Ozempic and Alzheimer’s Prevention
Tina is a lovely 67-year-old female who was recently found to be an ApoE4 gene carrier (a gene associated with increased risk of developing Alzheimer’s and with earlier age of disease onset) with diffused amyloid protein deposition her brain. Her neuropsychiatric testing was consistent with mild cognitive impairment. While Tina is not a doctor herself, her entire family consists of doctors, and she came to me under their advisement to consider treatment with Ozempic for early Alzheimer’s. While this would usually be simple, in Tina’s case, there was a complicating factor. At 5’ and 90lbs, she was already considerably underweight and was at risk for becoming severely undernourished.
In order to understand the potential role for GLP-1 receptor agonists like Ozempic in Alzheimer’s prevention, a quick primer on Alzheimer’s is necessary.
The exact cause of Alzheimer’s remains elusive but it is likely due to a combination of factors including:
the buildup of abnormal amyloid and tau proteins around brain cells
brain shrinkage with subsequent blood vessel damage, mitochondrial* damage, and inflammation. *Mitochondrion are the “powerhouses” of the cell which help produce energy
genetic predisposition
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 the 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 an early generation GLP-1 agonist called liraglutide improved cognitive function[1] and MRI volume in patients with Alzheimer’s.[2]
A study recently published in Alzheimer’s and Dementia Journal analyzed data from 1 million people with type 2 diabetes with 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. 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.[3]
Given the reassuring safety profile of GLP-1 receptor agonists and lack of other effective treatment for Alzheimer’s, 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%.[4] 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 with a high percent uptake. 2) Trulicity has a minimal effect on weight loss compared to the newer generation GLP-1 receptor agonists. Even so, I connected Tina to my dietitian to ensure a high protein/high calorie diet.
Tina has now been taking Trulicity for the past six months. While it is certainly too early to draw firm conclusions about the efficacy of her treatment, she is not experiencing any weight loss and occurs to be 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.
[1] Paul Edison et al. Evaluation of liraglutide in the treatment of Alzheimer's disease. Alzheimer’s and Dementia. 2021.
[2] Carranza- Naval et al. Liraglutide Reduces Vascular Damage, Neuronal Loss, and Cognitive Impairment in a Mixed Murine Model of Alzheimer's Disease and Type 2 Diabetes. Front Aging Neurosci. 2021.
[3] William Wang et al. Associations of semaglutide with first-time diagnosis of Alzheimer’s disease in patients with type 2 diabetes: Target trial emulation using nationwide real-world data in the US. Alzheimer’s and Dementia. 2024
[4] Rhea EM et al. Brain uptake pharmacokinetics of albiglutide, dulaglutide, tirzepatide, and DA5-CH in the search for new treatments of Alzheimer’s and Parkinson’s diseases. Tissue Barriers. 2023.