Chemo Brain in Older Women May Be Linked to Specific Version of APOE Gene

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Many women treated for breast cancer say they have problems remembering, thinking, and concentrating during and after treatment. These problems are commonly called “chemo brain” or “chemo fog” — though women treated with hormonal therapy also complain about memory issues. Doctors call these issues “cognitive impairment” or “cognitive problems.”

Some women may have trouble with:

  • learning new tasks
  • remembering names
  • paying attention and concentrating
  • finding the right words
  • multitasking
  • organizing thoughts
  • making decisions
  • remembering where things are (keys, glasses, etc.)

In what is being called the first large study of cognitive issues in older women treated for breast cancer, researchers found that women treated with chemotherapy and/or hormonal therapy had poorer cognitive skills compared to similar women who had not been diagnosed with and treated for breast cancer. Additionally, women with a certain version of the APOE gene —APOEe4 — who were treated with chemotherapy and/or hormonal therapy had the poorest cognitive skills.

The research was published online on Oct. 3, 2018, by the Journal of Clinical Oncology. Read the abstract of “Cancer-Related Cognitive Outcomes Among Older Breast Cancer Survivors in the Thinking and Living With Cancer Study.”

The researchers focused on older women for this study because getting older is associated with cognitive decline. Also, research has shown that chemotherapy treatment produces changes in brain structure that are similar to what happens when a person gets older.

The Thinking and Living With Cancer study was designed to help identify risk factors for cognitive decline in older women because 75% of breast cancer survivors in the United States are age 60 or older.

This analysis included information from 344 women diagnosed with stage I to stage III breast cancer who were age 60 or older. The women’s ages ranged from 60 to 98. These women were matched to a similar group of 347 women who had not been diagnosed with cancer. None of the women had dementia or neurological disease.

At the beginning of the study, which was before any of the women diagnosed with cancer had chemotherapy or hormonal therapy, the researchers did a baseline assessment of cognitive function in both groups of women and also collected a blood or saliva sample to determine which version of the APOE gene each woman had.

The APOE gene gives the body instructions for making a protein called apolipoprotein E. This protein combines with fats in the body to form molecules called lipoproteins. Lipoproteins package up cholesterol and other fats and carry them through the bloodstream.

There are three different versions, or alleles, of the APOE gene: APOEe2, APOEe3, and APOEe4. The most common allele is APOEe3, which is found in more than half the population. About 20% to 25% of people have the APOEe4 allele. The APOEe4 allele is linked to a higher risk of Alzheimer’s disease. People with one copy of the APOEe4 allele have a higher risk of Alzheimer’s. People with two copies of the APOEe4 allele have a much higher risk of Alzheimer’s. Researchers don’t know how the APOEe4 allele increases the risk of Alzheimer’s disease.

The researchers assessed cognitive function again at 1 year and 2 years after the study started.

At the beginning of the study, there were no differences in cognitive scores, sociodemographic factors, or APOE versions between the two groups of women.

Of the 344 women diagnosed with breast cancer:

  • 94 women were treated with chemotherapy, with or without hormonal therapy; most of the chemotherapy regimens were anthracycline-based
  • 237 women were treated with hormonal therapy alone; most of the women were treated with an aromatase inhibitor

Overall, the researchers found that both chemotherapy and hormonal therapy were linked to declines in cognitive function.

Compared to the women who had not been diagnosed with cancer:

  • Women treated with chemotherapy had worse scores on tests of attention, ability to process information quickly, and ability to make decisions.
  • Women treated with hormonal therapy had worse scores on tests of learning and memory.

But when the researchers looked at the version of the APOE gene the women had, they found that women who had the APOEe4 allele were more likely to have a decline in cognitive function, especially after being treated with chemotherapy. The researchers also found that almost all the women who had a decline in cognitive function after hormonal therapy had the APOEe4 allele.

"It is not that the chemotherapy causes Alzheimer's disease, but that these patients may be at risk for both cancer-related cognitive problems and Alzheimer's — perhaps through a process of accelerated aging or other shared disease processes," said Jeanne Mandelblatt, M.D., M.P.H., professor of oncology at Georgetown Lombardi Comprehensive Cancer Center and the study’s lead author.

The researchers said that the results confirmed a number of earlier studies showing that chemotherapy has negative effects on cognitive function. They also cautioned that these results need to be verified in a larger group of women. And while the results are not conclusive, the data do support other studies showing that by speeding up the aging process, chemotherapy and possibly hormonal therapy can lead to cognitive decline.

"Aging processes, APOEe4 [allele], and insulin resistance (seen with diabetes) each has been related to inflammation, which in turn is one of the putative risks for cancer-related cognitive decline and Alzheimer's disease," the researchers wrote. "Aging and the APOEe4 [allele] also reduce brain plasticity and repair, another possible mechanism of cancer-related cognitive decline."

Right now, testing to figure out which version of the APOE gene you have isn’t routinely done. Still, if you have a family history of dementia or Alzheimer’s disease and will be treated with chemotherapy and/or hormonal therapy for breast cancer, you may want to talk to your doctor and see if APOE testing makes sense for your unique situation.

Other studies have shown that most people who have thinking and memory problems during breast cancer treatment are able to recover and remember and think clearly after treatment is done. Still, a number of people continue to have problems after treatment ends.

If you’ve been diagnosed with breast cancer and are having thinking and memory problems, there are things you can do to help yourself. You might want to check out the Breastcancer.org page on Memory Loss in our side effects section. You’ll find tips on:

  • managing memory challenges
  • keeping your mind alert
  • keeping track of things when you’re forgetful

Other research suggests that exercising regularly can help ease chemo brain symptoms. You can visit the Breastcancer.org Exercise section for tips on how to find the right exercise for you, exercising safely, and how to stick to an exercise routine.

To talk with others about the cognitive effects of breast cancer treatment, join the Breastcancer.org Discussion Board forum Managing Side Effects of Breast Cancer and Its Treatment.


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