An international team of scientists has evaluated a potential blood test that measures the level of a biomarker to detect nerve cell damage in the brain. The team studied the biomarker for assessing individuals at high risk for developing early-onset familial Alzheimer disease (AD) before they develop symptoms.
The research was conducted by scientists and clinicians from the German Center for Neurodegenerative Diseases, the Hertie Institute for Clinical Brain Research and the University Hospital Tübingen, both in Germany, the Washington University School of Medicine in St. Louis, and several other institutions around the world. The findings have been published in the journal Nature Medicine.
The researchers evaluated a biomarker called neurofilament light chain (NfL) protein. NfL forms part of the internal "scaffolding" for nerve cells. When nerve cells are damaged, NfL seeps into the fluid that surrounds the brain and spinal cord (cerebrospinal fluid, CSF) and then into the blood. This can occur with neurodegenerative diseases like AD as well as other types of brain damage.
AD is an irreversible form of dementia that affects more than 5.5 million Americans. It slowly destroys the nerve cells in the brain, gradually affecting a person's memory and thinking skills—and this damage eventually makes everyday tasks challenging. AD causes other physical changes in the brain, including shrinking of the brain's outer layer (cortical thinning) and harmful deposits of beta-amyloid and tau proteins (called amyloid or senile plaques) in the brain. Many of these changes occur well before AD-specific symptoms appear and continue to get worse as the disease progresses.
Most people with AD have symptoms that first appear in their mid-60s (late-onset). However, people with a rare type called early-onset familial AD have symptoms that appear in their 30s to mid-60s. Early-onset familial AD accounts for less than 10% of all AD cases and is caused by an inherited gene mutation (disease-causing variant) in one of three genes. (A parent with one of these mutations has a 50% chance of passing it on to their child. If this child inherits the disease-causing mutation, the child has a nearly 100% chance of developing symptoms of dementia around the same age as that child's parent.)
Because of the strong association between the genetic mutations and development of early-onset AD, the research team based their study on individuals with this rarer form of AD. They used an international database of 405 individuals called the Dominantly Inherited Alzheimer Network (DIAN). The DIAN database includes medical information for 243 people with an early-onset familial AD genetic mutation and 162 of their family members who do not have a disease-causing mutation. The researchers used blood tests to measure NfL levels and looked at how the amount of neurofilament light chain (NfL) protein changed over time in blood samples from DIAN individuals.
For DIAN individuals with an early-onset AD genetic mutation, the NfL level in the earliest samples (baseline) was higher and rose significantly over time compared to the NfL level in their unaffected relatives, which was lower at baseline and stayed about the same over time. The team also found that the speed at which NfL increased in their blood, rather than the concentration of NfL, could be used to predict when that person would start experiencing AD symptoms. In fact, they showed that they could predict early-onset familial AD in DIAN individuals with the mutation 16.2 years before symptoms appeared. The researchers also found that the rate of NfL change was associated with some but not all tests for AD progression, such as memory tests and imaging scans.
The team hopes their NfL blood test will eventually be approved for clinical use, which could someday lead to earlier treatment to fight AD progression. Senior author Mathias Jucker, PhD said in a press release: "The fact that there is still no effective treatment for Alzheimer's is partly because current therapies start much too late." The researchers also say the test could be used to monitor disease progression and possibly as a tool for investigating new AD treatments in clinical trials.
The test is not specific for detecting pre-symptomatic early-onset familial AD, warn authors of the Nature Medicine article, because NfL also collects in the blood of people with other neurodegenerative diseases and brain damage, like multiple sclerosis, traumatic brain injury, or stroke. The biomarker was not evaluated in patients with the more common late-onset AD, so there is no evidence yet, and more research is needed to determine, how well the blood test would perform in detecting and monitoring disease progression in these patients.
"We validated [the blood test] 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," said Brian Gordon, PhD, an author on the study stated in a press release. "I could see this being used in the clinic in a few years to identify signs of brain damage in individual patients. We're not at the point we can tell people, 'In five years you'll have dementia.' We are all working towards that."