Comparison of Tirzepatide, Retatrutide, and Crocetin, for Mitigation of Alzheimer's-like Pathology in a Mouse Model of Alzheimer’s Disease

PROJECT SUMMARY The relationship between Type 2 Diabetes Mellitus (T2DM) and Alzheimer's disease (AD) underscores a pressing need for novel therapeutic interventions to mitigate the underlying pathologies and reduce cognitive decline. While current treatments for AD primarily target symptomatic relief without modifying disease processes, recent developments suggest that antidiabetic drugs used to treat T2DM could hold promise in mitigating AD development. The incretin class of antidiabetic drugs, particularly GLP-1 agonists (e.g. semaglutide, liraglutide), have shown efficacy in treating T2DM while also demonstrating neuroprotective effects in both humans and animal models of AD. However, newer compounds like tirzepatide (“twincretin”, GLP-1 + GIP agonist) and retatrutide (“triplecretin”, GLP-1 + GIP + glucagon agonist) have yet to be investigated, despite the likelihood that they may be more effective given their combined GLP-1 agonism with additional receptor activations. Additionally, agonism of free fatty acid receptors (FFAR1 and FFAR4; also known as GPR40 and GPR120) presents another therapeutic avenue, with crocetin, a natural compound, emerging as a dual agonist of GPR40 and GPR120 receptors. Crocetin's multifaceted neuroprotective properties, including anti-inflammatory and memory-enhancing effects, position it as a potential disease-modifying therapy for AD. To address gaps in current understanding, the proposed research aims to evaluate the therapeutic potential of tirzepatide, retatrutide, and crocetin in a clinically relevant animal model of comorbid AD with obesity/prediabetes induced by a high-fat diet. The experimental design includes sustained consumption of a high fat diet from the age of 4 to 13 months, an 18-week chronic treatment with tirzepatide, retatrutide or crocetin, beginning at 8 months of age, followed by behavioral testing and neuropathological analyses of the brains post-mortem at ~ 13 months. The chronological ages of the mice correspond to early adulthood (4 months) and middle age (13 months) according to Jackson Labs to include the additional risk factor of older age. While it would be ideally to extend the study to 15 months of age, classified as old by Jackson Labs, our previous experience with the 3xTg-AD strain indicates that the attrition rate of male mice would preclude their inclusion in this study. By assessing cognitive-behavioral function, neuropathological changes, and cardiometabolic alterations, this study aims to elucidate the efficacy of these interventions in mitigating AD-like pathology and cognitive decline. Importantly, the inclusion of sex as a biological variable acknowledges sex disparities in AD prevalence and progression, as well as the ability of sex to modulate treatment outcomes, thereby enhancing the translational relevance of the findings. Ultimately, this research aims to elucidate novel therapeutic targets for AD, particularly in patients with comorbid metabolic disease, ultimately contributing to the development of more accessible and effective treatments for these conditions.