● Half life of most GLP-1 agonists is 47 days, so daily dosing is likely too excessive. Thin line between therapeutic dose and adverse effects. Micro dosing (significantly lower than dose used for weight loss) probably effective, but no actual data on best dose (1)

● Neurocognitive benefits are observed after a few months of use (1)

● GLP-1 agonists contribute to metabolic health and re-myelinate nerves. May prevent serious cognitive decline in individuals with mild cognitive impairment. (1)

● Prospective studies have shown mixed results. Larger studies with longer follow up are needed. (2)

● "Study showed GLP-1 (liraglutide) preserved brain volume and reduced cognitive decline by as much as 18% compared with placebo after one year of use. Neuroprotective effects likely are a combination of reducing amyloid and normalizing the brain's ability to process glucose. (3)

● Population: 204 patients with mild Alzheimer's disease

● Medication: Liraglutide

○ Dose: 1.8 mg subcutaneous injection daily for one year "

○ "There are multiple different brain cells (neurons, endothelial cells, oligodendroglia, etc). All have GLP-1 receptors. Dulaglutide (GLP-1 agonist) enters into brain tissue the easiest out of all the GLP1 agonists (61.8% brain uptake, significantly higher than other GLP-1 agonists), therefore likely being the most promising at curing AD. One large, randomized, placebo controlled study showed dulaglutide had significant benefit on cognition. (4)(6)

○ Population: Patients ≥50 years with established or newly diagnosed type 2 diabetes and additional cardiovascular risk factors

● Medication: Dulaglutide

○ Dose: 1.5 mg subcutaneous injection weekly for two years"

○ "Another study found that use of GLP-agonist was associated with statistically significant decrease in inflammatory proteins associated with AD. (5) (7)

○ Population: Adults with type 2 diabetes

● Medication: Exanitide

○ Dose: 2 mg subcutaneous injection weekly for one year"

○ 2 large US observational studies comparing adults on GLP-1 for DM and those not on GLP-1 for DM tx will be published in JAMA Neuro in 2025. Initial insight is that the drugs look promising.

Version: GJ 12/4/2024