Roger J. Mullins, Maja Mustapic, Chee W. Chia, Olga Carlson, Seema Gulyani, Joyce Tran, Yazhou Li, Mark P. Mattson, Susan Resnick, Josephine M. Egan, Nigel H. Greig and Dimitrios Kapogiannis* Pages 741 - 752 ( 12 )
<P>Background: Strong preclinical evidence suggests that exenatide, a glucagon-like peptide-1 (GLP- 1) receptor agonist used for treating type 2 diabetes, is neuroprotective and disease-modifying in Alzheimer’s Disease (AD). </P><P> Objective: We performed an 18-month double-blind randomized placebo-controlled Phase II clinical trial to assess the safety and tolerability of exenatide and explore treatment responses for clinical, cognitive, and biomarker outcomes in early AD. </P><P> Method: Eighteen participants with high probability AD based on cerebrospinal fluid (CSF) biomarkers completed the entire study prior to its early termination by the sponsor; partial outcomes were available for twentyone. </P><P> Results: Exenatide was safe and well-tolerated, showing an expectedly higher incidence of nausea and decreased appetite compared to placebo and decreasing glucose and GLP-1 during Oral Glucose Tolerance Tests. Exenatide treatment produced no differences or trends compared to placebo for clinical and cognitive measures, MRI cortical thickness and volume, or biomarkers in CSF, plasma, and plasma neuronal extracellular vesicles (EV) except for a reduction of Aβ42 in EVs. </P><P> Conclusion: The positive finding of lower EV Aβ42 supports emerging evidence that plasma neuronal EVs provide an effective platform for demonstrating biomarker responses in clinical trials in AD. The study was underpowered due to early termination and therefore we cannot draw any firm conclusions. However, the analysis of secondary outcomes shows no trends in support of the hypothesis that exenatide is diseasemodifying in clinical AD, and lowering EV Aβ42 in and of itself may not improve cognitive outcomes in AD.</P>
GLP-1 agonist, exenatide, memory, diabetes, placebo, Alzheimer's disease.
Laboratory of Neurosciences, National Institute on Aging/National Institutes of Health (NIA/NIH), 3001 S. Hanover St, NM531, Baltimore, MD, 21225, Laboratory of Neurosciences, National Institute on Aging/National Institutes of Health (NIA/NIH), 3001 S. Hanover St, NM531, Baltimore, MD, 21225, Laboratory of Clinical Investigation, National Institute on Aging/National Institutes of Health (NIA/NIH), 3001 S. Hanover St, NM531, Baltimore, MD, 21225, Laboratory of Clinical Investigation, National Institute on Aging/National Institutes of Health (NIA/NIH), 3001 S. Hanover St, NM531, Baltimore, MD, 21225, Laboratory of Neurosciences, National Institute on Aging/National Institutes of Health (NIA/NIH), 3001 S. Hanover St, NM531, Baltimore, MD, 21225, Laboratory of Neurosciences, National Institute on Aging/National Institutes of Health (NIA/NIH), 3001 S. Hanover St, NM531, Baltimore, MD, 21225, Translational Gerontology Branch, National Institute on Aging/National Institutes of Health (NIA/NIH), 3001 S. Hanover St, NM531, Baltimore, MD, 21225, Laboratory of Neurosciences, National Institute on Aging/National Institutes of Health (NIA/NIH), 3001 S. Hanover St, NM531, Baltimore, MD, 21225, Laboratory of Behavioral Neuroscience, Intramural Research Program, National Institute on Aging/National Institutes of Health (NIA/NIH), 3001 S. Hanover St, NM531, Baltimore, MD, 21225, Laboratory of Clinical Investigation, National Institute on Aging/National Institutes of Health (NIA/NIH), 3001 S. Hanover St, NM531, Baltimore, MD, 21225, Translational Gerontology Branch, National Institute on Aging/National Institutes of Health (NIA/NIH), 3001 S. Hanover St, NM531, Baltimore, MD, 21225, Laboratory of Neurosciences, National Institute on Aging/National Institutes of Health (NIA/NIH), 3001 S. Hanover St, NM531, Baltimore, MD, 21225