2023 Sex and Gender in Alzheimer’s (SAGA) Grant (SAGA)

Sex hormones in CSF: Neuroendocrine contributions to Alzheimer’s disease

How do sex hormones and genetics contribute to Alzheimer’s?

Erin Sundermann, Ph.D.
University of California, San Diego
San Diego, CA - United States

Background

Of the more than 6.5 million Americans aged 65 and older with Alzheimer’s, nearly two-thirds are women, according to the 2023 Alzheimer’s Association Facts & Figures report. Studies also indicate that women suffer worse cognitive symptoms than men. However, the reasons underlying sex differences in Alzheimer’s remain unclear. 

One hypothesis is that sex hormones—such as estrogen, testosterone, and progesterone—play a role in Alzheimer’s. It may also relate to genetics—one gene that involved in Alzheimer’s is called apolipoprotein E (APOE), which provides instructions for making ApoE, a protein believed to help carry fats throughout the body. There are several genetic variations of APOE, including APOE-e2, APOE-e3 and APOE-e4. 

In a previous study, Dr. Erin Sundermann found that women with APOE-e4 genes had higher levels of abnormal tau, a protein that forms tangles in the brain, a hallmark of Alzheimer’s. However, they noted that when they adjusted for testosterone levels, the difference between men and women disappeared, suggesting that women with low testosterone might have a higher burden of abnormal tau. Moreover, they found that women with lower testosterone had higher levels of brain inflammation.

Research Plan

Dr. Erin Sundermann and team will study 100 individuals ages 65-90 who are at higher risk for Alzheimer’s in their study. They will collect samples of cerebrospinal fluid (CSF; the biological fluid surrounding the brain and spinal cord) to look for markers of brain inflammation and Alzheimer’s-related proteins and  blood samples to measure sex hormones and APOE genotype. They will also conduct brain scans, perform neuropsychological tests and collect other Alzheimer’s-relevant clinical/behavioral data. They will then analyze the relationships between these factors. They predict that testosterone and estrogen levels will be linked to  Alzheimer’s and contribute to poorer cognition. 
 

Impact

The results of this study may help understand the role of sex hormones and genetics in development of Alzheimer’s.