Can GLP-1s Reduce Alzheimer’s Disease Risk?

Tina is a lovely 67-year-old woman who was recently found to be an APOE gene carrier (a gene associated with increased risk of developing Alzheimer’s disease as well as an earlier age of disease onset), with diffused amyloid protein deposition her brain. 

Her neuropsychiatric testing was consistent with mild cognitive impairment. Although Tina is not a doctor herself, her entire family consists of doctors, and she came to me under their advisement to consider semaglutide (Ozempic) for early Alzheimer’s disease prevention. 

This would usually be simple, but in Tina’s case, there was a complicating factor: At 5’ and 90 lb, she was already considerably underweight and was at risk of becoming severely undernourished. 

To understand the potential role for glucagon-like peptide-1 (GLP-1) receptor agonists such as Ozempic in prevention, a quick primer on Alzheimer’s Disease is necessary.

The exact cause of Alzheimer’s disease remains elusive, but it is probably due to a combination of factors, including:

• Buildup of abnormal amyloid and tau proteins around brain cells;
• Brain shrinkage, with subsequent damage to blood vessels and mitochondria, and inflammation;
• Genetic predisposition; and
• Lifestyle factors, including obesity, high blood pressure, high cholesterol, and diabetes.

GLP-1 receptor agonists can cross the blood-brain barrier and bind to GLP-1 receptors expressed by neurons. Once in the brain, they can reduce inflammation and improve functioning of the neurons. In early rodent trials, GLP-1 receptor agonists led to reduced amyloid and tau aggregation, downregulation of inflammation, and improved memory.

In 2021, multiple studies showed that liraglutide, an early GLP-1 receptor agonist, improved cognitive function and MRI volume in patients with Alzheimer’s disease. 

A study recently published in Alzheimer’s & Dementia analyzed data from 1 million people with type 2 diabetes and no prior Alzheimer’s disease diagnosis. The authors compared Alzheimer’s disease occurrence in patients taking various diabetes medications, including insulin, metformin, and GLP-1 receptor agonists. The study found that participants taking semaglutide had up to a 70% reduction in Alzheimer’s risk. The results were consistent across gender, age, and weight.

Given the reassuring safety profile of GLP-1 receptor agonists and lack of other effective treatment or prophylaxis for Alzheimer’s disease, I agreed to start her on dulaglutide (Trulicity). My rationale was twofold:

1. In studies, dulaglutide has the highest uptake in the brain tissue at 68%. By contrast, there is virtually zero uptake in brain tissue for semaglutide (Ozempic/Wegovy) and tirzepatide (Mounjaro/Zepbound). Because this class of drugs exert their effects in the brain tissue, I wanted to give her a GLP-1 receptor agonist with a high percent uptake.
2. Trulicity has a minimal effect on weight loss compared with the newer-generation GLP-1 receptor agonists. Even so, I connected Tina to my dietitian to ensure that she would receive a high-protein, high-calorie diet.

Tina has now been taking Trulicity for 6 months. Although it is certainly too early to draw firm conclusions about the efficacy of her treatment, she is not experiencing any weight loss and is cognitively stable, according to her neurologist. 

The EVOKE and EVOKE+ phase 3 trials are currently underway to evaluate the efficacy of semaglutide to treat mild cognitive impairment and early Alzheimer’s in amyloid-positive patients. Results are expected in 2025, but in the meantime, I feel comforted knowing that Tina is receiving a potentially beneficial and definitively low-risk treatment.