The glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide did not meet its primary endpoint for changing cerebral glucose metabolism but did show a beneficial effect on a secondary cognitive outcome in patients with mild to moderate Alzheimer's disease (AD), according to results from the phase 2b ELAD trial.¹

Liraglutide is a GLP-1 receptor agonist approved for the treatment of type 2 diabetes and obesity. Preclinical models have suggested it may have neuroprotective effects by influencing multiple pathological pathways in AD, including β-amyloid deposition, tau aggregation, and neuroinflammation.

The Evaluating Liraglutide in Alzheimer’s Disease (ELAD; NCT01843075) study was a 52-week, multicentre, randomised, double-blind, placebo-controlled trial conducted across 24 sites in the UK. The trial enrolled 204 participants aged 50 years or older with mild to moderate AD and no diabetes.

Participants were randomised 1:1 to receive either daily subcutaneous injections of liraglutide, escalated to a target dose of 1.8 mg, or a matching placebo.

The primary outcome was the change in cerebral glucose metabolic rate from baseline to 52 weeks. Key secondary outcomes included changes in cognitive function, measured by the Alzheimer’s Disease Assessment Scale-Executive domain (ADAS-Exec), as well as safety and tolerability.

The trial did not meet its primary endpoint, with no significant difference observed in cerebral glucose metabolism between the treatment and placebo groups (difference = -0.17; 95% CI: -0.39 to 0.06; P=0.14).

For secondary outcomes, patients treated with liraglutide demonstrated a significantly slower decline in cognition on the ADAS-Exec score compared to those receiving placebo (0.15; 95% CI: 0.03–0.28; unadjusted P=0.01). No significant differences were observed in the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) or Clinical Dementia Rating-Sum of Boxes (CDR-SoB) scores.

Liraglutide was generally safe and well tolerated. The most common adverse events were gastrointestinal disorders, which were more frequent in the liraglutide group. Notably, serious adverse events were less common in the treatment arm (6.9%) compared to the placebo arm (17.6%).

While the ELAD study failed to show an effect on its primary metabolic endpoint, the positive signal on a key cognitive measure suggests a potential neuroprotective role for liraglutide in AD. The study authors noted that "the secondary outcome—score on the Alzheimer’s Disease Assessment Scale-Executive domain (ADAS-Exec)—performed better in liraglutide-treated patients compared to placebo."¹ The findings, particularly the slowing of cognitive decline and a favourable safety profile, support further investigation of GLP-1 analogues in larger, longer-term studies to confirm these potential benefits.

This study was funded by the Alzheimer’s Society, the Alzheimer’s Drug Discovery Foundation, the Van Geest Foundation, the NIHR Imperial Biomedical Research Centre, and Novo Nordisk A/S.

References

1. Edison P, Femminella GD, Ritchie C, et al. Liraglutide in mild to moderate Alzheimer’s disease: a phase 2b clinical trial. _Nat Med_ (2025). https://doi.org/10.1038/s41591-025-04106-7

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