Alzheimer’s Diagnostics 101
Understanding the Diagnostic Journey
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Identifying and Confirming AD
The Diagnostic Journey
Each patient’s diagnostic journey will vary but will typically follow a standard process – comprising various tests, assessments, and analyses.
- Most patients will start with a cognitive assessment – these have traditionally been analog but are increasingly becoming digital.
- Following that assessment, the next step is to determine the underlying cause of their cognitive challenges. For AD, that means leveraging blood tests, CSF analysis, and PET scans to identify specific biomarkers.
Early AD
Early AD includes mild cognitive impairment and mild dementia due to AD pathology
- Mild Cognitive Impairment:
Characterized by cognitive impairment that does not affect function - Mild Dementia:
Characterized by cognitive impairment that causes mild functional impairment - Individuals with early AD dementia may be eligible for amyloid-lowering treatments
AD-Related Symptoms
AD-related symptoms include
- Consistent and progressive forgetfulness
- Other cognitive changes that represents a clear decline from past function
AD Biomarkers
- AD biomarkers reflect AD pathology
- A biomarker is a measure of biological processes
- Hallmark biomarkers of AD include amyloid and tau
- AD biomarkers measure aspects of AD pathology:
- Certain proteins in the blood & cerebrospinal fluid characterize pathological processes of AD
Biomarker Testing
Biomarker testing may be performed following an initial workup (e.g., cognitive testing) if a clinician suspects a patient has symptoms caused by AD pathology
- IF a clinician/healthcare provider suspects a patient has symptoms caused by AD
- Based on a history of functional decline AND
- After a work-up including a cognitive assessment
- THEN biomarker testing may be performed to determine whether the patient has AD pathology
Additional testing is done to rule our reversible causes of cognitive impairment such as sleep or vitamin deficiencies.
Alzheimer’s Disease (AD) Pathology
Plaques, Tangles, Neurodegeneration
- AD pathology includes the deposition of amyloid plaques, tau neurofibrillary tangles, and neurodegeneration
- Individuals being considered for amyloid-lowering treatments must have evidence of elevated amyloid
AD Pathology Accumulation
AD pathology starts to accumulate in the brain years before symptom onset
- AD pathology starts to accumulate 10-20 years before the onset of symptoms and therefore, cognitively normal individuals may have evidence of elevated amyloid
- Some asymptomatic individuals with AD pathology may not develop symptoms and therefore should not be currently referred for BBM testing
Disease-Modifying Treatments
- Current disease-modifying treatments (DMTs) work by lowering amyloid in the brain
- Asymptomatic individuals are not currently eligible for amyloid-lowering treatments
Considerations for Current Testing Modalities
Informed Decision-Making
Empower patients to make more informed decisions about their testing options
- Engage the patient and their caregiver/care partner in discussion about the recommended plan in light of the advantages and disadvantages
- Explain the likely alternative outcomes and implications (e.g., what would a positive result mean for their care)
- Review test results with the patient and their support system
- Consider other needs that should be taken into account and can impact decisions about BBM testing and DMT eligibility (e.g., APOE genotype, cardiovascular risk factors, anticoagulant use, etc.)
Accuracy of Diagnostic Test
Sensitivity and specificity are indicators used to describe the accuracy of a diagnostic test
- Sensitivity: How often does the test correctly identify patients who have AD pathology?
- Specificity: How often does the test correctly identity patients who do not have AD pathology?
Predictive Values
Predictive values indicate the likelihood that AD pathology is present or absent for a patient (i.e., positive results are actually positive)
Positive and negative predictive values are used to describe the performance of a diagnostic test in a clinical context
- PPV is the likelihood that a patient with a positive test has AD pathology
- A high PPV “rules in” (i.e., confirms) the presence of AD pathology
- NVP is the likelihood that a patient with a negative test does not have AD pathology
- A high NPV “rules out” (i.e., excludes) the presence of AD pathology
Predictive Values & Prevalence
Predictive values change in relation to the prevalence of Alzheimer’s disease in the test population
Both NPV and PPV are dependent on the prevalence of Alzheimer’s disease in a given population:
- Different populations (i.e., AD clinics, nursing homes, or the general population) have varying likelihoods of AD pathology
- AD prevalence varies according to factors including age, race / ethnicity, family history, APOE genotype, cognitive impairment, and the general nature of cognitive symptoms
- In clinics where there is a high likelihood of people with AD pathology, predictive value of BBM testing is higher
- Generally, as the prevalence of AD pathology decreases, a given diagnostic test’s ability to predict a patient’s likelihood of having AD pathology also decreases
AD Pathology Confirmation
Disease Modifying Therapies will only be available to patients with clinical confirmation of AD pathology
- Elevated amyloid can be detected via PET imaging, cerebrospinal fluid (CSF) analyses, or blood-based biomarkers (BBMs)
- High accuracy BBMs could replace PET/CSF testing for many patients
DCA Tools
The Cognitive Assessment Landscape
Cognitive assessments are essential screening tools for cognitive impairment and Alzheimer’s disease.
Current types of assessments include:
- Brief screening tools: Used in primary care for quick identification of cognitive deficits
- Includes the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Mini-Cog
- Domain-specific tests: Used in neurology to assess specific cognitive domains
- Includes the Rey Auditory Verbal Learning Test (RAVLT), Trail Making Test (TMT), Boston Naming Test (BNT), and Digit Span / Letter-Number Sequencing
- Composite and global scales: Used in research to detect changes over time
- Includes the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog), Preclinical Alzheimer Cognitive Composite (PACC), and Clinical Dementia Rating (CDR)
Digital Cognitive Assessments (DCAs) expand on this landscape to improve scalability, efficacy, and efficiency of testing. DCAs can include digital versions of current cognitive assessments or novel testing platforms.
Benefits of DCAs
Digital Cognitive Assessments (DCAs) can enhance cognitive testing and support early, accurate diagnosis for Alzheimer’s disease.
- DCAs detect signs of cognitive impairment, characterize the level of cognitive impairment, and help develop a cognitive profile.
- DCAs have the potential to reduce variability, improve accessibility and provide more insights into cognitive condition compared to analog assessments.
An Integrated Approach to Cognitive Assessments
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Integrating DCAs into clinical practice delivers key benefits for clinicians
- Improve detection of cognitive impairment
- Address causes and risk factors
- Develop treatment plans that support patient needs
BBM Tests
BBM Test Considerations
BBMs can be used either to triage patients (i.e., help determine who is best suited for follow on testing) or as a confirmatory tool for identifying AD pathology.
High accuracy and well validated BBM tests offer unique advantages over testing modalities like PET and CSF.
BBMs may address capacity constraints, financial burden, and existing bottlenecks to diagnosis / care for AD patients:
- Largely viewed as less invasive, safe, and acceptable by most patients
- Can be ordered by primary care providers (PCPs) and blood can be collected by clinical staff without highly specialized training, making BBMs more accessible versus PET / CSF
- Facilitate more timely diagnosis of AD and can rapidly scale to enable broader access to treatment
BBMs as a Triaging Tool
As a triaging tool, BBM tests with a high NPV and moderate PPV may be sufficient to “rule out” AD pathology
Triaging using a BBM test with high NPV and moderate PPV
- Negative test results can be used to definitively rule out AD pathology and patient should undergo further evaluation for other causes of their cognitive symptoms
- A positive result should be treated with caution and is not necessarily evidence that the patient has AD pathology. Clinicians must clearly communicate implications of potential outcomes to patients prior to undergoing testing. In this circumstance, further evaluation will be needed to make a definitive diagnosis.
BBMs as a Confirmatory Tool
As a confirmatory tool, BBM tests with high NPV and high PPV may be sufficient to confirm AD pathology
Confirmation using a BBM test with high NPV and high PPV:
- A positive test indicates a higher risk for having amyloid plaques in patients with higher suspicion of AD pathology but may not provide a definitive diagnosis of AD pathology:
- If higher suspicion of AD pathology and blood test is positive, patient is likely to have AD pathology; further evaluation is required
- If lower suspicion of AD pathology and blood test is positive, further evaluation is required
- A negative test is likely to rule out AD pathology in patients with lower AD pathology suspicion but may not provide a definitive diagnosis of AD pathology:
- If higher suspicion of AD pathology and blood test is positive, patient is likely to have AD pathology; further evaluation is required
- If lower suspicion of AD pathology and blood test is negative the patient is unlikely to have AD pathology; further evaluation is required
Minimum Thresholds for BBMs
Minimum acceptable BBM thresholds in patient care determine how the test should be used
- Interpretation of BBM test results is dependent on the accuracy of each individual test (i.e., triage vs. confirmation)
- Tests with a high PPV that have been validated in real world clinical settings may be an acceptable diagnostic tool for confirming AD pathology
- Interpretation of BBM test results for these high accuracy tests will vary depending on the pre-test likelihood (e.g., age, family history, etc.) of a patient having AD pathology
CSF Analysis
CSF Considerations
CSF tests are a reliable and widely adopted method for early Alzheimer’s detection that come with some notable limitations
- CSF tests require a lumbar puncture. While this process is generally well-tolerated, some patients perceive the procedure as invasive or uncomfortable.
- Patients may be subject to long wait times for the procedure.
Interpreting CSF Results
CSF testing collects a small sample of the fluid that surrounds the brain and spinal cord through a lumbar puncture or spinal tap.
- This fluid can be tested for specific proteins—like amyloid and tau—that are linked to Alzheimer’s disease.
- In people with Alzheimer’s, the levels of these proteins in the CSF are often abnormal.
- By measuring these changes, doctors can get important clues about whether someone’s symptoms are likely caused by Alzheimer’s.
In the U.S., CSF testing is covered by Medicare and many insurance plans when it is considered medically necessary. Like PET scans, CSF tests are often used alongside other evaluations to help doctors make a confident and informed diagnosis.
PET Scans
PET Considerations
Amyloid PET scans are the current gold standard in diagnosing Alzheimer’s Disease, but they are not immune from barriers that can impose significant burden on patients and health systems
- PET scans provide direct visual evidence of amyloid plaque on the brain and are a non-invasive diagnostic method
- Limitations for PET include capacity constraints (i.e., limited availability of specialized equipment and personnel) and potential financial burden
- Patients referred to secondary care for confirmatory biomarker testing and infusion treatment have limited access to specialists and face long wait times that contribute to delays in timely diagnosis
Interpreting PET Scans
There are two types of Positron Emission Tomography (PET) scans approved by the FDA to show how the brain is functioning.
- An amyloid-PET scan measures buildup of abnormal amyloid protein in the brain, one of the hallmarks of Alzheimer’s disease.
- A fluorodeoxyglucose (FDG) PET scan measures the concertation of glucose in the brain, showing how the brain is using energy.
- By visualizing these protein deposits and activity changes in the brain, PET scans provide a direct window into Alzheimer’s disease processes.
- PET scans are usually combined with other tools, like memory tests and physical exams, to get the full picture.
Brain Imaging Resources
The Society of Nuclear Medicine & Molecular Imaging (SNMMI) compiled a comprehensive library of Patient Resources and Professional Resources. Review their educational offerings and research articles here.
In the US, Medicare and many private insurance plans now cover PET scans for Alzheimer’s diagnosis.