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A pilot study of exenatide actions in Alzheimer's disease.

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Published:13th Sep 2019
Author: Mullins RJ, Mustapic M, Chia CW, Carlson O, Gulyani S, Tran J et al.
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Ref.:Curr Alzheimer Res. 2019.
DOI:10.2174/1567205016666190913155950

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).

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 bio- marker outcomes in early AD.

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 twenty-one.

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.

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 disease- modifying in clinical AD, and lowering EV Aβ42 in and of itself may not improve cognitive outcomes in AD.

 

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