Biomarkers for diagnosing Alzheimer's disease, and grading its severity according to updated criteria
- Prof. Yehudit Aharon Peretz
- Published in the book EMDA Conference 2025
- No comments
On the clinical stages of Alzheimer's disease and how to diagnose them
Alzheimer's disease is a clinical syndrome that describes a deterioration in cognitive functions and behavior to the point where the patient is no longer able to function normally in daily life, ceases to be independent, and usually requires the help of others. Alzheimer's disease is caused by pathological processes that occur in brain tissue and impair the functional capacity of the nervous systems in the brain. The diagnosis of Alzheimer's disease is based on a combination of medical history, cognitive assessment, brain imaging tests, and laboratory tests of biomarkers.
Updated criteria for diagnosing and staging Alzheimer's disease were published in 2024 by the Alzheimer's Association, led by Prof. Clifford Jack. According to the new criteria, Alzheimer's disease is defined as a biological process that begins with measurable brain changes, even before the appearance of clinical symptoms. The new criteria emphasize the importance of biomarkers in diagnosing and determining the stages of the disease, while combining biological findings with clinical assessment. The disease is not diagnosed by biomarkers alone.
The pathology of Alzheimer's disease is characterized by the deposition of amyloid proteins (in the amyloid cell Aβ-42 in plaques) and phosphorylated tau proteins (phospho-tau, to which a phosphorus molecule has been added) in neurofibrillary tangles. Amyloid proteins also deposit in the walls of blood vessels and may cause infarcts and hemorrhages in cerebral blood vessels. The disease processes are accompanied by an inflammatory response and cause damage to brain tissue, which is manifested by shrinkage - tissue degeneration (atrophy).
Diagnostic biomarkers
Biomarkers in Alzheimer's disease are objectively measurable biochemical, molecular, or physiological indicators that are used to detect the characteristic pathology and assess its severity. The markers are grouped in a model ATN, where A represents the amyloid proteins, T represents the tau proteins, and N represents the neurodegeneration processes.
What do biomarkers enable?
- Early diagnosis, even before cognitive decline and/or behavioral changes become apparent,
- Differentiating between Alzheimer's disease and other diseases that impair cognitive function
- Monitoring the course of the disease
Today's common markers and their measurement
A-markers
They indicate the presence of beta-amyloid plaques, which is a characteristic pathology in Alzheimer's disease. A-markers can be measured using:
- Amyloid PET scan, a scan using a radioactive substance that shows the accumulation of beta-amyloid in the brain.
- A cerebrospinal fluid (CSF) test for amyloid levels in the cell. A low level indicates that the protein is settling in the brain tissue and forming plaques.
T-markers
They indicate the presence of neurofibrillary tangles composed of tau protein in its abnormal form (phosphorylated tau protein). T markers can be measured using:
- PET-Tau test, a scan that demonstrates the accumulation of pathological tau proteins in the brain.
- CSF testing for phospho-tau (p-tau) A high level indicates damage due to tau accumulation.
N-markers
Neurodegeneration markers. These markers measure damage or loss of cells in brain tissue, which occurs in the advanced stages of Alzheimer's disease. Neurodegeneration markers are demonstrated by
- Brain MRI (magnetic resonance imaging). In Alzheimer's disease, loss of tissue volume can be seen in areas responsible for memory (hippocampus) and other areas of the cerebral cortex.
- FDG-PET test. In Alzheimer's disease, a decrease in sugar consumption is evident in areas of the brain affected by the characteristic pathology.
- Tau levels include total tau in spinal fluid. A high level indicates cellular damage.
Measuring biomarkers in blood tests
Recently, it has become possible to measure the biomarkers of Alzheimer's disease (ATN) in blood tests. Testing the reliability and validity of blood tests is still in the research, validation, and measurement stages.
Measuring Alzheimer's disease markers in Israel
Biomarker tests for diagnosing Alzheimer's disease are not included in the health basket.
Location of testing
- Amyloid PETThe test is performed at nuclear medicine institutes in major medical centers.
- Tau-PET: The test is not performed in Israel.
- Spinal fluid tests –CSF To measure the level of amyloid and tau proteinsLumbar puncture tests to obtain spinal fluid are performed by specialist neurologists in hospitals. Protein measurements are performed in specialized laboratories.
- Blood biomarker tests: Performed in dedicated laboratories.
Recommendations for testing to measure biomarkers for Alzheimer's disease
It is recommended that a test be performed to measure markers for Alzheimer's disease only upon the recommendation of a physician who specializes in diseases that cause cognitive decline and dementia and when the possibility of dedicated treatment is being considered.
Grading the stages of Alzheimer's disease according to the updated criteria
The Alzheimer's disease continuum represents the progression of the disease, from brain changes that are not noticeable to the person themselves, to changes and symptoms that impair daily functioning. The length of time a person spends in each stage varies, depending on age, genetics, and other factors.
Clinical Phase 0
The person has been diagnosed as carrying a deterministic gene for Alzheimer's disease (approximately 1-2% of Alzheimer's disease patients carry deterministic genes). These people function normally, cognitively, behaviorally, and functionally as usual. Diagnostic tests for biomarkers for Alzheimer's disease are negative. ( A deterministic gene for Alzheimer's disease is a gene that, if carried, almost certainly leads to the development of the disease).
Clinical Phase 1
At this stage, people do not experience cognitive impairments or changes in behavior, and there are no signs of changes in functional abilities. Tests can detect biomarkers for Alzheimer's disease.
Clinical Phase 2
At this stage, a slight decline in cognitive and/or behavioral functions begins. The decline represents a change from the cognitive-behavioral state of recent years and lasts for at least six months. Functionally, these individuals are completely independent and have little, if any, impact on functioning.
Clinical Phase 3
At this stage, deficiencies are already apparent in performing specific tests for cognitive assessment. The person themselves or a close person notices that a deterioration is occurring compared to the known basic ability. Daily functioning is usually independent, however, due to the cognitive difficulties, functional efficiency and level of performance will decrease and activities, even routine ones, will require more time.
Clinical Phase 4
This is the stage where the severity of cognitive-behavioral impairment is that of dementia and functional impairment is significant, although usually mild. At this stage, most people are able to independently perform basic daily activities such as bathing and dressing, but may need help with activities such as paying bills, cooking, shopping, and managing medications. These people often still drive well, but may sometimes need help to maintain their personal safety, functioning, and social functioning.
Clinical Phase 5
At this stage, the functional impairment is moderate. These people usually need help with daily activities. Sometimes there are problems with memory and language, an increased tendency to confusion, and increasing difficulty performing basic multi-step tasks such as bathing and dressing. These people sometimes suffer from a lack of control over their bowels, sometimes they do not recognize close family members, and sometimes their behavior and personality change, and suspiciousness and/or restlessness and/or delusions appear.
Clinical Phase 6
In clinical stage 6, people suffer from symptoms of dementia and functional impairment is severe. These people are usually dependent on others for basic daily activities, such as dressing, eating, and taking medication. Their ability to communicate socially is often impaired and in most cases they will need constant supervision and care. In severe cases, patients will be unable to walk or eat.
Prof. Yehudit Aharon-Peretz She is the chair of the Scientific Advisory Committee of EMDA Association and a senior physician at the Institute for Stroke and Cognition, Rambam Medical Center.
Previously, Director of the Institute for Cognitive Neurology.