Researchers used a blood test to look for biomarkers indicative of Alzheimer disease in a group of people with a genetic mutation for a familial form of the disease, and they said the test can predict differences about 16 years before affected patients are expected to begin showing symptoms. The hope is that a blood test could one day be used to identify brain disease for not only Alzheimer disease but also other neurodegenerative conditions, such as multiple sclerosis, traumatic brain injury, or stroke.
Researchers used a blood test to look for biomarkers indicative of Alzheimer's disease in a group of people with a genetic mutation for a familial form of the disease, and they said the test can predict differences about 16 years before affected patients are expected to begin showing symptoms. The hope is that a blood test could one day be used to identify brain disease for not only Alzheimer disease but also other neurodegenerative conditions, such as multiple sclerosis, traumatic brain injury, or stroke.
The findings were published Monday in Nature Medicine. The study was conducted by Washington University School of Medicine in St. Louis and the German Center for Neurodegenerative Diseases in Germany.
In most neurodegenerative diseases, brain changes begin many years before clinical symptoms are evident. In Alzheimer disease, presymptomatic brain changes include cortical thinning and the proteins amyloid-β and tau. Currently, these brain changes can only be assessed by magnetic resonance imaging, positron-emission tomography, and measurement of amyloid-β and tau protein levels in the cerebrospinal fluid. These methods are expensive and, as in the case of a spinal tap, invasive.
The blood 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 and into the bloodstream.
The researchers studied group of families with rare genetic variants that cause Alzheimer disease 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), an international consortium led by Washington University. DIAN participants have a 50% of carrying an autosomal-dominant Alzheimer disease mutation in 1 of 3 genes (APP, PSEN1, and PSEN2). A parent with such a mutation has a 50% chance of passing the genetic error to a child; 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, who served as controls. 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 2 to 3 years apart.
In those with the faulty gene variant, protein levels were higher at baseline and rose over time. But protein levels were low and largely steady in people without the variant. This difference was detectable 16 years before cognitive symptoms were expected to arise.
"This is something that would be easy to incorporate into a screening test in a neurology clinic," Brian Gordon, PhD, an assistant professor of radiology at Washington University's Mallinckrodt Institute of Radiology and an author on the study, said in a statement. "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."
In addition, when the researchers looked at participants' brain scans, they discovered 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.
To find out whether protein blood levels could be used to predict cognitive decline, the researchers collected data on 39 people with disease-causing variants when they returned to the clinic an average of 2 years after their last visit. The participants underwent brain scans and 2 cognitive tests: the Mini-Mental State Exam and the Logical Memory test. The researchers found that people whose blood protein levels had previously risen rapidly were most likely to show signs of brain atrophy and diminished cognitive abilities when they revisited the clinic.
It is too early for the test to be put into use, the authors said. While a commercial kit, similar to the one used in the study, is available to test for protein levels in the blood, 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 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.
Preische O, Schultz SA, Apel A, et al. Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s Disease. [published online January 21, 2019]. Nat Med. doi: 10.1038/s41591-018-0304-3.