The objective of this proposal is to develop small molecule drugs as novel disease modifying therapies for Alzheimer's disease (AD). We will use two well-characterized small molecules, a selective androgen receptor agonist (SARM) ACP-105 and selective estrogen receptor β (ERβ) ERb-186, both these compounds were discovered by ACADIA Pharmaceuticals and have the potential to move into the clinic. We propose to evaluate ERb-186 alone and in combination with ACP-105 and using estradiol (E2) as a reference compound in male 3xTg-AD mice. This study by focusing on the estrogen axis will mirror the previous one supported by ADDF that focused on on the androgen axis that tested dihydrotestosterone (reference compound), ACP-105, and the combination of ACP-105 and ERb-186. Most studies involving estrogens have focused on the female gender, however based on our previous studies we propose that a selective ERβ agonist would not only have a better safety profile, but also a unique pharmacology in both men and women, compared to the unselective 17β-estradiol that activates both ERα and ERβ. In addition, we found in our previous study supported by ADDF that simultaneous activation of both androgen receptor (AR) and ER gave a synergetic and sometimes a unique profile compared to only activating AR. In this study we will expand the number of proteolytic enzymes studied. The regulation and processing of amyloid-β (Aβ)-peptides catabolizing enzymes including Neprilysin, Insulin degrading enzyme, Cathepsin D, and BACE1, will be evaluated. In addition, cognition, neuronal plasticity, and tau hyperphosphorylation will be studied in mouse models of AD. We hypothesize that treatment of patients with AD using SARMs or ERβ agonists or a combination thereof will stop the progression of AD by clearance of aggregated Aβ-peptides and the reduction of tau pathology.