From the Guidelines
GLP-1 receptor agonist therapies, such as liraglutide, semaglutide, and dulaglutide, show promising but preliminary results for Alzheimer's disease, with no FDA-approved indications for this purpose yet, and should not be prescribed specifically for Alzheimer's disease outside of clinical trials. Early research suggests these medications may offer neuroprotective benefits through multiple mechanisms including reduced inflammation, improved insulin sensitivity in the brain, and decreased amyloid accumulation 1. Clinical trials have demonstrated modest cognitive benefits in some studies, with a trial with liraglutide showing slowed decline in cerebral glucose metabolism compared to placebo, while semaglutide has demonstrated potential to reduce neuroinflammation. The most substantial evidence comes from observational studies showing GLP-1 users with diabetes had lower rates of Alzheimer's diagnosis compared to those using other diabetes medications.
Key Findings
- The LEADER trial, a randomized, double-blind trial, assessed the effect of liraglutide on cardiovascular outcomes in 9,340 patients with type 2 diabetes at high risk for cardiovascular disease or with cardiovascular disease, and showed that the primary composite outcome occurred in fewer participants in the treatment group (13.0%) when compared with the placebo group (14.9%) (HR 0.87; 95% CI 0.78–0.97; P < 0.001 for noninferiority; P = 0.01 for superiority) 1.
- The SUSTAIN-6 trial, a moderate-sized trial of semaglutide, found that the primary outcome occurred in 108 patients (6.6%) in the semaglutide group vs. 146 patients (8.9%) in the placebo group (HR 0.74 [95% CI 0.58–0.95]; P < 0.001) 1.
- The Harmony Outcomes trial randomized 9,463 patients with type 2 diabetes and cardiovascular disease to once-weekly subcutaneous albiglutide or matching placebo, and found that the GLP-1 receptor agonist reduced the risk of cardiovascular death, MI, or stroke to an incidence rate of 4.6 events per 100 person-years in the albiglutide group vs. 5.9 events in the placebo group (HR ratio 0.78, P = 0.0006 for superiority) 1.
Current Status
The typical doses being studied mirror those used for diabetes treatment: liraglutide at 1.8mg daily, semaglutide at 1mg weekly, and dulaglutide at 1.5mg weekly. Side effects include nausea, vomiting, and potential weight loss, which may be problematic for elderly patients already experiencing weight loss. Until more definitive evidence emerges, these medications should not be prescribed specifically for Alzheimer's disease outside of clinical trials. Ongoing clinical trials, with several Phase 2 and 3 studies currently underway, will provide more insight into the potential benefits and risks of GLP-1 receptor agonist therapies for Alzheimer's disease.
From the Research
Current Outcomes for GLP-1 Therapies in Alzheimer's Disease
The current outcomes for GLP-1 receptor agonist therapies in the prevention or treatment of Alzheimer's disease are as follows:
- A systematic review of clinical studies on GLP-1 receptor agonists in Alzheimer's disease found that these therapies did not alter amyloid-β and tau biomarkers nor show improvements in cognition, but showed potential metabolic and neuroprotective benefits 2.
- GLP-1 receptor agonists have been shown to have metabolic benefits, such as lower body mass index and improved glucose levels, in patients with type 2 diabetes 3.
- Treatment with GLP-1 receptor agonists may reduce the incidence of dementia in patients with type 2 diabetes, with a lower dementia rate observed in patients randomized to GLP-1 receptor agonists versus placebo 4.
Preclinical Studies
Preclinical studies have investigated the potential pro-cognitive and neuroprotective effects of GLP-1 receptor agonists in animal models of Alzheimer's disease:
- The GLP-1 receptor agonist liraglutide has been shown to improve memory function and increase hippocampal CA1 neuronal numbers in a senescence-accelerated mouse model of Alzheimer's disease 5.
- Liraglutide has also been shown to have a protective effect on Alzheimer's disease in vivo and in vitro, which may be mediated by preventing neuronal apoptosis and inhibiting the activation of tau and the expression of BACE1 6.
Potential Mechanisms of Action
The potential mechanisms of action of GLP-1 receptor agonists in Alzheimer's disease include:
- Neuroprotection: GLP-1 receptor agonists may have neuroprotective effects, such as preventing neuronal apoptosis and inhibiting the activation of tau and the expression of BACE1 6.
- Metabolic benefits: GLP-1 receptor agonists may have metabolic benefits, such as improving glucose levels and reducing body mass index, which may also have a positive effect on Alzheimer's disease 3.