Alzheimer’s disease seems to have a gender preference.

According to the most recent statistics from the Alzheimer’s Association, women are nearly twice as likely as men to develop the condition in their 60s, making dementia as real a concern for women’s health as breast cancer.

Now, researchers from Stanford University may have a better understanding as to why.  In a new study published in the Annals of Neurology, scientists have found that a specific gene variant called ApoE4 substantially increases a woman’s risk for Alzheimer’s disease – much more so than it does for men.

Researchers have known for some time that the ApoE4 gene variant is associated with an increased risk for Alzheimer’s, though the molecular mechanisms linking the variant to the brain-wasting condition are not well understood.   Furthermore, very few studies have focused on the different effects of ApoE4 in men versus women – a distinction that the researchers thought needed further attention.

“I was looking through the literature, and [I saw that] when mouse models of ApoE4 only use female mice, the effects are much more evident.  So the mouse literature had caught on to this interaction between ApoE4 and sex…but the four papers that have come out on this [gene] are all over the map,” study author Dr. Michael Greicius, assistant professor of neurology and medical director of the Stanford Center for Memory Disorders, told  “So we entered the fray with this notion, which was the problem with these studies is they didn’t account for a sex affect.”

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The ApoE gene comes in three different versions, or alleles: ApoE2, ApoE3 and ApoE4. Most people carry two copies of the ApoE3 allele (one from each parent), but around 20 percent of individuals have at least one copy of the ApoE4 allele, and an even smaller percentage carry two copies of ApoE4.

To better understand how those combinations of ApoE alleles affect men and women, Greicius and his team analyzed the records of more than 8,000 people who had been monitored over time by approximately 30 Alzheimer’s centers nationwide.  The patients – most of whom were over 60 – were separated into two groups: those whose cognitive test results were normal at the study’s onset and those who had initially shown signs of mild cognitive impairment.

After analyzing the participants’ genotypes, the researchers found that being an ApoE4 carrier did increase an individual’s risk for Alzheimer’s – but there was a significant difference in risk between genders.

“We were comparing people who have two copies of ApoE4 gene, against people with one ApoE3 and one ApoE4 allele,” Greicius said.  “…And if you’re a woman, your risk bumps up about two-fold with just one copy of ApoE4, compared to women with no copies.”  

Comparatively, the increased risk was extremely small for men who carried one copy of the ApoE4 allele.  However, both men and women who carried two copies of ApoE4 had a substantially increased risk for Alzheimer’s disease.

Responsible for the transportation of cholesterol throughout the body, the ApoE gene is critical for maintaining brain cell stability, since cholesterol is needed to repair the membranes of cells that have been damaged.  It is thought that ApoE4 does not work as efficiently as the other two allele types, slowing this repair process.

However, it is unclear why ApoE4 is seemingly more potent in women. Greicius speculated that the variant may interact more heavily with female-oriented genes.

“There’s a gene that makes the estrogen receptor, which is more relevant in women.  It’s possible we can find common polymorphisms in the estrogen receptor gene that interact with ApoE4,” Greicius said. “Then there’s the whole X chromosome, which often gets ignored, because it’s difficult to deal with.  But there are a lot of brain relevant genes on the sex chromosome, so it could be a genetic interaction there.”

Given their findings, Greicius hopes to study ApoE4 further, in order to gain a better understanding of its effects on the female brain.  Meanwhile, he hopes this study will serve as a reminder to doctors that certain genotypes mean different outcomes depending on gender.

“The data shows we have to counsel people differently,” Greicius.  “For men, your risk may be up a little bit…as in you’re 20 percent more likely, and in women, it’s twice the risk. So genetic counseling is going to differ between men and women.”