What if we could diagnose Alzheimer's disease before symptoms started? The hope is, future treatments could then target the disease in its earliest stages, before irreversible brain damage or mental decline has occurred. Research on new strategies for earlier diagnosis is among the most active areas in Alzheimer's science, and funding from the Alzheimer's Association has spurred significant advances and steady progress.
Biomarkers for earlier detection
Current diagnosis of Alzheimer's disease relies largely on documenting mental decline, at which point, Alzheimer's has already caused severe brain damage. 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, such as 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 (CSF) 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.
There are currently no validated biomarkers for Alzheimer's disease, but researchers are investigating several promising candidates, including brain imaging, proteins in CSF, blood and urine tests, and genetic risk profiling.
Neuroimaging is among the most promising areas of research focused on early detection of Alzheimer's 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).
Having shown that the brains of people with Alzheimer's shrink significantly as the disease progresses, structural imaging research also has 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.
Today, a standard workup for Alzheimer's disease often includes structural imaging, and these tests are currently used 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.
Functional imaging research 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 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.
These 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 been approved for clinical use:
- Florbetaben (Neuraceq®), Florbetapir (Amyvid®) and Flutemetamol (Vizamyl®) have been approved for detection of beta-amyloid in the brain.
- Flortaucipir F18 (Tauvid®) has been approved for detection of tau in the brain.
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. Because amyloid plaques cannot be used to diagnose Alzheimer's, amyloid imaging is not recommended for routine use in patients suspected of having the disease.
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 Alzheimer's.
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.
Blood and urine tests
Researchers are also investigating whether Alzheimer's disease causes consistent, measurable changes in urine or blood levels of tau, beta-amyloid or other biomarkers before symptoms appear. In addition, scientists are exploring whether early Alzheimer's leads to detectable changes elsewhere in the body, such as the lens of the eye.
Genetic risk profiling
23 Chromosome Pairs; 4 Alzheimer's Genes Identified:
Amyloid precursor protein (APP),
discovered in 1987, is the first gene with mutations found to cause an inherited form of Alzheimer's.
identified in 1992, is the second gene with mutations found to cause inherited Alzheimer's. Variations in this gene are the most common cause of inherited Alzheimer's.
discovered 1993, is the third gene with mutations found to cause inherited Alzheimer's.
Apolipoprotein E-e4 (APOE4),
discovered in 1993, is the first gene variation found to increase risk of Alzheimer's and remains the risk gene with the greatest known impact. Having this mutation, however, does not mean that a person will develop the disease.
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. Learn more about genetics and Alzheimer's disease.
Mild cognitive impairment (MCI)
Mild cognitive impairment (MCI) is an early stage of memory loss or other cognitive ability loss (such as language or visual/spatial perception) in individuals who maintain the ability to independently perform most activities of daily living.
MCI causes cognitive changes that are serious enough to be noticed by the person affected and by family members and friends but do not affect the individual’s ability to carry out everyday activities. Approximately 12-18% of people age 60 or older are living with MCI.
MCI can develop for multiple reasons, and individuals living with MCI may go on to develop dementia; others will not. For neurodegenerative diseases, MCI can be an early stage of the disease continuum including for Alzheimer's if the hallmark changes in the brain are present.
In June 2021, aducanumab (Aduhelm™) received accelerated approval as a treatment for Alzheimer’s disease from the U.S. Food and Drug Administration (FDA). Treatment with aducanumab should be initiated in patients with MCI or mild dementia stage of disease, the population in which treatment was initiated in clinical trials.
Aducanumab was studied in people living with early Alzheimer’s disease and MCI due to Alzheimer’s who showed evidence of a buildup of amyloid plaques in the brain. There is no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied.