Gene variant puts women at higher risk of Alzheimer's than it does men, study finds

April 14, 2014

Carrying a copy of a gene variant called ApoE4 confers a substantially greater risk for Alzheimer's disease on women than it does on men, according to a new study by researchers at the Stanford University School of Medicine.

The scientists arrived at their findings by analyzing data on large numbers of older individuals who were tracked over time and noting whether they had progressed from good health to mild cognitive impairment—from which most move on to develop Alzheimer's disease within a few years—or to Alzheimer's disease itself.

The discovery holds implications for genetic counselors, clinicians and individual patients, as well as for clinical-trial designers. It could also help shed light on the underlying causes of Alzheimer's disease, a progressive neurological syndrome that robs its victims of their memory and ability to reason. Its incidence increases exponentially after age 65. An estimated one in every eight people past that age in the United States has Alzheimer's. Experts project that by mid-century, the number of Americans with Alzheimer's will more than double from the current estimate of 5-6 million.

According to the Alzheimer's Association, it is already the nation's most expensive disease, costing more than $200 million annually. (The epidemiology of mild cognitive impairment is fuzzier, but this gateway syndrome is clearly more widespread than Alzheimer's.)

The number of with Alzheimer's far exceeds that of men with the condition. That's partly because women on average live longer than men. But greater longevity explains only part of women's increased susceptibility to Alzheimer's. "Even after correcting for age, women appear to be at greater risk," said Michael Greicius, MD, assistant professor of neurology and neurological sciences and medical director of the Stanford Center for Memory Disorders.

Greicius was the senior author of a study, to be published April 14 in the Annals of Neurology, in which he and his colleagues analyzed records on more than 8,000 people, most of them older than 60, who have been monitored over time at any one of about 30 Alzheimer's centers nationwide. Postdoctoral scholar Andre Altmann, PhD, was the lead author.

The records were stored in two large, publicly available repositories. In one, the researchers analyzed clinical assessments of 5,000 people whose test results were normal at the outset and 2,200 people who had initially showed signs of mild cognitive impairment. In both groups, being an ApoE4 carrier increased the likelihood of Alzheimer's disease, as expected. But a closer look revealed that among those who initially tested normal, this increased risk was only marginal for men, whereas women who carried the ApoE4 variant had close to twice the likelihood of progressing to mild cognitive impairment or Alzheimer's disease as those who didn't.

"Our study showed that, among healthy older controls, having one copy of the ApoE4 variant confers a substantial Alzheimer's disease risk in women, but not in men," Greicius said.

The second repository holds imaging data and measurements of several biochemical substances from spinal fluid that can serve as useful biomarkers of impending and eventual Alzheimer's disease. Analysis of 1,000 patients' records from this database not only confirmed ApoE4's differential effect on women versus men, but also yielded clues that may help investigators begin to explore, and perhaps someday explain, the molecular mechanisms linking ApoE4 to Alzheimer's disease, Greicius said.

The ApoE gene is a recipe for a protein important for shuttling fatty substances throughout the body. This is particularly important in the central nervous system, as brain function depends on rapid rearrangement of such fatty substances along and among nerve cell membranes. The ApoE gene comes in three varieties—ApoE2, ApoE3 and ApoE4—depending on inherited variations in the gene's sequence. As result, the protein that the gene specifies also comes in three versions, whose structures and fatty-substance-shuttling performance differ.

Most people carry two copies of the ApoE3 gene variant (one from each parent). But about one in five people carries at least one copy of ApoE4, and a small percentage have two ApoE4 copies. Numerous studies going back to the early 1990s have confirmed that ApoE4 is a key risk factor for Alzheimer's disease, with a single copy of ApoE4 increasing that risk twofold or fourfold. Carrying two copies confers 10 times the risk of Alzheimer's.

One of those many studies, published in 1997 in The Journal of the American Medical Association, suggested that female ApoE4 carriers are more at risk for Alzheimer's than male carriers are. But for various reasons, that study wasn't followed up, and both clinicians and scientists designing clinical trials tend to dismiss this distinction to this day, Greicius said. "I'd been practicing for five years before I ever heard of this paper, which had essentially been ignored for 10 years already," he said.

But on unearthing the 1997 paper, Greicius became curious. In 2012, an imaging study by his group showed provocative differences in brain function in female versus male ApoE4 carriers even when they were still completely asymptomatic. "Brain connectivity in the ApoE4 men didn't differ much from normal. But connectivity in the ApoE4 women did," he said. "That convinced me that this is a real phenomenon."

The pooled data of numerous dedicated Alzheimer's centers continuously accumulates, yielding ever-larger population samples for enterprising researchers to mine. There lies the beauty of the large government- and industry-supported repositories to which Greicius and his team turned.

Drug developers designing clinical trials for Alzheimer's are already paying plenty of attention to whether or not their trial participants carry a copy of the ApoE4 variant, as previous trials have showed a differential effect on carriers versus noncarriers. Greicius said they would do well also to differentiate between a candidate drug's effect on male versus female ApoE4 carriers. Meanwhile, basic researchers can take a cue from his findings and ask themselves, "Why the difference?" The effort to answer that question may reveal an important molecular mechanism, or set of them, that explains the differential effect. "Now we can work toward understanding the cause of this sex difference, which may reveal new potential drug targets, "Altmann said.

Greicius, who in addition to his research spends about one-fifth of his time seeing patients, said that the differential male/female ApoE4 effect implies that clinicians need to take different approaches to patients with this , depending on their sex. "These days, a lot of people are getting genotyped either in the clinic or commercially. People come to me and say, 'I have an ApoE4 gene, what should I do?' If that person is a man, I would tell him that his risk is not increased much if at all. If it's a woman, my advice will be different."

Explore further: Unlikely gene variants work together to raise Alzheimer's risk

Related Stories

Unlikely gene variants work together to raise Alzheimer's risk

October 23, 2013
(Medical Xpress)—Studying spinal fluid from people at risk for Alzheimer's disease, researchers at Washington University School of Medicine in St. Louis have found that a gene variation that had not been considered risky ...

Major Alzheimer's risk factor linked to red wine target

October 21, 2013
The major genetic risk factor for Alzheimer's disease (AD), present in about two-thirds of people who develop the disease, is ApoE4, the cholesterol-carrying protein that about a quarter of us are born with. But one of the ...

Alzheimer's risk gene disrupts brain function in healthy older women, but not men

June 12, 2012
A team led by investigators at the Stanford University School of Medicine has found that the most common genetic risk factor for Alzheimer's disease disrupts brain function in healthy older women but has little impact on ...

Highest risk Alzheimer's genetic carriers take positive steps after learning risk status

July 16, 2013
People who found out they carried an uncommon genetic risk for Alzheimer's disease did not experience more anxiety, depression or distress than non-carriers, and were more active in efforts to reduce their risk of Alzheimer's ...

Study reveals how variant forms of APOE protein impact risk of Alzheimer's disease

November 20, 2013
Carrying a particular version of the gene for apolipoprotein E (APOE) is the major known genetic risk factor for the sporadic, late-onset form of Alzheimer's disease, but exactly how that variant confers increased risk has ...

Recommended for you

Lifestyle changes to stave off Alzheimer's? Hints, no proof

July 20, 2017
There are no proven ways to stave off Alzheimer's, but a new report raises the prospect that avoiding nine key risks starting in childhood just might delay or even prevent about a third of dementia cases around the world.

Steering an enzyme's 'scissors' shows potential for stopping Alzheimer's disease

July 19, 2017
The old real estate adage about "location, location, location" might also apply to the biochemical genesis of Alzheimer's disease, according to new research from the University of British Columbia.

Brain scans may change care for some people with memory loss

July 19, 2017
Does it really take an expensive brain scan to diagnose Alzheimer's? Not everybody needs one but new research suggests that for a surprising number of patients whose memory problems are hard to pin down, PET scans may lead ...

Can poor sleep boost odds for Alzheimer's?

July 18, 2017
(HealthDay)— Breathing problems during sleep may signal an increased risk for Alzheimer's disease, a trio of studies suggests.

Hearing is believing: Speech may be a clue to mental decline

July 17, 2017
Your speech may, um, help reveal if you're uh ... developing thinking problems. More pauses, filler words and other verbal changes might be an early sign of mental decline, which can lead to Alzheimer's disease, a study suggests.

Bacteria found in Alzheimer's brains

July 17, 2017
Researchers in the UK have used DNA sequencing to examine bacteria in post-mortem brains from patients with Alzheimer's disease. Their findings suggest increased bacterial populations and different proportions of specific ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.