Women’s brains are superior to men’s in at least in one respect — they age more slowly. And now, a group of researchers reports that they have found a gene in mice that rejuvenates female brains.
Humans have the same gene. The discovery suggests a possible way to help both women and men avoid cognitive declines in advanced age.
The study was published Wednesday in the journal Science Advances. The journal also published two other studies on women’s brains, one on the effect of hormone therapy on the brain and another on how age at the onset of menopause shapes the risk of getting Alzheimer’s disease.
A gene that slows brain aging
The evidence that women’s brains age more slowly than men’s do seemed compelling.
Researchers, looking at the way the brain uses blood sugar, had already found that the brains of aging women are years younger, in metabolic terms, than the brains of aging men.
Other scientists, examining markings on DNA, found that female brains are a year or so younger than male brains.
And careful cognitive studies of healthy older people found that women had better memories and cognitive function than men of the same age.
Dr. Dena Dubal, a professor of neurology at the University of California, San Francisco, set out to understand why.
“We really wanted to know what could underlie this female resilience,” Dr. Dubal said. So she and her colleagues focused on the one factor that differentiates females and males: the X chromosome. Females have two X chromosomes; males have one X and one Y chromosome.
Early in pregnancy, one of the X chromosomes in females shuts down and its genes go nearly silent. But that silencing changes in aging, Dr. Dubal found.
She and her colleagues looked in the hippocampus, the brain’s center of memory and cognition, which deteriorates as one ages and is ravaged by Alzheimer’s.
When looking at aging hippocampuses, “we were astounded to find that genes woke up,” Dr. Dubal said, referring to the silent X chromosomes. The study was done in aging mice, but the researchers believe the finding is applicable to humans because mice show the same age-related effects on brain functioning, with females performing better than males.
Her group focused on one particular awakened gene, Plp1. It makes a protein that is part of myelin, a fatty sheath around nerve cells that “allows information to flow back and forth, like a highway,” Dr. Dubal said.
What would happen, she asked, if she used gene therapy to give aging male mice a dose of Plp1 in their hippocampuses?
Her team found that the mice regained memory and cognition. They did not even have to give the gene to many cells, Dr. Dubal added. “Just a little boost went a long way,” she said.
Then she gave the gene therapy to female mice, although they were already making Plp1. Their memories and cognition got even better.
“I’m so excited about this,” Dr. Dubal said. “Even an old brain can become more youthful and function better.”
Alzheimer’s and hormone therapy
Millions of women use hormone therapy to relieve symptoms of menopause like hot flashes and vaginal dryness, but there remains a concern about how it might affect the brain.
The issue was raised when a large and rigorous federal study, the Women’s Health Initiative, published in 2003, concluded that Prempro, a popular hormone treatment at the time, doubled the risk of dementia.
Since then, other scientists have argued that the risk depends on when a woman takes hormones. If she takes them within 10 years of menopause, they say, her brain will be fine. Current treatment guidelines reflect that view.
To examine what happens inside the brain after hormone therapy, Rachel F. Buckley, a neuroscientist at Massachusetts General Hospital, and her colleagues recruited 146 healthy women aged 51 to 89. They scanned the women’s brains for tau, a protein that accumulates in the brains of people with Alzheimer’s.
The investigators knew only the ages of the women, and whether they had ever taken hormone therapy. To Dr. Buckley’s surprise, they saw an effect.
The women over 70 who had received hormone therapy had a greater accumulation of tau than the women who had never had it. Having more tau did not mean the women had Alzheimer’s, but it could have put them on the path toward the disease.
Women under 70 in the study did not have more tau in their brains. But, the researchers said, they did not know if younger women who took hormones would have more tau later in life.
The study was observational, meaning it cannot prove cause and effect. The women with more tau might have been different in other ways that the researchers did not account for, which has left uncertainty about the finding.
Dr. Buckley, asked what advice she would give women about hormone therapy and the risk of Alzheimer’s, said “talk to your doctor,” acknowledging that it was not a satisfactory answer.
Age of menopause and Alzheimer’s
Another study published on Wednesday used clinical records and autopsy data to compare the brains of 268 women. Some started menopause early, around age 45, while the rest started at the more typical age of around 50.
The researchers who led the study reported that age at the start of menopause had no effect on cognitive decline, the integrity of brain synapses or on brain markers of Alzheimer’s.
The results, said Madeline Wood Alexander, the study’s lead author and a doctoral student at Sunnybrook Research Institute in Toronto, were “not what we expected.” The researchers thought the women who started menopause earlier would have worse brain functioning. That is because levels of estrogen, which can protect neurons, plummet at menopause, the authors said.
The researchers did identify one correlation that they emphasized as their main finding: The synapses of women who begin menopause earlier may become more vulnerable to changes linked to Alzheimer’s as they naturally deteriorate.
They reported that they did not see that effect in women with early menopause who used hormone therapy.
The result clashes with those of the other study, which indicated hormone therapy might increase the risk of Alzheimer’s-like changes in the brain. There was no clear explanation for the seemingly contradictory findings.
But experts not involved with either study questioned the conclusions about early menopause and hormone therapy. They said they were not convinced by the statistical analyses and modeling that led to this correlation.
Dr. Deborah Grady, emeritus professor of epidemiology and biostatistics at the University of California, San Francisco, said it was difficult to interpret studies that looked at things like the vulnerability of synapses. If menopause timing had an effect, she said, she’d like to see it show up in the actual incidence of Alzheimer’s in these women.
Dr. Jacques Rossouw, who was a program officer for the Women’s Health Initiative, had a similar concern. He added that the authors did so many statistical tests that it was possible the correlation they found occurred by chance.
And even if it is real, he said, “this can’t be a big effect if there was no effect of age of menopause on Alzheimer’s pathology.”
