of AD (Zimmermann, et al., JCI, 2020; Yang, et al., Molecular Psychiatry, 2021; Zhou, et al., Aging, 2023). In comparison, during the early, asymptomatic stage of AD models, selective suppression of AMPKα2 (but not AMPKα1) results in aggravation of AD-associated cognitive dysfunction (unpublished data). We have used multiple approaches to investigate the underlying mechanisms potentially associated with these functional phenotypes. Our findings reveal previously unrecognized roles of AMPKα isoform homeostasis in the development of AD pathophysiology.