Risk Gene for Alzheimer’s Appears to Affect Women Differently than Men

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A well known risk gene for Alzheimer’s Disease may have a more potent effect on women, according to research published today in the Annals of Neurology.

Everyone has 2 copies of a gene called APOE but some people carry a form of the gene, called APOE4, that has been associated with an increased risk for developing Alzheimer’s Disease (NIH Alzheimers Disease Genetics fact sheet).

Researchers from Stanford took advantage of a large publicly available database from the National Institute on Aging which gathered more than ten years of data on healthy older people and patients with Alzheimer’s. They wanted to know whether having the risk gene made people likely to “convert” either from healthy aging to mild cognitive impairment or from mild cognitive impairment to Alzheimer’s Disease. They looked at data from 5,496 healthy controls and 2,588 subject with Mild Cognitive Impairment.

They found that over time, people who had two copies of the risk gene were more likely to convert- either to mild cognitive impairment or Alzheimer’s Disease. That was to be expected. But when they looked at people with just one copy APOE4, so-called “carriers,” they found something surprising: it only seemed to affect women’s risk. This was an unexpected finding for study author Dr. Michael Greicius, Assistant Professor in the Department of Neurology and Neurological Sciences at Stanford and Medical director of Stanford Center for Memory Disorders. “So now we can say that if you are a male with one copy- it probably doesn’t bump your risk up more. But if you are woman , it looks like your risk is bumped up twofold,” he explained.

There had been some studies suggesting this many years ago but for some reason they had been largely unknown, even to experts like Dr. Greicius. “for whatever reason this wasn’t widely known,” he said, “ I thought i knew a lot about APOE but I’d never really encountered this. [The other study demonstrating this] sort of disappeared. Looking at some of the mouse researchers- it looked like they picked it up but the human researchers ignored it.”

So Dr. Greicius and his team set out to replicate this finding with a more rigorous study design. He hopes that his results serve as a launching pad to direct further research and one day, perhaps, future therapies and preventative efforts.

The results certainly have larger implications, especially for future research. It is well known that Alzheimer’s Disease disproportionately affects women, and this study show that genes are a partial factor in this trend. “Now we can get a better handle on how apoe affects the risk for AD, “ said Dr. Greicius, “could it be estrogen related? Could there be other genes, for example on the X chromosome that affect APOE?”

Few doctors currently test for the risk gene in routine practice. But several direct to consumer tests are available and many doctors are facing patients who want this information. But experts fear that we don’t know enough about the risk gene to make this information valuable to the average patient. Having the risk gene, even two copies does not guarantee that a person will develop Alzheimer’s and some question the merit of arming people with data that can serve to confuse or even create unnecessary fear.

A study published in 2009 attempted to measure the potential psychological risk of disclosing APOE status to adult children who had parents with Alzheimer’s disease. They found that this disclosure did not have significant negative psychological harm in the short term and that people who were found to carry no copies of the risk gene demonstrated less distress. But it wasn’t easy for everyone- the researchers found that adult children who had high levels of emotional distress before undergoing genetic testing for APOE4 were more likely to have emotional difficulties after disclosure.

Dr. Greicius has had to counsel patients who independently found out their APOE status and feels that his study now adds more meaningful information and specificity to how he can counsel them. “[Doctors] don’t typically get APOE genotyping,” he said, “but increasingly people are getting their genome sequenced for good or not-so-informed reasons. So I’ve had patients come to me in their mid fifties, healthy, saying that they have one or more copies of the APOE4 risk gene….So now we can be more specific about what it means for them.”

Hayley Goldbach, MD
2013-2014 Stanford-NBC News Global Health and Media Fellow

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About Hayley Goldbach

Hayley Goldbach, 2013-2014 Stanford-NBC News Global Health and Media Fellow