Males and females appear to differ in their responses to some Alzheimer’s drugs – reboot

This post originally appeared on my blog in August.  Somehow, I accidently deleted it this week.  Here it is again with my apologies to those who have been unable to find it. If only rebooting my brain were as easy as rebooting my computer!

One of my first assigned research projects as a graduate student at Emory University was a study of the hypothalamic hormone called gonadotropic hormone releasing hormone (GnRH) in female rats.  The point was to verify if an increase in GnRH could be found in the pituitary portal circulation, specialized blood vessels connecting the hypothalamus and the pituitary gland, during specific times of the estrous cycle when the pituitary is secreting high levels of these gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). I was trying to answer the question of whether the pulses seen in LH and FSH in peripheral blood were associated with and perhaps caused by pulses of GnRH in the pituitary portal blood. Each day of the week including weekends, I came to the lab to perform vaginal swabs on my rats and examine the vaginal cells under the microscope to determine what day of the 4- or 5-day estrous cycle each rat was on. This was a challenging project for a brand-new graduate student.  I learned a lot of useful techniques, and I experienced my first failure of a project that just wouldn’t come together. Perhaps most significantly, I just couldn’t collect enough of the portal blood to measure pulses.  Other researchers in the lab were working on similar projects with larger animals that were easier to work with. So, my mentor switched me to a new project measuring dopamine in the pituitary portal blood of male rats to see if dopamine was important in regulation of the pituitary hormone prolactin. This project was a success.  I was able to demonstrate that dopamine released by nerve cells in the hypothalamus is a physiologically important inhibitor of the pituitary secretion of prolactin. This resulted in my first published scientific paper as first author, and the paper received more citations than anything I have written since. I think this proved two things: 1) I was in the right place at the right time to finally resolve a dispute in the field and 2) male rats are, at times, less complicated than female rats as models for human physiology.

Recent studies have shown that male and female humans with Alzheimer’s disease differ in a number of important ways. These studies are discussed in an opinion paper in the August issue of JAMA Neurology titled “A Call to Action to Address Sex Differences in Alzheimer Disease Clinical Trials.” Clinically normal, older females carrying the APOE-4 allele have a higher burden of global tau protein seen on brain PET scans than male APOE-4 carriers, and the women’s risk for progression to dementia is greater than men APOE-4 carriers. Women have a higher lifetime risk of getting dementia than men. Most alarming is that the small but statistically significant cognitive benefit seen in the aducanumab EMERGE trial and the more robust benefit seen in the lecanumab CLARITY-AD trial occurred primarily in males, not in women. The authors claim that only 8 of 118 dementia trials published so far have reported sex-disaggregated outcomes, and even when present, these sex-related differences may be buried in supplemental data or other hard-to-find sources. The authors of this opinion paper conclude that “as we anticipate more [Alzheimer’s] drugs to be approved and enter the market, it is imperative to ensure that sex differences in treatment effects are well understood before [these drugs] are prescribed to patients.”