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 meet the criteria for mental decline.
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. Biomarkers are reliable predictors and indicators of a disease process. Biomarkers include proteins in blood or spinal fluid, genetic variations (mutations) or brain changes detectable by imaging. Sign up for our weekly e-news and stay up-to-date on the latest advances in Alzheimer's diagnosis, treatments, care and research.
Biomarkers must be "validated" — their value as predictors and indicators must be confirmed by multiple studies in large groups of people. For example, high cholesterol is a validated biomarker for coronary heart disease. It is now accepted medical practice to monitor cholesterol and consider heart-healthy lifestyle changes or medications when blood levels exceed 200 mg/dL, before a person develops active symptoms of heart disease.
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.
Preliminary research suggests that emerging imaging technologies and new applications of current technology may be able to detect hallmark changes associated with Alzheimer's disease in the brains of living individuals. If further research confirms the potential value of brain imaging, its use may one day be expanded to play a more direct role in diagnosing Alzheimer's and in earlier detection of the disease.
|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. Molecular imaging compounds currently used in Alzheimer research include:
- 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 Association in 2006 also awarded a $2.1 million grant to the Alzheimer's Disease Neuroimaging Initiative (ADNI) to expand this long-term, nationwide study to include PIB-PET imaging.
- 18F flutemetamol (flute), another radiotracer that highlights beta-amyloid in a PET scan, is structurally identical to PIB except for one fluorine atom in place of a carbon atom. That small chemical change enables flutemetamol to remain stable significantly longer than does PIB, potentially increasing its usefulness outside research settings. In phase II study results reported in the Annals of Neurology, flutemetamol performed similarly to PIB. Additional testing is under way.
- Florbetapir F 18 (18F-AV-45) is also a radiotracer that highlights brain beta-amyloid during a PET scan. At the 2010 Alzheimer's Association International Conference on Alzheimer's Disease (AAICAD), florbetapir's developer first reported data, later published in the JAMA, showing nearly perfect correlation between brain amyloid levels detected by florbetapir PET scans in study volunteers and levels found in autopsies of the same individuals a few months later. The developer has sought Food and Drug Administration (FDA) approval to market florbetapir under the brand name Amyvid. The FDA has said it will withhold approval until the developer establishes a professional training program to ensure accuracy and consistency in reading and interpreting Amyvid scans.
- Florbetaben (BAY 94-9172) is another radiotracer designed to detect beta-amyloid during a PET scan. Phase II study results and other florbetaben data were reported at the 2010 Alzheimer's Association International Conference on Alzheimer's Disease (AAICAD). Phase II data were also later published in Lancet Neurology. Further studies are now under way.
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 its earliest 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. Organizations interested in participating may contact the QC Programme Coordinator at firstname.lastname@example.org or Henrik Zetterberg at email@example.com.
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; 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 guidelines for Alzheimer's.
While individuals with MCI often 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. A recent two-year ADNI extension funded by a Grand Opportunities (GO) grant awarded under the 2009 American Recovery and Reinvestment Act allows an additional 200 individuals with very early MCI (eMCI) to enroll. ADNI-GO participants will undergo lumbar puncture and amyloid PET imaging with Florbetapir F 18 (18F-AV-45).
In 2010, the National Institutes of Health (NIH) announced five further years of ADNI funding under ADNI-2, adding even greater statistical power to ADNI-1 and ADNI-GO. ADNI-2 aims to recruit 550 new volunteers — 150 with no memory problems, 100 with eMCI, 150 with MCI and 150 with mild Alzheimer's disease. ADNI-2 also will continue long-term follow-up of some volunteers previously enrolled in ADNI-1 or ADNI-GO. In addition to other procedures and assessments, all ADNI-2 study participants will undergo brain beta-amyloid imaging.
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