Project Summary Alzheimer's disease (AD) is a devastating disease with no disease-modifying therapies. A key contributing factor to AD is impaired glucose metabolism. However, it is unknown how glucose metabolism contributes to neurodegeneration in AD. Our recent work demonstrated that we could enhance glycolysis via an existing drug, terazosin (TZ). This drug is an alpha-1 antagonist, but it also binds to and enhances activity of phosphoglycerate kinase-1 (PGK1), the first ATP-generating step of glycolysis. Excitingly, our preliminary data from the Truven database of Medicare claims suggest that patients taking TZ are protected from developing AD relative to those taking tamsulosin, another alpha-1 antagonist that does not bind PGK1. Additionally, our review of the Alzheimer's Disease Neuroimaging initiative (ADNI) indicates that patients taking TZ have slower progression on FDG-PET and on cognitive impairment, compared to those taking tamsulosin. In this proposal, our goal is to test TZ target engagement and efficacy in animal models of AD. To our knowledge, no drug for AD directly engages PGK1 or metabolism and mitigates protein aggregation; thus, this mechanism is entirely novel for AD. Our overall hypothesis is that TZ is protective in rodent models of AD. In Aim 1, we will quantify TZ target engagement in rodent AD models. We will administer TZ orally for six-months to transgenic tau (P301S) and amyloid (5XFAD) mice relevant for human AD, along with littermate and vehicle controls. We will evaluate blood and brain metabolomics and [ATP], as well as in vivo magnetic resonance spectroscopy (MRS). In Aim 2, we will evaluate whether improving glycolysis mitigate neurodegeneration in rodent AD models. We will use the same mice as in Aim 1 and evaluate cognitive function via novel-object recognition, spatial working memory, and interval timing assays. We will also perform immunohistochemistry, ELISA, and western blot to assess tau/amyloid pathology. These studies will elucidate the basic principles of how TZ enhances brain energetics, and affects neurodegeneration. These fundamental mechanisms could be highly relevant for inspiring novel disease-modifying therapies in AD and related dementias.