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 to develop AD, especially if they have a specific gene variant (APOE4 genotype). Women APOE4 carriers are at greater risk of developing AD than men, and we can use this information to understand the disease better. Although certain hormone therapies (HTs) containing estradiol can reduce memory deficits and may decrease the risk for AD, long-term use of certain HTs is associated with increased cancer risk, and thus other therapies targeting the hormone system are sought.

Modifiable risk factors for AD include obesity and type 2 diabetes (T2D). Another hormone called glucagon-like peptide-1 (GLP-1) reduces appetite and regulates blood sugar levels, and this hormone is used as a treatment for obesity and T2D. Indeed GLP-1 treatments are in trials for AD symptom relief. A compound was recently developed in which estradiol (the most potent of one of the estrogens) and GLP-1 are linked together (GLP-1+estradiol), making it possible to avoid side effects associated with estrogens alone. GLP-1+estradiol improves blood glucose levels and reduces body weight more effectively than GLP-1 alone. However, GLP-1+estradiol’s effects on memory, and its protective characteristics on the brain, have not yet been examined. Thus, we will investigate potential effects of this compound to preserve memory decline and provide neuroprotection in an AD mouse model (which possesses the APOE4 genotype) under a metabolic challenge (diet of high fat and high sugar). We suspect that the linked hormones will be protective for both males and females—providing protection via different sex-specific pathways—and we will examine different pathways in our research. Our research has the potential to uncover new roles for GLP-1+estradiol as a novel treatment for AD in both men and women.

Funding to Date



Drug Development, Preclinical Drug Development


Liisa Galea, Ph.D.

Annie Ciernia, Ph.D.