Pauline Anderson

July 27, 2016

TORONTO — Contrary to prevailing wisdom among clinicians, the incidence of Alzheimer's disease (AD) is not higher among women than men, new research shows.

"If you look just at the pure numbers, yes, there are more women that have AD, but there are also more women at older ages," Michelle M. Mielke, PhD, Department of Health Sciences Research, professor of epidemiology, College of Medicine, Mayo Clinic, Rochester, Minnesota, told Medscape Medical News.

"When we actually look at the epidemiological data, when we are talking about incidence, we are seeing that the rates are equivocal."

An important message from this emerging research, said Dr Mielke, "is that we have to be cautious about how we talk to the public and try not to 'over-scare' women about their greater risk."

Dr Mielke presented her research here Alzheimer's Association International Conference (AAIC) 2016.

Sex-Specific Risk Factors

She stressed that the focus in coming years should be on risk factors for AD that are important for women and those that are important for men.

Sex-specific risk factors for women include pregnancy and menopause.

"There is good evidence that women who have natural menopause, or who undergo surgical menopause, under age 45 are at increased risk of Alzheimer's disease," said Dr Mielke. "However, if they take hormone therapy to age 50 or so then the risk levels out."

Researchers are also finding that women who have had hypertensive pregnancy disorder "already have more cognitive decline and brain atrophy in their 60s," she said.

Changing demographics may affect future AD risks for women. Those who are in their 70s and 80s today grew up at a time when it wasn't typical to go on to higher education or to have a demanding job. But this is no longer the case.

For men, recent research suggests that those who undergo androgen deprivation therapy as a prostate cancer therapy may also be at increased risk for AD, said Dr Mielke.

A unique risk factor for men is marital status. Those who are widowed or never married are at higher risk for AD than married men. A possible explanation for this is that women, who tend to be more social, bring their husbands out to events and make sure they go to the doctor, said Dr Mielke.

There are also risk factors that affect men and women to a greater or lesser degree. For example, said Dr Mielke, the APOE4 allele raises AD risk. However, compared with men, women with this allele are at greater risk for the disease and have more hippocampal volume loss and cognitive decline.

"We really should be looking at an interaction with sex to understand what's going on there," said Dr Mielke.

Differing Response to Treatment

Women also tend to respond to some therapies, including cholinesterase inhibitors, differently than men do. In addition, they may experience unique side effects.

From her position as a member of the US Food and Drug Administration advisory panels, Dr Mielke has noted that some new drugs up for approval have more side effects in women.

"It's not just because of a different body size; there is a different metabolism, some of which is due to hormones."

In addition, for some drugs that have already been approved, "we're trying to figure out the correct dose for women."

In research, she said, women are often treated as a "nuisance variable" that researchers adjust for, but the researchers don't examine sex interactions or stratify for by sex.

The argument, she said, has been that if you stratify by sex, the sample sizes would be much smaller. "So then people say 'we can't really believe your data because maybe it was just by chance'," said Dr Mielke.

In addition, the incidence of dementia by sex may differ by country.

A United Kingdom study showed that several decades ago there was a higher risk for dementia in men compared with women but that during the last 20 or so years, the risk has been declining much more in men than in women. The Framingham study in the United States, on the other hand, recently found that dementia risk in women is declining more than in men.

Some experts emphasize the importance of "personalized medicine," wherein sex is considered. Still, when you look at genome-wide research in the hunt for therapies (eg, cancer drugs), "the XY chromosome never comes up, so you don't automatically separate by sex, and that kind of floors me," said Dr Mielke.

"We are trying to get it out there that that's one of the first things and the easiest things that you can do."

Brain Structure Differences

As treatment rates of hypertension and hypercholesterolemia increase and more strokes are being prevented, Dr Mielke noted it will be interesting to see how this will affect the sex differences and the risk for AD and/or all-cause dementia.

Dr Mielke and her colleagues would like to develop more sex-specific risk scores for AD. They've looked at the Framingham Risk Score, which uses a sex-specific algorithm to estimate a patient's 10-year risk for heart disease, but according to Dr Mielke, this score doesn't work as well for women as it does for men.

More research is needed to identify what AD risk factors are more important for men and which are important for women, she said.

"If we take this at the front end and identify risk scores for men and risk scores for women, maybe it would be more predictive for each sex."

In addition to differences in risk factors, there is evidence of sex differences in brain structure and in accumulation of amyloid plaque and tau protein.

Another speaker at the session, Timothy J. Hohman, PhD, assistant professor of neurology, Vanderbilt Memory & Alzheimer's Center, Vanderbilt University School of Medicine, Nashville, Tennessee, noted there is some evidence of sex differences in amyloid deposition but perhaps more evidence of differences in tau pathology.

"Tau may be the place where we should be focusing our efforts in identifying sex-specific molecular drivers."

Alzheimer's Association International Conference (AAIC) 2016. Dr Mielke, S1-01-02; Dr Hohman, S1-01-03. Presented July 24, 2016.

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