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Center for Cognitive Health

Insulin Resistance and Alzheimer’s: A Two Way Street (and How GLP-1 Receptor Agonists May Help Cross It)

       Previously, we described the relationship between insulin resistance and AD, and treatments pertaining to such (https://www.centerforcognitivehealth.com/insulin-and-ad/). However, the overarching principle of how insulin signaling ties into development of neurodegenerative conditions is only loosely understood, indicating the need for further research.

       Insulin, produced by the pancreas, signals to maintain glucose homeostasis and cell growth/survival by binding to insulin receptors (IRs). Insulin resistance is caused by a downregulation of these IRs, which in turn instigates an overproduction of insulin (hyperinsulinemia) to try to overcome the limited signaling. IRs are present in large quantities in the brain, especially in the hippocampus, a prominent structure for memory. During hyperinsulinemia episodes our bodies downregulate the transporters that allow insulin into the brain, possibly increasing cell death, decreasing cell growth, and impairing memory. Diseases, such as AD and Parkinson’s disease (PD), are twice as likely to develop in individuals with diabetes, supporting this relationship.

       While diabetes increases the risk of AD, AD also increases the risk of developing type II diabetes mellitus (T2DM). Research into AD’s role in causing T2DM showed that toxic amyloid-ꞵ (Aꞵ) oligomers in the AD brain interact with hippocampal tissues to reduce the number of IRs present, and is predictive of insulin resistance outside the brain, eventually inducing T2DM. Furthermore, inflammation is strongly tied to the development of both T2DM and AD, possibly explained by the fact that insulin resistance increases circulating inflammatory cytokines.

       It appears that treating peripheral insulin resistance has both a direct and indirect impact on risk/prevention of AD on top of the obvious impact on diabetes/insulin resistance. Clinical trials aimed at treating AD have taken notice. For instance, we currently have a trial utilizing semaglutide, a medication already approved as an antidiabetic treatment, to attempt to stop/slow progression of AD in individuals with Mild Cognitive Impairment or Early AD. A hormone called GLP-1 has also been implicated in playing a role in both diabetes and AD. GLP-1 is similar to insulin with a strong role in glucose homeostasis but is quickly degraded under normal circumstances. Semaglutide, a GLP-1 receptor agonist (RA), simulates the effects of GLP-1 while avoiding quick degradation, creating lasting impacts on glucose regulation without being impacted by insulin resistance.

       Before semaglutide, several other molecules were tested for this purpose. The first GLP-1 RA, exendin-4, improved cognition and reduced Aꞵ presence in the brains of both AD mice and wild-type mice. The next major GLP-1 RA, liraglutide, produced longer lasting effects than exendin-4 and was shown to prevent Aꞵ neurotoxicity and reduce Aꞵ plaques in the hippocampus and cortex, reduce cell death, alleviate brain insulin resistance, and improve memory in the same mouse model exendin-4 was tested on. It also lowered levels of phosphorylated Tau, the other major protein implicated in AD progression. When administered before significant plaque burden was present and memory impairment began, liraglutide slowed disease progression in AD mouse models. Yet another marketed diabetes drug, lixisenatide, enhances long-term potentiation, and lowers Aꞵ plaque load, microglial activation, and neurofibrillary tangles. Despite these other treatments, semaglutide shows the greatest effectiveness compared to other GLP-1 RAs with regards to glycemic regulation. Given how intertwined insulin resistance and neurodegeneration seem to be, greater efficacy in one instance may offer benefit in the other. Furthermore, semaglutide is already approved and marketed for treatment of diabetes so it’s safety and tolerability are well studied.

       With all this therapeutic potential surrounding semaglutide and GLP-1 RAs, if you or someone you know between the ages of 55 and 85 is experiencing Mild Cognitive Impairment (MCI) or mild Alzheimer’s dementia they may be eligible to screen for the trial! Feel free to contact our office or inquire about potential involvement on our website.

Batista, A.F., Bodart-Santos, V., De Felice, F. G., & Ferreira, S.T. Neuroprotective Actions of Glucagon-Like Peptide-1 (GLP-1) Analogues in Alzheimer’s and Parkinson’s Diseases [Internet]. CNS Drugs. 2018. Available from: https://www.researchgate.net/publication/329373799_Neuroprotective_Actions_of_Glucagon-Like_Peptide-1_GLP-1_Analogues_in_Alzheimer’s_and_Parkinson’s_Diseases
Insulin and Alzheimer’s Disease [Blog]. 2020. Available from: https://www.centerforcognitivehealth.com/insulin-and-ad/
Alsugair, H.A., Alshugair, I.F., Alharbi, T.J., Bin Rsheed, A.M., Tourkmani, A.M., Al-Madani, W. Weekly Semaglutide vs. Liraglutide Efficacy Profile: A Network Meta-Analysis [Internet]. Healthcare. 2021. Available from: https://pubmed.ncbi.nlm.nih.gov/34574899/