Invisible Women: default male miracles
animal studies on neurodegenerative diseases that use only males outnumber those that include females at a rate of 5.5 to 1
Hello GFPs! I’m starting off this week from an update from the exciting world of Great British Gaslighting. Last week’s heroine, Rose George, has continued with her journalistic endeavours, trying to get to the bottom of the Estradot supply issues that are Definitely Not Happening despite women not being able to get hold of any.
The indefatigable Rose managed to get a press officer at one of the wholesalers to talk (this sounds more ominous than it is, I’m pretty sure she just charmed them with her Yorkshire accent.) Anyway it turns out that despite the absolutely NO ISSUES with supply, that Novartis, the manufacturer of Estradot have in fact had rationing in place since the summer.
Rose’s pharmacy is allowed four boxes of 100mcg estradot per month. She got to the pharmacy at 10am on the first day of the month — and her pharmacy had already run out.
Meanwhile, Novartis continues to insist that there is no supply issue. Also meanwhile, Rose still hasn’t managed to get hold of her Estradot.
In more jolly news, at least one GFP did obey my instructions last week and got in touch with his MP about this unofficial supply issue; his MP replied to say he would be tabling a Parliamentary Question on the subject so…watch this space!
Gender data gap of the week
I’m sure many of you will have seen the breathless headlines over the past week or so heralding the arrival of a new miracle drug for Alzheimer’s. According to media reports, this “ground-breaking” and “momentous” drug represents a “historic breakthrough”. We are witnessing a “new era,” a “new dawn,” and even “the beginning of the end.” Researchers are said to be “vindicated” after a “decade of dead ends.”
GFPs, let’s start with the good news. It’s been three decades since scientists discovered a protein called “beta-amyloid” that appears in the brains of Alzheimer’s patients, and despite multiple attempts to find a drug that will work on this protein, so far researchers have come up empty handed. Until now.
The game-changing drug at the centre of the media reports is called lecanemab; it’s an antibody that binds to the amyloid, enabling the body’s immune system to clear the amyloid protein. And a muilticentre, double-blind phase 3 trial of lecanemab showed that the drug reduced the rate of cognitive decline in Alzheimer’s patients by 27%. It’s not a cure, but this is the first time a drug has been shown to really do anything much beyond treating Alzheimer’s symptoms as opposed to actually changing the course of the disease. So this is potentially huge, even if only from a proof of concept perspective.
But then….
Meanwhile in men, this tweet thread goes on to point out, the improvement was in fact 43%. So this drug may in fact be both worse AND better than the headline results — the things you discover when you sex disaggregate your data!!!
We’ll come back to exactly how good or bad this drug may or may not be in men and women, but I mean, you knew this was coming, right? Never mind that two-thirds of Alzheimer’s patients are women and no this isn’t just because women on average live longer. We don’t know the mechanism behind the sex difference (lol of course we don’t, we haven’t done the research), but studies of age-matched women and men still show a higher risk for women. There are a bunch of theories for why women have a higher risk that cover things like oestrogen exposure and women’s freaky (and under-researched) immune systems.
And then there’s ApoE-4.
ApoE-4 is a gene variant whose function I am not going to explain, because I am not a geneticist. But what I can tell you about is a study which found that women who carry this gene variant are twice as likely to go on to develop Alzheimer’s disease as women without the gene. But men who carry this variant are hardly more at risk than men who don’t.
Given all these sex discrepancies, you might expect that Alzheimer’s research would be a) female dominated and b) really bl**dy excellent at sex disaggregation.
Hahahahahahahahahahahaha. You sweet summer GFPs.
Let’s start with how Alzheimer’s is diagnosed, because if you can believe it (I know you can), the diagnostic test for this female-dominated disease...under-diagnoses women. This is because the tests most frequently used to diagnose Alzheimer’s are verbal memory tests — for which there is a lifelong female advantage, even when women have cognitive problems:
Studies in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort show a female advantage in verbal memory not only during normal cognitive aging but also during amnestic mild cognitive impairment even though women's level of disease burden—as measured by hippocampal atrophy, brain hypometabolism, and cortical Aβ [beta-amyloid] deposition—is similar to men, even after adjusting for APOE genotype.
Since there are generally not even sex-specific cut-offs for these tests, women tend to get diagnosed later, by which time the disease is far more progressed and the window of opportunity for early intervention has passed (btw lecanemab has only been shown to work for patients in the early stages of the disease so this feels relevant here).
Employing a “gender neutral” approach to diagnosing a clearly sex-impacted disease obviously makes no sense, but this nonsensical approach should not surprise us because Alzheimer’s research is notoriously terrible when it comes to sex-based analysis. And this goes all the way through from cell trials to human trials.
A 2021 review paper which looked at how sex differences were considered in preclinical Alzheimer’s research between 2013-18 (preclinical research means cell and animal trials), found that basically, it just…isn’t, really. Only about a third of the 150 studies even included female mice (remember, female-dominated disease!) and of those studies that bothered to include females only 15 of them considered sex as an outcome of interest.
And sex is an outcome of interest! As this paper points out,
A growing body of research suggests that studies conducted using mouse models of Alzheimer's reveal sex differences in amyloid beta (Aß) plaque formation and burden, levels of neuroinflammation, number of pathological tau tangles, and timing and severity of cognitive decline.
These differences affect outcomes: a 2020 mouse study found that a treatment that was intended to target amyloid worked in male mice but not female mice. They also found a sex difference when they analysed the mechanism in post mortem human tissue.
It’s not all bad news. The 2021 preclinical review paper does point out that some progress has been made, if only in actually including females in studies in the first place. But what we haven’t got better at is actually doing any sex analysis. In fact, the study says, the number of papers that do sex analysis has actually slightly decreased in the past decade.
This male bias coupled with a reluctance to do any form of sex analysis whatsoever is replicated across the field. Another review reveals that “animal studies on neurodegenerative diseases that use only males outnumber those that include females at a rate of 5.5 to 1.”
Things are slightly better when it comes to human trials, in that we do tend to include female humans (we haven’t got much of a choice since they’re the ones overwhelmingly with Alzheimer’s). But even so, according to a 2021 review, men are still overrepresented compared to the proportion of men who actually have Alzheimer’s in the general population.
In fact, according to Carolee Lee, founder and CEO of Women’s Health Access Matters,
just 12% – $280 million of the $2.4 billion NIH Alzheimer’s research budget went to studying just women. That’s like spending $3 in research on each woman over 35, and $24 on every man.
For a female-dominated disease.
We are also absolutely rubbish at doing sex disaggregation and analysis — even when we say we’re going to do it! The 2021 review paper on human trials found that “an analysis of sex-based data was included in many available study protocols,” hooray! But actually “the results of such analyses were not published in most cases.” Boo. In fact this review found that only 12.5% of articles reported sex-stratified results, although “this proportion that appeared to increase over time” and we should be grateful for small mercies because there certainly aren’t any big ones.
Let’s return now to our good friend lecanemab.
The trial for this drug did include women, hooray! It did also overrepresent men compared to the proportion of men in the Alzheimer’s population, but let’s overlook that for now, because we have bigger fish to fry. Like the fact that the sex disaggregated data referred to in the tweet at the top of this section was hidden away in a supplementary appendix that clearly no one in the media looked at. Or the fact that the paper did no sex based analysis for a disease that is female dominated, for which sex differences are well established, and for which their results seem to indicate a potentially large sex difference in effect.
Now, to be strictly fair, it is not certain that women only experienced a 12% improvement in decline while men experienced a 43% improvement. Let’s have a look at the table.
The table suggests that the mean slowing of decline for women is 12% while the mean slowing of decline for men is 43%. Which is a pretty big difference. BUT, there is also quite a large confidence interval for both those results, and the confidence intervals do overlap. So, in theory, it’s possible that there isn’t actually a sex difference. With these figures it’s impossible to say for sure one way or another. It’s just suggestive.
But given all we know about sex differences in Alzheimer’s it would not be at all weird if there was indeed a sex specific response to this drug. Remember ApoE4? That gene that makes women much more likely to develop Alzheimer’s, but doesn’t have much of an impact on men? Well here it is in this table, showing a differential interaction — although the data is not sex disaggregated so who knows what that means for women versus men. We also have studies (some of which I flagged earlier) showing that other drugs which target the beta-amyloid protein have sex specific (male-biased) effects, although of course these are in mice.
Nevertheless, these are ALL things you might think worth mentioning in the main paper. Even if just in the limitations section where the paper authors address all sorts of other potential issues. If absolutely nothing else, these results call for a much more rigorous sex-based analysis. But we get not a peep. The study does not address sexed impact at all and makes no reference to the need for further study to nail down any sex differences in effect.
Meanwhile, the Alzheimer’s Association has called for the FDA to rush this drug through approval.
Default male of the week
Over to the world of sports this week, and we’re back to an old favourite topic of mine: the revelation that women’s feet are not just small men’s feet! I know right! This is unprecedented, given women are just small men in every other way.
Anyway. In entirely unsurprising news it transpires that treating female athletes as if they are tiny male athletes is harming said female athletes:
…football boots fail to account for the fact women's feet, heels and arches are shaped differently.
And wearing boots designed for men is causing blisters and stress fractures in elite female players.
Women also move and run in a different way to men and yet the length of studs on boots are designed around male movement and traction.
This increases the risk of women getting their boot stuck in the surface and an injury being caused, author and sports rehabilitation lecturer Dr Kat Okholm Kryger, from St Mary's University, Twickenham, says.
As we have discussed in previous editions, ACL injuries are much more common in female athletes — could this default male bias be contributing? Who knows! Who cares!
Poppy pic of the week
That’s it! Until next time my dear GFPs….xoxoxo