New methods for picking up on Alzheimer’s disease warning signs years before patients develop irreversible symptoms are becoming a fast-growing target for brain researchers around the world. The disease is expected to afflict 115 million people by 2050 but still remains the only leading cause of death where there is no effective way to prevent or even stall its progression. A key challenge continues to be successfully predicting if the disorder will develop before it becomes symptomatic. In the absence of effective treatment for Alzheimer’s, efforts to diagnose the disease earlier could help to get the right people into clinical trials for therapies.



A new study adds to the short-list of potential methods for identifying Alzheimer’s before its symptoms emerge. The tool would tap existing technology that detects misfolded proteins responsible for prion diseases such as “mad cow” (bovine spongiform encephalopathy) in bodily fluids, but it would be modified to detect misfolded amyloid beta proteins that could be a precursor to the big plaques that form in the brain in Alzheimer’s disease.



The group has successfully detected tiny quantities of misfolded prion proteins in the past using their specialized technology, through a process roughly akin to polymerase chain reaction, the DNA amplification technique used in genome sequencing. The new process, however, hinges on amplifying hallmark proteins. With prions, the group has been able to pinpoint even a single particle of misfolded proteins (oligomers) in the blood or urine of animals, both at symptomatic and presymptomatic stages of disease. Therein lies the promise, because the team hopes that oligomers linked to Alzheimer’s could be picked up in human blood or urine in the future.



Definitive diagnosis of Alzheimer’s is only made on examination of brain cells from a deceased patient under a microscope when studying the buildup of telltale amyloid plaques. Other technologies that pick up signs of the plaque in vivo, however, have made significant progress in recent years, including brain scans and spinal taps that detect proteins implicated in the disease. Still, it remains unclear how well they can be used to predict the malady before the appearance of symptoms.



In the new study this latest identification technology was able to detect misfolded proteins with a high amount of accuracy among patients already diagnosed with Alzheimer’s—differentiating them from patients with other maladies including other forms of dementia. But this technology still relies on painful spinal taps.



Lead author Claudio Soto, director of the Mitchell Center for Alzheimer’s Disease and Related Brain Disorders at the University of Texas Medical School at Houston, and his colleagues think these oligomers could form years or perhaps decades prior to when Alzheimer’s symptoms take hold, circulating through the brain and causing toxic damage, but also creeping, in small quantities, into other parts of the body where they could potentially be detected.



Soto’s approach involved scouring cerebrospinal fluid samples from 50 Alzheimer’s patients, 39 cognitively normal individuals afflicted by nondegenerative neurological disease and 37 patients suffering from other neurodegenerative disorders, including non-Alzheimer’s forms of dementia. The investigators were blinded to which samples they were testing. The team says their analysis correctly identified those who have Alzheimer’s 90 percent of the time and correctly flagged those who do not have it 92 percent of the time. The findings are published in the April 10 Cell Reports.



The team did not attempt to detect Alzheimer’s among seemingly healthy patients—a crucial next step. “This is just a proof of concept that this technology works,” Soto says. Indeed, before this technology could be employed to pick up early signs of disease there would be many hurdles it would need to overcome to get there. First, would be proving that small quantities of these telltale oligomers of amyloid beta protein exist in human blood or urine because healthy patients would not typically want to have painful spinal taps to check for future disease. Moreover, the team does not yet know if there is an oligomer threshold that would indicate disease risk because it is possible that some level of oligomers naturally course through the body and cellular machinery disposes of them.



The findings from Soto and colleagues come on the heels of findings published in Nature Medicine earlier this month, which indicated that testing levels of 10 fats in the blood could accurately predict with a high degree of accuracy the onset of Alzheimer’s several years before clinical symptoms appeared. But that approach, like this one, is far from being ready for prime time. Many such blood tests that have looked promising in initial trials have not been reproducible. (Scientific American is part of Nature Publishing Group.)



“We won’t have therapeutics if we can’t identify the right people and get them into the clinical trials,” says Michael Wolfe, professor of neurology at Harvard Medical School. “A major problem is we have been running these clinical trails and they have been failing, but a large reason for the failures is that people enrolled in the trials already have Alzheimer’s disease and already have damage.” Correctly pinpointing these patients would give a much-needed boost to research going forward.

