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July 23, 2018 -- The tests that doctors use to diagnose Alzheimer’s find the disease later in women, a problem that may deny women early care and skew research.

And the same tests may also overdiagnose some men, putting them on a path to treatment they really don’t need, according to a new study presented at the Alzheimer’s Association International Conference in Chicago.

Researchers have long noted the strong sex differences in Alzheimer’s disease, which hits women harder than men.

In the U.S., two-thirds of people living with Alzheimer’s disease are women. Alzheimer’s is the fifth leading cause of death for women and the eighth leading cause of death for men. Even though some cases may be missed early, overall, a woman is more likely to be diagnosed with Alzheimer’s over the course of her lifetime than a man is. Once diagnosed, she’s likely to decline faster than a man would.

One reason for the gender gap is age. Women live longer than men do, and age is what makes getting any kind of dementia most likely.

Another major reason is hormones, says Pauline Maki, PhD, a professor of psychiatry and psychology at the University of Illinois at Chicago.

“There are sex differences in our mental abilities,” she says.

One of those differences is better verbal memory, or the ability to remember spoken words.

“The story that I’m telling you right now, as a female, you would be able to remember it better than a man would,” she says.

Estrogen's Key Role

The reason is the hormone estrogen. It directs the organization of the brain during a baby’s development in the womb. Later in life, the estrogen that women are exposed to through the menstrual cycle and pregnancy activates key structures in the brain related to memory, like the hippocampus. The hippocampus is the part of the brain responsible for making new memories.

“In our work, we find that the hippocampus is bigger in women than in men; the size of the hippocampus increases at time of the menstrual cycle when estrogen levels are high,” Maki says, like ovulation.

Women keep this advantage in verbal memory throughout their lives, even after menopause.

Generally, that’s a good thing, Maki says, except when it comes to getting a diagnosis of Alzheimer’s disease.

“When you diagnose Alzheimer’s in the clinic, you’re given these standard neuropsychological tests. These are tests that are ‘normed,’ meaning we know what to expect based on the performances of thousands of people,” she says.

It’s a bit like being graded on the class curve. A person’s grade isn’t just based on how well they answer the questions, but the performance of the entire class they belong to.

But the tests are adjusted based on just two things: a person’s age, because older people tend to do worse on these tests, even when they’re healthy; and their education, because people who are more highly educated will perform better on the tests.

But the tests are not adjusted for a person’s sex.

“If women have this advantage in verbal memory, and it’s lifelong, and if verbal memory tests are used to diagnose the early stages of Alzheimer’s disease, then we might be missing women in the early stages,” Maki says. “Because they might be better to start with.”

Maki and her team tested this theory. They looked at women’s performance on Alzheimer’s screening tests and compared that performance with three different physical indicators of brain health. They looked at how well their brains were using blood sugar. They also looked at the size of the hippocampus, since that tends to shrink as Alzheimer’s disease gets worse. And they used brain scans to measure the amount of beta amyloid plaques in the brain. Beta amyloids are sticky proteins that clog the brains of patients with Alzheimer’s disease.

All three of those tests showed the same thing: Women could still perform better on the verbal memory tests, even when their brains had just as much disease as men.

Maki and her team then asked what might happen if they adjusted the test results for sex differences.

For example, in a common screening test for Alzheimer’s, a doctor asks their patient to listen to a list of words. Twenty minutes later, after distracting the patient with other tests, they will ask that patient to recall as many words on the list as possible. If they can only remember four or fewer words, the patient is flagged as being likely to get memory problems.

The researchers wondered what would happen if they made the cutoff five remembered words for women and three remembered words for men. They applied the new cutoffs to patient records on 744 men and women collected by the large Alzheimer’s Disease Neuroimaging Initiative, or ANDI.

After reclassifying the patients, they found that about 9% of women who’d been told they were normal actually had mild cognitive impairment, or harm to their mental skills, which is thought to be an early stage of Alzheimer’s disease.

Among the men, the adjusted tests found that about 10% of patients who’d at first been classified as having mild cognitive impairment were actually normal.

Brain Scans Vs. Verbal Tests

The team checked their results by comparing them with the patients’ brain scans. The findings were in line with the researchers’ expectations. The women had more diseased brains than you’d have thought from talking to them, and the men had less disease than their verbal tests seemed to show.

Maki cautions that this is just one study. Her findings need to be duplicated by other researchers working with different groups of patients before they can be treated as fact.

But if her research is borne out in future studies, she thinks it could have big implications for patients and scientists.

Maki says that if current tests aren’t doing a good job of catching the disease early in women, it means that some women may be missing out.

“They would miss the opportunity to get medications like cholinesterase inhibitors [like the drugs Aricept or Exelon] early, to be given the good advice to engage in aerobic activity, to lower drinking, things like that could also slow the course of the disease,” she says.

Current tests may also be making it harder for researchers to find women in the earliest stages of the disease, when experimental therapies could do the most good.

Michelle Mielke, PhD, a researcher who studies sex differences in Alzheimer’s disease at the Mayo Clinic in Rochester, MN, says the study’s implications are important.

“It’s profound, and it could certainly change the field,” she says. She collaborated on part of the study.

Mielke says scientific studies show that there’s a higher prevalence of mild cognitive impairment in men than in women, but that women tend to progress faster to dementia.

“Nobody could explain why that was,” she says.

She says the studies by Maki and her team may help to solve that mystery.

“Men are at higher prevalence because they’re either overdiagnosed or they do poorer on the verbal memory test,” Mielke says. For women, “because they’re further along in the process, once they really do start to decline, they really do tend to drop off faster,” she says.

Other experts who were not involved in the research agreed.

“Getting to the biology is critical,” says Suzanne Craft, PhD, a professor of gerontology and geriatric medicine at Wake Forest School of Medicine in Winston-Salem, NC.

Craft said the strength of Maki’s study was that she was able to compare her results with brain scans showing that the disease had taken a similar toll on men’s and women’s brains, even when their screening test results were different.

“It’s hard to underestimate the contribution of that study,” Craft says.

Show Sources

Pauline Maki, PhD, professor of psychiatry and psychology, University of Illinois at Chicago.

Michelle Mielke, PhD, epidemiologist, Mayo Clinic, Rochester, MN.

Alzheimer’s Association International Conference, July 22-26, 2018, Chicago.

Suzanne Craft, PhD, professor of gerontology and geriatric medicine, Wake Forest School of Medicine, Winston-Salem, NC.

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