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Plasma Is the New Risk Factor


It may not be right around the corner, but a biomarker test for increased susceptibility to Alzheimer's disease might be waiting down the road. In a recent study, researchers at the Mayo Clinic Jacksonville found that blood levels of amyloid beta proteins were higher in young relatives of patients with late onset Alzheimer's disease than in non-relative controls, which suggests that genetic factors controlling the Aβ proteins — including the APOE4 genetic variant, a well known risk factor — are related to higher risk of developing the disease. The team's research was published in the journal Neurology last month.

In comparing control groups to first-degree relatives of 25 extended multigenerational families with a history of late onset Alzheimer's disease, and an additional approximately 100 first-degree relatives of patients with Alzheimer's, they found elevated levels of both Aβ40 and Aβ42 compared to non-related control groups. To find out whether these elevations were caused by any of the genes known to contribute to late onset Alzheimer's, the scientists sequenced the Aβ proteins and found no mutations. They then genotyped the participants for the APOE4 allele, hypothesizing that having this risk factor might have something to do with their higher Aβ levels. "We found that, in fact, it was those individuals with lower amyloid beta levels that had the APOE4 allele," says Nilufer Ertekin-Taner, the study's lead author. "What we postulate … might be going on there, possibly APOE4 might be promoting deposition of amyloid beta in the brain, and with the deposition of amyloid beta in the brain, the plasma levels drop. That's one postulate — but certainly it tells us that the elevations are not due to the E4, leading us to conclude that it must be some other genetic variant or variants leading to that."

Taner likens plasma amyloid beta protein to cholesterol, in that it's a quantitative trait that varies in the general population. While it's not a given that someone with a high blood cholesterol level will end up with heart disease, it's a good predictor. In many cases, Taner believes, a test to track the levels of plasma Aβ in people with a family history of Alzheimer's disease might help with early diagnosis and treatment of the disease. "When you compare the young first-degree relatives to the control population, you see that the young first-degree relatives have higher levels," Taner says. "[That] tells us that there must be genetic factors underlying elevations in amyloid beta levels that you can detect years before people develop Alzheimer's disease."

Taner sees the possibility for a clinical biomarker test that would track plasma Aβ levels and use that information to determine the probability of getting Alzheimer's disease, but not before classic longitudinal tests are performed to measure these levels through generations of large populations. "I think that there may come a day when we follow the amyloid beta levels in individuals and be able to say that if you have a family history of Alzheimer's disease, if you have higher amyloid beta levels at earlier ages — and perhaps we might be even able to say if you have genetic risk factor A, B, or C — then your likelihood of getting Alzheimer's disease is higher compared to if you didn't have those risk factors."

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