Biomarkers for earlier detection
Current diagnosis of Alzheimer's relies largely on documenting mental decline. We now know that Alzheimer's has already caused severe brain damage in individuals who are diagnosed in this way.
Researchers hope to discover an easy and accurate way to detect Alzheimer's before these devastating symptoms begin. Experts believe that biomarkers (short for "biological markers") offer one of the most promising paths. A biomarker is something that can be measured to accurately and reliably indicate the presence of disease. An example of a biomarker is fasting blood glucose (blood sugar) level, which indicates the presence of diabetes if it is 126 mg/dL or higher.
Several potential biomarkers are being studied for their ability to indicate early stages of Alzheimer's disease. Examples being studied include beta-amyloid and tau levels in cerebrospinal fluid and brain changes detectable by imaging. Recent research suggests that these indicators may change at different stages of the disease process.
Before a biomarker can be used in medical clinics, it must be validated, in which multiple studies in large groups of people establish that it accurately and reliably indicates the presence of disease. Furthermore, the laboratory methods used to measure the biomarker must be shown to be stable and reliable. Sign up for our weekly e-news and stay up-to-date on the latest advances in Alzheimer's diagnosis, treatments, care and research.
There are currently no validated biomarkers for Alzheimer's disease, but researchers are investigating several promising candidates, including brain imaging, proteins in cerebrospinal fluid, proteins in blood and genetic risk profiling.
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Brain Imaging/ neuroimaging
Neuroimaging is among the most promising areas of research focused on early detection. Today, a standard workup for Alzheimer's disease often includes structural imaging with magnetic resonance imaging (MRI) or computed tomography (CT). These tests are currently used chiefly to rule out other conditions that may cause symptoms similar to Alzheimer's but require different treatment. Structural imaging can reveal tumors, evidence of small or large strokes, damage from severe head trauma or a buildup of fluid in the brain.
In 2012, the U.S. Food and Drug Administration approved the first molecular imaging tracer for use in patients being evaluated for possible Alzheimer's disease or other causes of cognitive decline. This tracer (brand name Amyvid but also known as florbetapir F-18), is a molecule that binds to beta-amyloid in the brain. Because it is labeled with a radioactive tracer it can be visualized during a positron emission tomography (PET) brain scan, thereby revealing the presence of amyloid plaques in the brains of living patients.
A second molecular imaging tracer (brand name Vizamyl but also known as flutametamol F18) was approved in 2013. It also binds to and reveals amyloid plaques in the brain during PET imaging. A third molecular imaging tracer (brand name Neuraceq but also known as florbetaben F18) was approved in 2014, and like its two predecessors, binds to and reveals amyloid plaques in the brain during PET imaging.
Even though amyloid plaques in the brain are a characteristic feature of Alzheimer's disease, their presence cannot be used to diagnose the disease. Many people have amyloid plaques in the brain but have no symptoms of cognitive decline or Alzheimer's disease. Because amyloid plaques cannot be used to diagnose Alzheimer's disease, amyloid imaging is not recommended for routine use in patients suspected of having Alzheimer's disease.
A Task Force of the Society of Nuclear Medicine and Molecular Imaging (SNMMI) and the Alzheimer's Association has published criteria in which they believe the use of amyloid imaging would be appropriate.
|Imaging technologies used in Alzheimer's research
Structural imaging provides information about the shape, position or volume of brain tissue. Structural techniques include magnetic resonance imaging (MRI) and computed tomography (CT).
Functional imaging reveals how well cells in various brain regions are working by showing how actively the cells use sugar or oxygen. Functional techniques include positron emission tomography (PET) and functional MRI (fMRI).
Molecular imaging uses highly targeted radiotracers to detect cellular or chemical changes linked to specific diseases. Molecular imaging technologies include PET, fMRI and single photon emission computed tomography (SPECT).
- Structural imaging studies have shown that the brains of people with Alzheimer's shrink significantly as the disease progresses. Research has also shown that shrinkage in specific brain regions such as the hippocampus may be an early sign of Alzheimer's. However, scientists have not yet agreed upon standardized values for brain volume that would establish the significance of a specific amount of shrinkage for any individual person at a single point in time.
- Functional imaging research with positron emission tomography (PET) and other methods suggests that those with Alzheimer's typically have reduced brain cell activity in certain regions. For example, studies with fluorodeoxyglucose (FDG)-PET indicate that Alzheimer's disease is often associated with reduced use of glucose (sugar) in brain areas important in memory, learning and problem solving. However, as with the shrinkage detected by structural imaging, there is not yet enough information to translate these general patterns of reduced activity into diagnostic information about individuals.
- Molecular imaging technologies are among the most active areas of research aimed at finding new approaches to diagnose Alzheimer's in its earliest stages. Molecular strategies may detect biological clues indicating Alzheimer's is under way before the disease changes the brain's structure or function, or takes an irreversible toll on memory, thinking and reasoning. Molecular imaging also may offer a new strategy to monitor disease progression and assess the effectiveness of next-generation, disease-modifying treatments. Several molecular imaging compounds are being studied, and four have now been approved for clinical use:
- Pittsburgh compound B (PIB) was the first radiotracer capable of highlighting deposits of beta-amyloid—one pathological hallmark of Alzheimer's disease—in living individuals during a PET scan. The Alzheimer's Association helped fund early PIB development. The original phase of the ADNI project has now been completed, but the Alzheimer's Association has supported three follow-up study phases, known as ADNI-GO, ADNI-2 and ADNI-3. These studies are continuing research into the uses of brain imaging for detecting and monitoring Alzheimer's disease in its earliest stages.
- Florbetaben (Neuraceq®), Florbetapir (Amyvid®) and Flutemetamol (Vizamyl®) have also been approved for detection of beta-amyloid in the brain.
In addition, clinical trials are underway testing radiotracers for the protein tau, which is present in abnormally large quantities in the brains of people with Alzheimer’s.
Catalyst to progress
In 2006, the Alzheimer's Association awarded a $2.1-million grant to the Alzheimer's Disease Neuroimaging Initiative (ADNI) to expand the study to include PIB-PET imaging. ADNI began as a five-year, nationwide study launched by the National Institute on Aging (NIA) to establish standards for obtaining and interpreting brain images and biological samples. Its ultimate goal is to determine whether standardized imaging protocols, possibly combined with laboratory and psychological tests, may offer a better way to identify high-risk individuals, provide earlier diagnosis, track disease progression and monitor treatment effects, especially in clinical trials of disease-modifying drugs. Learn more about our commitment to research.
Cerebrospinal fluid (CSF) proteins
CSF is a clear fluid that bathes and cushions the brain and spinal cord. Adults have about 1 pint of CSF, which physicians can sample through a minimally invasive procedure called a lumbar puncture, or spinal tap. Research suggests that Alzheimer's disease in early stages may cause changes in CSF levels of tau and beta-amyloid, two proteins that form abnormal brain deposits strongly linked to the disease.
One challenge researchers face is that analysis of protein levels in the same sample often varies significantly from institution to institution. Achieving consistent measurement is a barrier that has been overcome in other medical conditions by using a standard procedure protocol and comparing results from the same sample at multiple sites designated as reference laboratories. To facilitate consistency in analyzing Alzheimer-related CSF proteins, the Alzheimer's Association has funded the Alzheimer's Association QC Program for CSF Biomarkers. Organizations can compare their sample analysis outcomes to results at reference laboratories in the United States and Europe.
Catalyst to progress
To facilitate cross-institutional consistency in analyzing Alzheimer-related spinal fluid proteins, the Alzheimer's Association has funded the Alzheimer's Association QC Program for CSF Biomarkers. Organizations can compare their sample analysis outcomes to results at reference laboratories in the United States and Europe. Learn more about our commitment to research.
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Proteins in blood or other parts of the body
Researchers are also investigating whether presymptomatic Alzheimer's disease causes consistent, measurable changes in urine or blood levels of tau, beta-amyloid or other biomarkers. In addition, scientists are exploring whether early Alzheimer's leads to detectable changes elsewhere in the body. For example, Lee Goldstein, MD, PhD, has been funded by the Alzheimer's Association to investigate whether beta-amyloid forms characteristic deposits in the lens of the eye.
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Genetic risk profiling
Scientists have identified three genes with rare variations that cause Alzheimer's and several genes that increase risk but don't guarantee that a person will develop the disease. Investigators worldwide are working to find additional risk genes. As more effective treatments are developed, genetic profiling may become a valuable risk assessment tool for wider use.
Genetic testing for APOE-e4, the strongest risk gene, is included in some clinical trials to identify participants at high risk for the disease. APOE-e4 testing is not currently recommended outside research settings because there are no treatments yet available that can change the course of Alzheimer's.
Catalyst to progress
In 2003, the Alzheimer's Association partnered with the National Institute on Aging (NIA) to publicize and recruit participants for the National Alzheimer's Disease Genetics Study, a landmark initiative launched in 2003 to clarify genes involved in late-onset Alzheimer's by creating a privacy-protected database of blood samples and family information. The National Alzheimer's Disease Genetics Study is still recruiting families with Alzheimer's disease. Learn more about participating.
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Mild cognitive impairment (MCI)
Research has shown that individuals with mild cognitive impairment (MCI) have a significantly increased risk of developing Alzheimer's disease within a few years, compared to people with normal cognitive function; research surrounding MCI offers another potential path to earlier diagnosis.
Individuals with MCI have a problem with memory or another mental function serious enough to be noticeable to themselves and those close to them and to show up on mental status testing. These problems, however, are not severe enough to interfere with daily activities, so the person does not meet current diagnostic criteria for Alzheimer's or another form of dementia.
Although individuals with MCI may go on to develop Alzheimer's disease, this is not always the case. In some people, MCI never gets worse. In others, it eventually gets better.
Investigators are trying to answer the following questions to increase MCI's usefulness as a diagnostic category:
- How should we standardize the definition of MCI?
- What are the best mental status tests to detect the earliest changes in memory and other cognitive areas?
- What biological changes are associated with MCI?
- Which individuals with MCI will progress to Alzheimer's disease or another dementia?
Individuals with MCI are among the participants currently enrolled in ADNI, and their participation will help bring researchers closer to answers for these questions.
The Alzheimer's Disease Neuroimaging Initiative, already mentioned in the section on Brain imaging, was extended in both 2009 and 2010 by the ADNI-GO and ADNI-2 initiatives. ADNI-GO is complete, but ADNI-2 is ongoing and recruiting participants. As with the original ADNI study, ADNI-2 seeks to understand how MCI and Alzheimer's disease progress. A primary goal is to determine how symptoms and biomarkers of MCI and Alzheimer's disease change during disease progression, and how the various symptoms and biomarkers are related. Another goal is to develop standards for brain imaging and biomarker tests.
The Alzheimer's Association is also a major sponsor of World Wide ADNI (WW-ADNI), an effort to unite scientists from the North American ADNI projects with those involved in other ADNI projects around the world including Europe, Japan, Australia, Taiwan, Korea, China, and Argentina. It is anticipated that this collaborative effort will accelerate the pace of progress and strengthen the scientific findings by including more diverse participants.
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