A simple blood test may soon detect Alzheimer's years in advance.
This was what an international group of scientists concluded after evaluating the simple test that used blood samples from people with a rare form of Alzheimer's disease that they had inherited.
The team included researchers from Washington University School of Medicine in St. Louis, MO and the German Center for Neurodegenerative Diseases in Tübingen, Germany.
The test looks for changes in levels of the neurofilament light chain (NfL) protein. The protein normally resides inside brain cells, or neurons, as part of their internal skeleton.
However, damaged and dying cells can leak NfL into surrounding cerebrospinal fluid. The protein then travels from the fluid into the bloodstream.
Others have already shown that raised levels of NfL in cerebrospinal fluid is a strong sign that some brain damage has occurred. Doctors can test for the protein using a lumbar puncture, or spinal tap, but many people are reluctant to undergo the procedure.
Now, in a Nature Medicine paper about the recent study, the authors report how they demonstrated that NfL levels in spinal fluid correlated with levels in blood and "are elevated at the presymptomatic stages of familial Alzheimer's disease."
"This could be," says co-first study author Stephanie A. Schultz, who is a graduate student at Washington University, "a good preclinical biomarker to identify those who will go on to develop clinical symptoms."
Alzheimer's damages the brain
Alzheimer's disease is a major cause of dementia that destroys brain cells and tissue. As the brain damage spreads, it leads to symptoms such as confusion, memory loss, and diminishing capacity to function. Eventually, the person can no longer lead an independent life.
Estimates from the National Institute on Aging suggest that there could be at least 5.5 million people with Alzheimer's in the United States.
Postmortem exams of the brains of people with Alzheimer's disease reveal three typical hallmarks: plaques of beta-amyloid protein, tangles of tau protein, and loss of connections between brain cells.
Alzheimer's disease mostly strikes people aged 65 years and older, but there are rarer forms that can strike earlier.
Scientists do not fully understand the causes of Alzheimer's disease, especially the forms that strike people later in life. They suggest that these forms likely arise from a complex interplay of genes, environment, and lifestyle.
Around 1 in 20 people who develop Alzheimer's disease will have an early-onset form that begins to show symptoms before the age of 65 years.
The most common cause of these early-onset forms of Alzheimer's disease is gene mutations that parents pass on to their offspring.
Dominantly inherited Alzheimer's disease
In the new research, the team studied a rare form that has the name dominantly inherited Alzheimer's disease (DIAD), or autosomal dominant Alzheimer's disease.
The data for the study came from the Dominantly Inherited Alzheimer's Network (DIAN), which is an international consortium that Washington University leads. The aim of the network is to investigate the causes of Alzheimer's disease.
DIAD arises from a mutation in one or more of three genes: PSEN1, PSEN2, or APP.
People with DIAD typically experience memory loss and other symptoms of dementia in their 30s, 40s, and 50s.
The researchers chose to study people with DIAD because the earlier onset of the disease gives a longer timespan over which to investigate brain changes before cognitive symptoms emerge.
The analysis took in data on more than 400 people in the DIAN network. This number included 247 who were carriers of a genetic mutation and 162 of their blood relatives who were not carriers.
All the individuals had attended a DIAN clinic and given a blood sample, completed cognition tests of memory and thinking skills, and undergone brain scans. In addition, around half had made repeat clinic visits, with up to 3 years between each.
NfL levels predict symptoms 16 years ahead
Examination of the blood samples from the first visit revealed higher levels of NfL in those people who carried a gene mutation. In these individuals, repeated visits showed NfL levels rising over time.
The individuals who did not carry a gene mutation, however, did not show this pattern. Their NfL levels were lower and remained fairly steady over time.
The team detected the rise in NfL levels some 16 years before the anticipated onset of symptoms.
Results from the brain scans were in line with the changes in NfL levels.
The rate of increase in the protein matched the rate of thinning and shrinkage in the brain's precuneus, which has a role in memory.
Schultz remarks that "16 years before symptoms arise is really quite early in the disease process, but we were able to see differences even then."
Further analysis revealed that NfL levels were also predictive for the decline in memory and thinking skills in the cognition tests.
Biomarker for brain-damaging conditions
Other conditions that damage the brain can also cause neurons to leak NfL. People with Huntington's disease and Lewy body dementia, for example, have higher blood levels of the protein.
Blood NfL levels also rise in football players immediately after a blow to the head and in people with multiple sclerosis during flare-ups.
Researchers now need to do further work, such as deciding the best NfL levels for biomarker significance and what rates of increase should trigger concerns, before doctors can start using the test.
"This is something," says study author Brian Gordon, Ph.D., who is an assistant professor of radiology at Washington University, "that would be easy to incorporate into a screening test in a neurology clinic."