When it comes to evaluating a person's health, doctors use a wide variety of tests and measurements called biomarkers. These can range from simple readings such as blood pressure to sophisticated genetic analyses. In between are dozens of tests performed on blood, urine, and other samples that can diagnose disease, measure damage, and collect information about the function of every organ in the body, from lungs and liver to bones and bowels. Biomarkers can provide a snapshot of a person's health, but their real power is seen when they track the course of change over time. By enabling individuals to follow the components of their health, biomarkers can chart the direction of wellness and provide benchmarks for personal health goals.

What are biomarkers?

Biomarkers are measures that indicate the presence or absence of disease or factors that can increase or decrease your risk of disease. You are most likely familiar with elevated blood cholesterol as a risk factor for heart disease. In the case of disease like Alzheimer's, biomarkers being studied include physical changes in the brain, such as shrinkage in specific brain regions, and certain protein levels in blood and cerebrospinal fluid. These changes, which are measured by imaging, blood, and lumbar puncture tests, may detect who is at risk for Alzheimer's disease. Biomarkers are also being studied to see how they may be used to measure disease progression or the effect of interventions.

Why are biomarkers important?

Biomarkers include the measurements of a physical exam, but most biomarkers are measurements taken at the cellular and molecular levels in an attempt to detect the presence of a wide range of substances and provide information about the function of every organ and system in the body, from lungs to liver and bones to bowels.

Our blood and other bodily fluids tell us stories about our bodies. The substances carried in these fluids reflect the lives and deaths of cells, which in turn mirror the function or failure of organs. We've known that, at least in principle, since antiquity. But measuring the levels of glucose in the blood or urine, for example, is not the same as measuring a person's pulse or the rate of respiration. While you can directly observe how fast or slow someone is breathing, you can't directly observe the cellular processes of nutrient metabolism. Instead, you can only measure the presence of a substance (in this example, glucose) that indirectly reflects how fast or slow this process is proceeding.

This might not seem like a significant difference, but in some cases it is. The goal of medical technology is to look as close as possible at the actual physiological processes of the body. Biomarkers are often only an approximation of what is happening in the body. Imagine being an archaeologist excavating an ancient campsite and finding piles of clam shells and the bones of rabbits. It would be reasonable to surmise from this evidence that the people who lived at the campsite relied on shellfish and rabbits as important components of their diet. But that's not the same as actually watching those people eat.

The same is true for many biomarkers. That doesn't mean biomarkers are not accurate; many are extremely sensitive and specific measurements. But it reminds us that the goal of medical science is to actually see cells function or fail directly; in many cases, biomarkers are (at least for now) an approximation of what is taking place, the next best thing to being there.

What does "normal" and "abnormal" really mean?

High-tech scans of the body can spot abnormalities the size of a pencil tip. That can be a good thing; we can all see the value of spotting problems when they are tiny. But such micro-detection does not always work in a patient's favor. It does, though, illustrate the problem of defining what is "normal" and what is not.

Finding out that you have an "abnormality" even though you still feel perfectly fine is not always helpful, because the fact is that we all have abnormalities that won't cause us problems. As Dr. Michael Stein of Brown University points out, when every organ, bone, and muscle is scanned, more than three-quarters of those without symptoms are discovered to have abnormalities. Among patients without any current knee pain or even a history of knee injury, for example, 40% have meniscal damage detected by MRI scans. Among adults without back pain, over 50% have bulging lumbar discs. Gallstones show up in 10% of adults with no symptoms, and 7% of adults under age 50 have had a stroke without knowing it.

The problem of determining what's normal also goes for blood tests. Normal and abnormal are statistical inventions. Test results of healthy people are basically compared to the results for people who have a particular disease or condition. If you imagine a standard bell curve, think of the ends as disease states and the middle as normal. And while age and gender are taken into account in these statistical calculations, they are still averages based on populations.

Normal is also often a moving target. Take blood glucose levels, for example. In 1965, the World Health Organization proposed the first definition of diabetes based solely on laboratory testing in 1965. But by 1979, explains Stein, the lab test this definition was based on was outdated. A new standard, a single fasting blood test (a glucose level higher than 140), was now "diabetes." In 1997, this glucose threshold was lowered to anything higher than 126, which in one stroke increased the number of diabetics in the country.

Around the same time, says Stein, new terms such as "pre-diabetes," were introduced, identifying persons whose glucose control was not quite "normal," but not quite diabetic. In 2003, this "pre-diabetes" cut-off number was lowered as well, further increasing the number of Americans worried about and monitored for sugar-related abnormalities. The development of new tests, such as hemoglobin A1C, further expanded the number of people considered to either have or be at risk for the disease. Human physiology hasn't changed in the past 50 years, but the definition of diabetes certainly has.

The power of repetition

Biomarkers can be used as snapshots to freeze a single moment in physiological time, but their real power is seen when they are used as a movie to capture the course of change over time.The critical question for patients, explains Dr. Michael Stein, of Brown University, is this: is it more useful to have your current glucose (let's say it's 98) compared to the statistical "normal" of 67-99, or would it be more clinically helpful to compare your current glucose to your glucose readings from the past 4 years (let's say it has trended upward from 68 to 78 to 88). If in year 5 it goes to 108, you "suddenly" become diabetic according to the average normal, even though it was clear you were on an unhealthy trajectory for years. Biosystems rarely fail suddenly, explains Stein; chronic deterioration is more typical. The potential of "personalized medicine" is to reveal the underlying trends, which will make it easier for individuals to understand their health and what they might do to improve it.

Results for lab tests are expressed in metric units or SI units (an updated version of the metric system, SI is abbreviated from the French, Systeme international d'unites, or International System of Units).

U and IU (units or international units) are measurements that have been agreed upon and standardized by the scientific and medical communities. An enzyme unit, for example, is the quantity of enzyme needed to cause a reaction to process 1 micromole of substance per minute under specified conditions. Units are also used to measure the activity (that is, the effect) of many vitamins and drugs. For example, 1 IU of insulin is 45.5 micrograms and 1 IU of penicillin is 0.6 micrograms. With vitamins, 1 IU is 0.3 microgram for vitamin A, 50 micrograms for vitamin C, 25 nanograms for vitamin D, and 0.67 milligrams for vitamin E.

Diagnostic tests are rarely painful (invasive sampling techniques, such as biopsies, are performed with local or general anesthetic), but they may cause discomfort or embarrassment for some patients. Preparation can help minimize such issues, especially when samples need to be taken from children, the elderly or patients with special needs.

The first step is to understand why tests are being performed. Knowing the purpose of the test and its importance to a patient's well being is essential; understanding what the biomarkers will measure and how this information will be used in diagnosis or treatment is also helpful. Most adults get through their tests with little stress, emotional or physical; it's even easier when tests are seen as the critical first step in taking charge of one's health and well being.

Young children and the elderly pose special considerations, but in general, the same guidelines apply. Step one is still to understand the basic purpose and importance of tests. Especially for these populations, knowing what to expect can alleviate the anxiety and helplessness that may accompany medical tests.

Biomarker testing is a way to look for genes, proteins, and other substances (called biomarkers or tumor markers) that can provide information about cancer. Each person’s cancer has a unique pattern of biomarkers. Some biomarkers affect how certain cancer treatments work. Biomarker testing may help you and your doctor choose a cancer treatment for you.

There are also other kinds of biomarkers that can help doctors diagnose and monitor cancer during and after treatment.

Biomarker testing is for people who have cancer. People with solid tumors and people with blood cancer can get biomarker testing.

Biomarker testing for cancer treatment may also be called:

• tumor testing
• tumor genetic testing
• genomic testing or genomic profiling
• molecular testing or molecular profiling
• somatic testing
• tumor subtyping

A biomarker test may be called a companion diagnostic test if it is paired with a specific treatment.

Biomarker testing is different from genetic testing that is used to find out if someone has inherited mutations that make them more likely to get cancer. Inherited mutations are those you are born with. They are passed on to you by your parents.

At a Glance

• Researchers identified two blood proteins that are linked to length of time needed by college athletes to return to play following a sports-related concussion.
• These blood biomarkers could help doctors predict which athletes need additional time to recover from a concussion.

Head injuries are a particularly concerning type of sports injury. There are millions of sports-related mild traumatic brain injuries, or concussions, in the U.S. each year. If you have a concussion, you may lose consciousness for a few minutes or experience a headache, confusion, lightheadedness, or dizziness.

Most people recover from a concussion within a couple of weeks. But some have symptoms that last for months. Returning to sports too soon can put you at increased risk for subsequent concussions, long-term symptoms, thinking problems, and even neurodegenerative disease.

Previous studies have found that certain proteins in the blood are associated with concussion or recovery time. These include tau protein, neurofilament light chain protein (Nf-L), and glial fibrillary acidic protein (GFAP).

A research team led by Dr. Jessica M. Gill of NIH’s National Institute of Nursing Research (NINR) tested whether these three proteins could be used as biomarkers to predict length of recovery time. They studied 127 male and female collegiate athletes at six U.S. universities, including two military service academies, who had sustained a sports-related concussion. Results were published on August 27, 2020, in JAMA Network Open.

Researchers took blood samples from the athletes shortly after their injuries, when their symptoms resolved, and one week after returning to play. Each athlete also had preseason, baseline blood testing. Using an ultrasensitive assay called single molecular array technology, which can detect minute amounts of protein, the team examined levels of the three blood proteins.

Two of the proteins were associated with the length of time needed by the athletes to return to play: tau and GFAP. Athletes who needed less than two weeks of recovery time had significantly higher tau within the first 48 hours after an injury. In contrast, GFAP was significantly lower for these athletes. Nf-L was not linked with the length of time needed for recovery.

“This study is an important step toward the development of methods to predict which athletes need more time to recover from a concussion and resume activity safely. The findings may ultimately help reduce the risk of multiple brain injuries in athletes,” Gill says.

More studies are needed to determine whether other factors affect these two proteins’ predictive value for recovery time, such as severity of the concussion or physical damage to the brain.

Biomarkers are measurable indicators of what’s happening in the body. These can be found in blood, other body fluids, organs, and tissues. Some can even be measured digitally. Biomarkers can help doctors and researchers track healthy processes, diagnose diseases and other health conditions, monitor responses to medication, and identify health risks in a person. For example, an increased level of cholesterol in the blood is a biomarker for heart attack risk.

Before the early 2000s, the only sure way to know whether a person had Alzheimer’s disease or another form of dementia was after death through autopsy. But thanks to advances in research, tests are now available to help doctors and researchers see biomarkers associated with dementia in a living person.

The different types of biomarkers for dementia detection and diagnosis are outlined below. When combined with other tests, these biomarkers can help doctors determine whether a person might have or be at risk of developing Alzheimer’s or a related dementia. However, no single test can alone diagnosis these conditions. Biomarkers are only part of a complete assessment.

In some cases, these biomarker tests are only available through a specialty clinic or medical research facility. Physicians with expertise in this area include neurologists, geriatric psychiatrists, neuropsychologists, and geriatricians. Medicare and other health insurance plans may cover only certain, limited types of biomarker tests for dementia symptoms. Check with Medicare or your insurance plan to find out what’s covered.

Biomarkers are also an important part of dementia research. They help researchers detect early brain changes, better understand how risk factors are involved, identify participants who meet particular requirements for clinical trials and studies, and track participants' responses to a test drug or other intervention, such as physical exercise. The following information notes how some of these biomarkers are used for research purposes, in addition to diagnosis.

Types of biomarkers and tests

Brain imaging

Several types of brain scans enable doctors and scientists to see different factors that may help diagnose Alzheimer’s or a related dementia. Doctors also use brain scans to find evidence of other sources of damage, such as tumors or stroke, that may aid in diagnosis. Brain scans used to help diagnose dementia include CT, MRI, and PET scans.

Computerized tomography (CT)

A CT scan is a type of X-ray that uses radiation to produce images of the brain or other parts of the body. A head CT can show shrinkage of brain regions that may occur in dementia, as well as signs of other possible sources of disease, such as an infection or blood clot. To help determine if a person has dementia, a doctor might compare the size of certain brain regions to previous scans or to what would be expected for a person of the same age and size. Sometimes a CT scan is used when a person isn’t eligible for an MRI due to metal in their body, such as a pacemaker.

Magnetic resonance imaging (MRI)

MRI uses magnetic fields and radio waves to produce detailed images of body structures, including the size and shape of the brain and brain regions. Because MRI uses strong magnetic fields to obtain images, people with certain types of metal in their bodies, such as a pacemaker, surgical clips, or shrapnel, cannot undergo the procedure.

Similar to CT scans, MRIs can show whether areas of the brain have atrophied (shrunk). Repeat scans can show how a person's brain changes over time. Evidence of shrinkage may support a diagnosis of Alzheimer's or another neurodegenerative dementia but cannot indicate a specific diagnosis. MRI also provides a detailed picture of brain blood vessels. Before making a dementia diagnosis, doctors often view MRI results to rule out other causes of memory changes such as bleeding or a build-up of fluid in the brain.

In research, various types of MRI scans are used to study the structure and function of the brain in both healthy aging and in Alzheimer's disease. MRIs can also be used to monitor the safety of novel drugs and examine how treatment may affect the brain over time.

Positron emission tomography (PET)

PET uses small amounts of a radioactive substance, called a tracer, to measure specific activity — such as energy use — or a specific molecule in different brain regions. PET scans take pictures of the brain, revealing regions of normal and abnormal chemical activity. There are several types of PET scans that can help doctors diagnose dementia.

• Amyloid PET scans measure abnormal deposits of a protein called beta-amyloid. Higher levels of beta-amyloid are consistent with the presence of amyloid plaques, a hallmark of Alzheimer's disease. Medical specialists may use amyloid PET imaging to help diagnose Alzheimer’s. A positive amyloid scan may mean symptoms are due to Alzheimer’s or a person is experiencing the early stages of Alzheimer’s. But it’s possible for people to have amyloid plaques and never develop the symptoms of Alzheimer’s, so doctors will consider these findings along with the results of other tests. An amyloid scan that shows just a few or no amyloid plaques usually means that Alzheimer’s is not the cause of the symptoms. These types of scans are often used in research settings to identify those at risk of developing Alzheimer’s disease and to test potential treatments.
• Tau PET scans detect the abnormal accumulation of the tau protein. Tau forms tangles within nerve cells in Alzheimer's disease and many other dementias. Tau PET scans may be used by doctors to monitor progression of Alzheimer's, but they are not commonly used in standard medical practice. These scans are more often used in research settings to help identify people who are at risk of developing Alzheimer’s and test potential treatments.
• Fluorodeoxyglucose (FDG) PET scans measure energy use in the brain. Glucose, a type of sugar, is the primary source of energy for cells. Studies show that people with dementia often have abnormal patterns of decreased glucose use in specific areas of the brain. In clinical care, FDG PET scans may be used if a doctor strongly suspects frontotemporal dementia as opposed to Alzheimer's.

Cerebrospinal fluid biomarkers (CSF)

CSF is a clear fluid that surrounds the brain and spinal cord, providing protection and insulation. CSF also supplies numerous nutrients and chemicals that help keep brain cells healthy. Proteins and other substances made by brain cells can be detected in CSF. Measuring changes in the levels of these substances can help diagnose neurological problems.

Doctors perform a lumbar puncture, also called a spinal tap, to get CSF. The most widely used CSF biomarkers for Alzheimer's disease measure beta-amyloid 42 (the major component of amyloid plaques in the brain), tau, and phospho-tau (major components of tau tangles in the brain, which are another hallmark of Alzheimer’s).

In clinical practice, CSF biomarkers may be used to help diagnose Alzheimer's or other types of dementia. In research, CSF biomarkers are valuable tools for early detection of a neurodegenerative disease and to assess the impact of experimental medications.

Blood tests

Proteins that originate in the brain may be measured with sensitive blood tests. Levels of these proteins may change because of Alzheimer's, a stroke, or other brain disorders. These blood biomarkers have historically been less accurate than CSF biomarkers for identifying Alzheimer's and related dementias. However, thanks to more research advances, improved methods to measure these brain-derived proteins are now available. For example, it is now possible for scientists and most doctors to order a blood test to measure levels of beta-amyloid, and several other similar tests are in development. Still, the availability of these diagnostic tests is limited: They are more common in research settings where scientists use blood biomarkers to study early detection, prevention, and the effects of potential treatments.

Genetic testing

Genes are structures in a body's cells that are passed down from a person's birth parents. They carry information that determines a person's traits and keep the body's cells healthy. Mutations in genes can lead to diseases such as Alzheimer's. A genetic test is a type of medical test that analyzes DNA from blood or saliva to determine a person's genetic makeup. A number of genetic combinations may change the risk of developing a disease that causes dementia.

Genetic tests are not routinely used in clinical settings to diagnose or predict the risk of developing Alzheimer's or a related dementia. However, a neurologist or other medical specialist may order a genetic test in certain situations, such as when a person has an early age of onset with a strong family history of Alzheimer's or frontotemporal dementia. A genetic test is typically accompanied by genetic counseling for the person before the test and when results are received. Genetic counseling includes a discussion of the risks, benefits, and limitations of test results.

In research studies, genetic tests may be used, in addition to other assessments, to predict disease risk, help study early detection, explain disease progression, and study whether a person's genetic makeup influences the effects of a treatment.

What is the future of biomarkers?

Advances in biomarkers during the past decade have led to exciting new findings. Researchers can now see Alzheimer's-related changes in the brain while people are alive, track the disease's onset and progression, and test the effectiveness of promising drugs and other potential treatments.

Researchers are continuing to study and develop biomarkers to improve dementia detection, diagnosis, and treatment. These may one day be used more widely in doctors' offices and other clinical settings. Learn more about biomarker advancements and biomarkers for dementia detection and research.

How you can help move biomarker research forward

The use of biomarkers is enabling scientists to make great strides in identifying potential new treatments and ways to prevent or delay dementia. These and similar advances have been possible only because of the thousands of volunteers who have participated in clinical trials and studies. Clinical trials need participants of all different ages, sexes, races, and ethnicities to ensure that study results apply to as many people as possible, and that treatments will be safe and effective for everyone who will use them. Major medical breakthroughs could not happen without the generosity of research participants who essentially become partners in these scientific discoveries.