A new study published in the journal Nature Medicine shows that a protein found in the blood can be used to precisely monitor Alzheimer’s disease progression long before first clinical signs appear.
“This is something that would be easy to incorporate into a screening test in a neurology clinic,” said Dr. Brian Gordon, a researcher at Mallinckrodt Institute of Radiology at Washington University.
“We validated it in people with Alzheimer’s disease because we know their brains undergo lots of neurodegeneration, but this marker isn’t specific for Alzheimer’s. High levels could be a sign of many different neurological diseases and injuries.”
“The fact that there is still no effective treatment for Alzheimer’s is partly because current therapies start much too late,” said Dr. Mathias Jucker, a senior researcher at the German Center for Neurodegenerative Diseases and the Hertie Institute for Clinical Brain Research.
The new test detects neurofilament light chain (NfL), a structural protein that forms part of the internal skeleton of neurons.
When brain neurons are damaged or dying, the protein leaks out into the cerebrospinal fluid that bathes the brain and spinal cord and from there, into the bloodstream.
Finding high levels of the protein in a person’s cerebrospinal fluid has been shown to provide strong evidence that some of their brain cells have been damaged. But obtaining cerebrospinal fluid requires a spinal tap, which many people are reluctant to undergo.
Dr. Gordon, Dr. Jucker and their colleagues studied whether NfL levels in blood also reflect neurological damage.
The scientists turned to a group of families with rare genetic variants that cause Alzheimer’s at a young age — typically in a person’s 50s, 40s or even 30s. The families form the study population of the Dominantly Inherited Alzheimer’s Network (DIAN).
A parent with such a mutation has a 50% chance of passing the genetic error to a child, and any child who inherits a variant is all but guaranteed to develop symptoms of dementia near the same age as his or her parent. This timeline gives researchers an opportunity to study what happens in the brain in the years before cognitive symptoms arise.
The researchers studied more than 400 people participating in the DIAN study, 247 who carry an early-onset genetic variant and 162 of their unaffected relatives. Each participant had previously visited a DIAN clinic to give blood, undergo brain scans and complete cognitive tests. Roughly half had been evaluated more than once, typically about two to three years apart.
In those with the faulty gene variant, NfL protein levels were higher at baseline and rose over time. In contrast, the protein levels were low and largely steady in people with the healthy form of the gene. This difference was detectable 16 years before cognitive symptoms were expected to arise.
In addition, when the team took a look at participants’ brain scans, they found that how quickly the protein levels rose tracked with the speed with which the precuneus — a part of the brain involved in memory — thinned and shrank.
“Sixteen years before symptoms arise is really quite early in the disease process, but we were able to see differences even then. This could be a good preclinical biomarker to identify those who will go on to develop clinical symptoms,” said Stephanie Schultz, a graduate student at Washington University.
All kinds of neurological damage can cause the NfL protein to spill out of neurons and into blood.
Protein levels are high in people with Lewy body dementia and Huntington’s disease; they rise dramatically in people with multiple sclerosis during a flare-up and in football players immediately after a blow to the head.
A commercial kit is available to test for protein levels in the blood, but it has not been approved by the FDA to diagnose or predict an individual’s risk of brain damage. Before such a test can be used for individual patients with Alzheimer’s or any other neurodegenerative condition, researchers will need to determine how much protein in the blood is too much, and how quickly protein levels can rise before it becomes a cause for concern.
“I could see this being used in the clinic in a few years to identify signs of brain damage in individual patients,” Dr. Gordon said.
“We’re not at the point we can tell people, ‘In five years you’ll have dementia.’ We are all working towards that.”
Oliver Preische et al. Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease. Nature Medicine, published online January 21, 2019; doi: 10.1038/s41591-018-0304-3