The mystery of the brain of an aging woman is being tested in a research trio

The female brain is superior to the male brain in at least one respect. And now, a group of researchers report that they have found genes in mice that rejuvenate female brains.

Humans have the same genes. This finding suggests methods that may help both women and men avoid cognitive decline in upper ages.

The study was published in Science Advances on Wednesday. The journal also published two other studies on the brain in women. One concerns the effects of hormone therapy on the brain, and the other concerns how age at the onset of menopause shapes the risk of developing Alzheimer's disease.

Genes that slow brain aging

The evidence that women's brains age more slowly than men seemed persuasive.

Researchers have already discovered in metabolic terminology that the brains use blood sugar levels, aging women's brains are younger than those of aged men.

Other scientists examining DNA markings have discovered that female brains are about a year younger than male brains.

And careful cognitive studies in healthy elderly people found that women had better memory and cognitive functions than men of the same age.

Dr. Dena Duval, a professor of neurology at the University of California, San Francisco, set out to understand why.

“We really wanted to know what underlies this woman's resilience,” Dr. Duval said. So she and her colleagues focused on the X chromosome, one factor that distinguishes women and men. Females have two X chromosomes. Men have one X and one Y chromosome.

In early pregnancy, one of the female X chromosomes is shut down, and the gene is almost silent. However, Dr. Dubal discovered that changes in aging.

She and her colleagues saw the hippocampus, the heart of the brain's memory and cognition.

When we saw the aging hippocampus, “We were surprised to discover that our genes had woken up,” Dr. Dubal said. Although this study was conducted in aged mice, the researchers believe the findings are applicable to humans as mice show similar age-related effects on brain function and women perform better than men.

Her group focused on a specific awakened gene, PLP1. It creates proteins that are part of myelin, the fat sheath around nerve cells that “make information flow back and forth, like on the highway.”

She asked what would happen, she asked if she would give the hippocampus a dose of PLP1 to aged male mice using gene therapy.

Her team discovered that mice had regained memory and cognition. They didn't even have to give genes to many cells, Dr. Dubal added. “A little boost came a long way,” she said.

She then subjected female mice to gene therapy, and had already made PLP1. Their memories and cognitions have improved even more.

“I'm very excited about this,” Dr. Duval said. “Even older brains can become more youthful and function better.”

Alzheimer's disease and hormone therapy

Millions of women use hormone therapy to relieve menopause symptoms such as hot flashes and dry vaginal vaginal, but concerns remain about how this will affect the brain.

The issue came when the Women's Health Initiative, a large, rigorous federal study 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 women take the hormones. If she takes them within 10 years of menopause, they say, her brain will be fine. Current treatment guidelines reflect that view.

To find out what happens in the brain after hormone therapy, Rachel F. Buckley, a neuroscientist at Massachusetts General Hospital, and her colleagues recruited 146 healthy women, ages 51 to 89.

Investigators knew the woman's age and whether she had taken hormone therapy. To Dr. Buckley's surprise, they saw the effect.

More than 70 women who were receiving hormone therapy had a greater accumulation of tau than women who had never had it. Having more tau did not mean that women had Alzheimer's, but that could have put them on the path to illness.

In this study, women under the age of 70 had no more tau in their brains. However, researchers said they didn't know if young women who took the hormones would have more tau later in their lives.

This study was observational. In other words, the cause and effect cannot be proven. Women with more tau may have been different in other ways that researchers did not explain.

Dr. Buckley asked what advice he would give women about hormone therapy and the risk of Alzheimer's disease, and he said, “Talking to your doctor,” admitted that it was not a satisfactory answer.

Menopause and age of Alzheimer's disease

Another study, published Wednesday, used clinical records and autopsy data to compare the brains of 268 women. Some people began menopause early at around 45 years old, while the rest began at a more typical age of about 50 years old.

The researchers who led the study reported that age at the onset of menopause had no effect on cognitive decline, brain synaptic integrity, or brain markers for Alzheimer's disease.

The results were “not what we expected,” Madeline Wood Alexander, a doctoral student and a lead author of the study at the Sunnybrook Institute in Toronto. Researchers believed that women who had previously started menopause would have worsened brain function. The authors said that this was because levels of estrogen that could protect neurons plummeted during menopause.

The researchers identified one correlation they highlighted as their main finding. Synapses in women who start menopause early can become more vulnerable to changes associated with Alzheimer's disease as they naturally worsen.

They reported that they did not see its effectiveness in women who had early menopause who used hormone therapy.

The results collide with other studies showing that hormone therapy may increase the risk of changes such as Alzheimer's disease in the brain. There was no clear explanation for the seemingly contradictory findings.

However, experts not involved in either study questioned the conclusions about early menopause and hormonal therapy. They said they were unsure of the statistical analysis and modelling that led to this correlation.

Deborah Grady, professor emeritus in epidemiology and biostatistics at the University of California, San Francisco, said it is difficult to interpret studies examining things like synaptic vulnerabilities. If menopause timing was effective, she said she would like to see it manifested in the actual incidence of Alzheimer's disease in these women.

Dr. Jack Rothau, the programme officer for the Women's Health Initiative, had similar concerns. He added that the authors conducted so many statistical tests that the correlations they found could have happened by chance.

And even if it's real, he said, “Unless the effect of menopause age on Alzheimer's disease, this is not a huge effect.”