Two teams of Emory researchers have discovered proteins in human cerebrospinal fluid that can serve as early indicators that the patient may develop Alzheimer's disease in the future.
The pathological changes that occur in the brains of Alzheimer’s disease patients are notoriously difficult to detect before visible symptoms show up. That’s because brain tissue is relatively inaccessible to scientific study, making it hard to fully understand the slowly developing biological processes in seemingly healthy people that eventually emerge as Alzheimer’s disease decades later. Recently, though, two teams of Emory scientists managed to identify a panel of proteins in human cerebrospinal fluid that provide important early insights into the development of Alzheimer’s disease long before actual cognitive deterioration sets in.
“What that panel was able to do was predict at baseline, when you were cognitively stable, whether you advanced to cognitive decline just based on the protein levels in that individual,” says Nicholas Seyfried, professor of biochemistry at Emory’s School of Medicine and co-senior author with Thomas Wingo and Allan Levey in the Goizueta Alzheimer’s Disease Research Center of one of the two papers, published recently in Science Translational Medicine.
The authors reasoned that a proteomics analysis of the clear, watery fluid that circulates constantly through the brain tissues and spinal cord could help identify levels of individual proteins that they could then relate to the growth of the amyloid plaques and tangles of protein called tau that are the direct cause of decline in Alzheimer’s disease.
In the research, scientists studied cerebrospinal fluid from 706 participants in the Alzheimer’s disease Neuroimaging Initiative (ADNI), a long-range study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer’s disease. Using sensitive assay techniques, they targeted 48 key proteins that were linked to the progression of Alzheimer’s disease. This is an improvement on existing biomarkers of amyloid and tau alone that don’t predict cognitive impairment.
“The idea is that could we come up with a peripheral marker to reflect the underlying brain pathology that's easier to obtain, faster to run, and that we could screen population wise,” Seyfried says. “Are you higher or lower than the average? You are either in the middle, which means you're normal, you're below, which is probably a good thing with this protein panel. Or you're a standard deviation above the mean. Which would indicate a risk profile.”
Tracking the evolution of Alzheimer’s disease
The second study focused on people with a rare form of inherited Alzheimer’s disease that nearly always shows up at 30 to 50 years of age. Knowing the subjects were highly likely to develop the disease in the future, the researchers measured proteins in the cerebrospinal fluid of their subjects and also in other family members who lacked the same genetic mutation. If the subjects had higher or lower levels of certain proteins than their siblings, the control group, that was a good indication that the proteins were biomarkers of Alzheimer’s disease.
“We have a control group and we have a carrier group,” says first author Erik Johnson, assistant professor in Emory’s Department of Neurology and the Goizueta Alzheimer’s Disease Research Center. “If we know they’re going to develop the disease at age 50 and they’re 20 years old, we measure their spinal fluid. We know, at that point, that that measurement is estimated year of onset minus 30. And then we measure the same thing in their brother, who doesn’t carry the mutation.”
If the subjects had different levels of proteins in their spinal fluid those could be used as early biomarkers for the future Alzheimer’s that would likely appear in coming years. In their article, published in Nature Medicine, Johnson’s team plotted a decrease in the ratio of two proteins in their subjects, showing a dramatic decline in subjects who were closer to the estimated year of Alzheimer’s disease onset. No such decline showed up in the control group.
Both researchers are optimistic that their discoveries could eventually lead to better therapies for Alzheimers disease, although they recognize that’s not imminent.
Seyfried believes knowing you have an elevated level of Alzheimer’s-related proteins could be a cue for possible diet or lifestyle interventions.
“Having the ability to measure different pathways associated with a disease is really important,” says Johnson.
“What we don’t know,” adds Seyfried, “is whether these biomarkers are modifiable.”
That is the critical question these two investigators and their colleagues are working to unravel, with the development and support of the Goizueta Institute @Emory Brain Health.