Alzheimer’s risk gene linked to post-chemotherapy cognitive decline

Proteins encoded by the APOE gene are involved in metabolism of cholesterol and fats through our body. Now, after experimenting on mice and observing older breast cancer patients, scientists at Georgetown University believe a less common version of the gene, APOE4, could put patients at higher risk of cognitive problems after chemotherapy.

APOE, or apolipoprotein E, comes in three variants, known as 2, 3 and 4. Scientists have long linked the APOE4 allele as a major genetic risk factor for nonfamilial Alzheimer’s, otherwise known as sporadic Alzheimer’s. A recent Neuron study by MIT scientists found it promotes the buildup of beta-amyloid in the brain, a hallmark of Alzheimer’s. And a Nature study last year also connected it to the toxic accumulation of tau, another culprit believed to cause neurodegeneration.

In a population study on older breast cancer patients, breast cancer patients with the APOE4 gene were found to have experienced faster cognitive decline than their peers, a Georgetown-led team reported in a study published in the Journal of Clinical Oncology.

As part of a large prospective cohort study of cognitive function among older breast cancer patients, this particular report included 344 newly diagnosed women and 347 cancer-free controls that were matched in factors such as age, lifestyle and race.

No one showed any cognitive problems or dementia at the start of the study. However, a small subset of patients who carry one or two copies of the APOE4 gene experienced pronounced, steady decline in cognitive function after chemotherapy.

“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 Georgetown geriatrician Jeanne Mandelblatt, M.D., who co-led the study, in a statement.

Mandelblatt cautioned that her study was still too small to reach any conclusion, but if future studies could replicate the findings, then breast cancer patients might need to be screened for APOE4 before they discuss treatment options with their oncologists, she said.

When Mandelblatt suspected early in the study that chemo might affect brain function in APOE4-positive patients, she went to talk to Georgetown neuroscientist G. William Rebeck, Ph.D., who then started testing the theory in mice.

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Rebeck’s team used a mouse model that expresses either human APOE3—the most common variant of APOE—or APOE4, and treated the animal with a commonly used chemo, doxorubicin.

Compared to a control group that didn’t get doxorubicin, both APOE3 and APOE4 mice had brain changes after chemo. Yet the difference was more severe in APOE4-expressing mice, as they displayed significantly impaired learning ability. The researchers detailed their findings in the Neurotoxicity Research.

“The data in the mice is very clear—APOE4 works in concert with doxorubicin to produce significant changes in the cortex and hippocampus and to markedly impair learning,” said Rebeck in a statement.

Rebeck for now cannot pinpoint the underlying mechanism for the increased risk of chemo in APOE4. But he hypothesized that the combination increases inflammation in the brain that accelerates aging or that APOE4 inhibits brain neuron renewal.

Because the mouse model worked well, Rebeck hopes to test chemotherapy drugs one by one to compare their effects on the brain. It might also be used to test drugs that aim to prevent cognitive decline in cancer patients with APOE4.