Inflammatory proteins associated with Alzheimer's disease reduced by a GLP1 receptor agonist: a post hoc analysis of the EXSCEL randomized placebo controlled trial

Abstract

Background: Glucagon-like peptide-1 receptor agonists are a viable option for the prevention of Alzheimer's disease (AD) but the mechanisms of this potential disease modifying action are unclear. We investigated the effects of once-weekly exenatide (EQW) on AD associated proteomic clusters.

Methods: The Exenatide Study of Cardiovascular Event Lowering study compared the cardiovascular effects of EQW 2 mg with placebo in 13,752 people with type 2 diabetes mellitus. 4,979 proteins were measured (Somascan V0.4) on baseline and 1-year plasma samples of 3,973 participants. C-reactive protein (CRP), ficolin-2 (FCN2), plasminogen activator inhibitor 1 (PAI-1), soluble vascular cell adhesion protein 1 (sVCAM1) and 4 protein clusters were tested in multivariable mixed models.

Results: EQW affected FCN2 (Cohen's d -0.019), PAI-1 (Cohen's d -0.033), sVCAM-1 (Cohen's d 0.035) and a cytokine-cytokine cluster (Cohen's d 0.037) significantly compared with placebo. These effects were sustained in individuals over the age of 65 but not in those under 65.

Conclusions: EQW treatment was associated with significant change in inflammatory proteins associated with AD.

Trial registration: EXSCEL is registered on ClinicalTrials.gov: NCT01144338 on 10th of June 2010.

Keywords: Alzheimer’s disease; Glucagon-like peptide-1 receptor agonists; Proteomics.

Fig. 1

CONSORT diagram of included samples

Fig. 2

Interquartile plots by visit and treatment of endpoints with a significant interaction term in model A (FDR p < 0.1). Abbreviations: C-reactive protein (CRP), Ficolin-2 (FCN2), vascular cell adhesion protein 1 (VCAM1)

Fig. 3

Interquartile plots for endpoints with significant interaction terms in model A in either subgroup. (*) indicates that the interaction term remains significant after adjusting for covariates (model C)

Fig. 4

Interquartile plots for endpoints with significant interaction terms in model A in either subgroup. (*) indicates that the interaction term remains significant after adjusting for covariates (model C)

Fig. 5

Exploratory analysis for individual proteins included in four clusters. 273/1767 individual proteins included in four clusters change differently from baseline to month 12 with EQW treatment (FDR-adjusted pvalue < 0.1). Model adjusted for age, sex, smoking, systolic blood pressure (BP), diastolic BP, BMI, HBa1C, HDL, LDL, triglycerides, baseline eGFR, and diabetes duration. The x-axis shows the average percentage change in the EQW group. Area to the right of the dashed line indicates increased protein levels in the exenatide group. Top 8 proteins that had average % change in the EQW group greater than and less than the placebo group are labeled in red and blue, respectively