Combined Hormone Therapy as a Novel Treatment for Alzheimer’s Disease in the Face of a Metabolic Challenge: Influence of Sex and Genotype

Alzheimer’s Disease (AD) is a progressive brain disorder that causes memory loss and death of brain cells. Women are at a greater lifetime risk of developing AD, especially if they have a specific gene variant (APOE4 genotype). Women APOE4 carriers are at greater risk of developing AD than men. Although certain hormone therapies containing estradiol (E2) can slow memory loss progression and decrease AD risk, long-term use is associated with increased cancer risk. Thus, other therapies targeting the hormone system are sought. 

 Modifiable risk factors for AD include obesity and type 2 diabetes (T2D). The hormone glucagon-like peptide-1 (GLP-1) reduces appetite, regulates blood sugar levels, and reduces body weight. GLP-1 treatments are in trials for AD symptom relief. A compound was recently developed in which E2 and GLP-1 are linked together (GE2), making it possible to avoid side effects associated with E2 alone. We are investigating the potential of this compound to preserve memory and provide neuroprotection in an AD mouse model (which possesses the APOE4 genotype) while consuming a high-fat and high-sugar (HFHS) diet. Our preliminary results show that GE2 reduced body weight and improved memory in both sexes, whereas brain inflammation was mainly reduced in females. Furthermore, an HFHS diet may be more detrimental to brain health in AD-risk gene carriers. Upcoming experiments will expand on these results in AD mouse models of both sexes. Our research has the potential to uncover a novel treatment for AD in both men and women.