Blood Tests To Predict Alzheimer’s Disease

Research over the last decade has clearly demonstrated that the pathological processes leading to Alzheimer’s disease start more than 20 years before the appearance of clinical symptoms. Beta-amyloid, one of the chemical hallmarks of Alzheimer’s disease, begins to accumulate in the brain decades in advance of symptoms and can be visualized with neuroimaging techniques. Amyloid levels also can be measured in the cerebrospinal fluid (CSF) that surrounds the brain and spinal cord; samples of CSF can be obtained using a straight forward procedure called lumbar puncture. Imaging procedures and lumbar punctures are time-consuming, expensive, and require substantial expertise, however. For these reasons, they are not suited as screening methods for presymptomatic Alzheimer’s disease in the general population.

Recently, another chemical known as neurofilament light chain (NfL) has been shown to increase in individuals with disorders that cause brain degeneration. NfL is a component of the part of nerve cells called axons that send signals to other neurons. When nerve cells degenerate, the level of NfL increases in CSF. It turns out that changes in NfL levels in the CSF and blood are exactly parallel, and, therefore, NfL levels in the blood are an excellent proxy for the levels in CSF.

In a paper recently published in the journal Nature Medicine, Oliver Preische and colleagues describe studies examining NfL levels in a group of individuals who have rare, genetic forms of Alzheimer’s disease. Fifty percent of individuals who have a parent with these highly familial forms of the disorder will inherit the mutation and experience onset of symptoms at about the same age as their parents did. Although this type of Alzheimer’s disease, called dominantly inherited Alzheimer’s disease (DIAD), is rare, many of the pathological changes associated with DIAD are the same as those associated with the common forms of Alzheimer’s disease making DIAD a highly instructive model for study.

Adult children of parents with DIAD have volunteered for longitudinal research studies, including treatment studies. Earlier studies involving imaging of brain amyloid and chemical analyses of CSF led to the discovery that changes associated with the disorder start more than 20 years prior to the anticipated onset of symptoms.

The current study describes the measurement of NfL in the CSF and blood serum of these DIAD volunteers. Preische and colleagues found that NfL levels increased in individuals with the genetic mutation about seven years before the expected onset of symptoms. Since NfL levels in CSF and serum are closely associated, they focused on measuring serum NfL levels longitudinally and calculating the rate of change of NfL levels over time.

The investigators found that there was a marked difference in the rate of increase of NfL levels in those with the genetic mutation when compared to those without the mutation and that this difference became apparent about 16 years prior to the expected onset of symptoms. In other words, by measuring NfL levels at several points over time, it may be possible to determine with a blood test which individuals are developing Alzheimer’s disease about 16 years in advance of clinical symptoms.

Much more work must be done before NfL measurements become a clinically useful test. First, it must be determined if the same results occur in the more common type of Alzheimer’s disease. Second, the optimal length of time between blood tests to achieve reliable results must be established. For instance, can meaningful differences be shown in tests that are one year apart? The fact that increases in NfL levels are observed in other neurodegenerative disorders also must be taken into consideration. Although Alzheimer’s disease is the most common degenerative brain disorder, other illnesses could be responsible for observed changes.

Blood tests that measure changes in amyloid levels are also being developed. In our opinion, it is highly likely that a combination of blood tests will become available over the next several years that will allow the identification of individuals who are headed towards clinical Alzheimer’s disease years prior to the manifestation of symptoms. Identifying such individuals should facilitate treatment studies. The ultimate goal is to be able to treat presymptomatic individuals in order to delay or stop the underlying illness process. Such a delay would have an enormous impact on the lives of our elderly population, their families, and society.

This post was written by Eugene Rubin MD, Ph.D. and Charles Zorumski M.D.