GLP-1 Agonists for Preventing Alzheimer's Disease in Mild Cognitive Impairment - ABSTRACT Alzheimer’s disease (AD) affects millions in the United States, with cases expected to further surge in the coming decades. There are no treatments currently available to halt or reverse AD progression, which indicates the urgent need for preventions before the onset of AD. Mild cognitive impairment (MCI), often considered as a potential precursor to AD, presents a critical window for preventive strategies. However, FDA-approved treatments for MCI are limited to recently approved anti-amyloid monoclonal antibodies (mAbs), which are costly. Given this, additional therapeutic options are needed to expand treatment choices for patients. Glucagon-like peptide-1 (GLP-1) agonists, originally developed for type 2 diabetes, have demonstrated potential neuroprotective effects, including reducing neuroinflammation. However, their long-term impact on AD prevention remains unclear, with concerns regarding safety and cost- effectiveness. The central hypothesis of this project is that GLP-1 agonists can reduce the risk of AD progression in MCI patients while maintaining an acceptable safety profile and cost -effectiveness. To investigate this, we propose two specific aims: (1) to evaluate the effectiveness of GLP-1 agonists in preventing AD progression compared to non-users and anti-amyloid mAb users, and (2) to assess the safety of GLP-1 agonists in MCI patients. In addition, an exploratory aim will assess the cost-effectiveness of GLP-1 agonists compared to non-users and anti-amyloid mAb users. This study will use real-world data (RWD) from TriNetX and employ a target trial emulation (TTE) framework to generate high-quality comparative evidence. By integrating real-world effectiveness, safety, and economic evaluations, this project will provide critical insights to guide clinical decision-making and future trials.
