The risk of Alzheimer’s disease and depression differs significantly between male and female bodies, and yet the vast majority of research on the human brain does not reflect that.
Instead, male anatomy is too often considered ‘the norm’ against which all other human brains are measured.
A new review, led by the neurobiologist Claudia Barth from the Diakonhjemmet Hospital in Norway, argues that this continued scientific bias has “grave consequences” for wellbeing and places a “disproportionate burden” on female health.
Barth and her colleagues are not the first group to call out the prevailing sex bias in neuroscience research, but their report is incredibly comprehensive, spotlighting the numerous ways in which sex hormones might impact healthy brain aging.
The international team, made up of psychiatrists, psychologists, and neuroscientists, point out that, to date, most preclinical studies on the health of the human brain have focused only on male brains, or they have otherwise ignored sex differences.
In 2019, only 5 percent of published neuroscience or psychiatry studies examined the influence of sex. Even in animal studies, male brains are too often the preference.
The goal of these studies is to be ‘sex-neutral’, but the reality is that focusing on only one sex is not neutral. Especially when there are numerous cognitive illnesses that show differences between physiological and behavioral classifications of sex and gender, possibly triggered by biological, cultural, or environmental factors.
The female risk for depression, for instance, is highest during a person’s reproductive years, while the risk for Alzheimer’s increases after menopause, when the hormone estradiol drops by up to 90 percent.
As such, some scientists have suggested that fluctuating sex hormones, like estrogens, androgens, and progesterones, play a crucial role in healthy brain aging.
These hormones are ‘master regulators’ of the human body, impacting the immune system, metabolism, vascular function, bone maintenance, and brain function.
In fact, the brain is full of sex steroid receptors, especially in the hippocampus, which is associated with mood, learning, and memory function.
Changes to the hippocampus are also features of Alzheimer’s and depression.
Nevertheless, only 2 percent of neuroimaging studies mention hormonal factors and only 0.5 percent bother to examine the differences between them.
In the few studies that do, more than 50 percent show a statistically significant association between female sex steroids and changes in the brain.
Barth and her colleagues, therefore, argue that understanding how “sex steroid concentrations affect the hippocampus during transitional life phases”, like puberty, pregnancy, or menopause, “could thus facilitate the development of mechanistic models of risk for depression and Alzheimer’s disease” – at least for some subtypes.
Adolescence, for instance, is marked by a shift in sex hormone concentrations, as well as substantial changes in the brain, and an increased risk of depression.
When some researchers manipulated sex hormones among a small group of healthy female volunteers, they found it triggered symptoms of subclinical depression.
Along with several other lines of evidence, such findings suggest the risk of developing depression is associated with hormonal transition periods.
What’s more, a history of depression is a potential risk factor for the later development of Alzheimer’s disease, sometimes decades down the road.
Nevertheless, studies on the relationship between depression arising from phases of endocrine transition and Alzheimer’s disease risk are lacking.
Today, the most widely studied female-specific risk factor for Alzheimer’s is menopause, and yet even then, there aren’t many conclusions that can be drawn about why this transitional time is associated with cognitive decline.
During menopause, estradiol concentrations plummet, and it’s possible that this change accelerates cellular aging in the brain, thereby increasing the risk of Alzheimer’s.
“Whether the female brain is capable of compensating for menopausal changes in [estradiol] concentrations might depend on many factors, including females’ exposure to [estradiol] during their reproductive years,” write Barth and colleagues.
Generally, brain imaging studies and epidemiological research suggest that the more a female-bodied person is exposed to estradiol in life, the lower their risk of Alzheimer’s disease later on.
But confusingly, other studies have observed the exact opposite effect.
Clearly, more research is needed on aging female brains to determine what is going on.
The review concludes that “prioritizing female brain health research across the lifespan is therefore an essential step towards the development of mechanistic models explaining sex differences in disease susceptibility, and is a crucial prerequisite for the development of personalized health care.”
The study was published in The Lancet Diabetes and Endocrinology.
