After analyzing health data on many older people who were followed for years, Stanford researchers in the US concluded that carrying a copy of the ApoE4 gene variant gives women a much higher risk for developing Alzheimer’s than it does men.

Writing in the Annals of Neurology, senior author Michael Greicius, assistant professor of neurology and neurological sciences, and colleagues suggest their findings have important clinical implications and point to new directions for research into Alzheimer’s disease.

On the clinical side, they affect genetic counselors and clinicians as well as individual patients, and on the research side, the findings will affect how clinical trials are designed, they say.

The discovery may also reveal some new clues about what causes Alzheimer’s, a progressive neurological disease that gradually destroys memory and ability to reason.

The chances of developing Alzheimer’s are much higher after the age of 65. Estimates suggest 1 in 8 Americans past this age is affected and that by 2050, there will be more than twice the current 5-6 million with the disease.

We already know that the number of women with Alzheimer’s is much greater than the number of men with the disease. Part of the reason is because women live longer, but that does not explain all of it, says Prof. Greicius, who is also medical director of the Stanford Center for Memory Disorders.

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Women who carry the ApoE4 gene variant have almost double the risk of MCI or Alzheimer’s, the study shows.

“Even after correcting for age, women appear to be at greater risk,” he adds.

For their study, he and his colleagues analyzed public data covering over 8,000 people, mostly over the age of 60, who were tracked over time at dozens of Alzheimer’s centers around the US.

Of these, around 2,500 had mild cognitive impairment (MCI) when their monitoring started.

The analysis showed that regardless of whether they had MCI at the start of monitoring, the risk of developing full-blown Alzheimer’s was higher for individuals carrying the ApoE4 gene variant. This was as expected.

But when they looked more closely, the researchers found among those without MCI when they started being monitored, men with the ApoE4 variant had only a slightly higher risk, whereas women carrying the gene version had nearly double the risk of progressing to MCI or Alzheimer’s, compared with non-carriers.

“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,” Prof. Greicius says.

The researchers then analyzed 1,000 patients’ records from a second public database that holds imaging and test results for MCI and Alzheimer’s. This includes tests of biomarkers obtained from spinal fluid.

This analysis of a separate data set not only confirmed the ApoE4 gene variant had a different effect in women than in men, but it also gave clues as to why this might be the case.

The ApoE gene codes for a protein that ferries fats around the body. The central nervous system is a big user of these fats, especially the brain, which relies on rapid reconfiguring of certain fats along cell membranes to function.

There are three versions of the ApoE gene – ApoE2, ApoE3 and ApoE4. These different versions produce different proteins, with varying structures and abilities to ferry the fats around the body.

Which version of the ApoE gene a person carries depends on what they inherit from their biological parents (each person inherits two copies, one from each parent). Most people have two copies of the ApoE3 version, but around 1 in 5 carries at least one copy of ApoE4, and an even smaller proportion has two.

Earlier studies have shown that carrying one copy of ApoE4 causes a four-fold higher risk of developing Alzheimer’s, and carrying two copies raises the risk 10-fold.

At around the time of these revelations, in the mid-1990s, there was a study that suggested female carriers of the ApoE4 version had a higher risk for Alzheimer’s than men, but this was never followed up, and clinical trial designers have tended to overlook this, as Prof. Greicius explains:

I’d been practicing for five years before I ever heard of this paper, which had essentially been ignored for 10 years already.”

It was coming across this paper that sparked Prof. Greicius’ interest, which was reinforced in 2012 when he and his group noted differences in brain images of female versus male carriers of the ApoE4 gene variant, even in individuals without any symptoms.

What they noticed was that brain connections in men carrying the ApoE4 variant looked no different to those of non-carriers, but in women who carried the variant, the brain connections looked quite different on the brain scans to those of non-carriers.

“That convinced me that this is a real phenomenon,” says Prof. Greicius.

He suggests developers of clinical trials for Alzheimer’s treatments, who are already differentiating between ApoE4 carriers and non-carriers, should now also take notice of different effects in male and female carriers.

Clinicians counseling patients who undergo gene testing for risk factors also need to take note, he adds. In his case, he spends around a fifth of his time seeing patients. He says if a male patient asks him what he should do as a carrier of the ApoE4 gene, he will now advise him that his risk is only slightly higher. “If it’s a woman, my advice will be different,” he says.

Funds from the National Institutes of Health and the JNA Foundation helped finance the study.

In the meantime, Medical News Today recently reported on a study that found a big clue to how caffeine wards off Alzheimer’s. The German and French team showed that caffeine has a positive effect on tau deposits, one of the hallmarks of Alzheimer’s disease. They showed that in mice bred to develop tau protein deposits in their brains, a diet including regular caffeine intake slowed memory decline.