Blood Based Markers

Resources

The BBM Workgroup has created a set of educational materials to help you better understand the Alzheimer’s disease diagnostic landscape and the value and implications of BBMs.

Select a topic along the roadmap to learn more:

Clinical Suspicion of Alzheimer’s Disease (AD)

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  • 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 include

    • Consistent and progressive forgetfulness

    • Other cognitive changes that represents a clear decline from past function

  • AD biomarkers reflect AD pathology

    • A biomarker is a measure of biological processes
      Biomarker is short for biological marker

    • Biomarkers can detect:

      • Normal or pathological processes

      • Responses to pharmacological intervention

    • AD biomarkers measure aspects of AD pathology:
      Certain proteins in the blood & cerebrospinal fluid characterize hallmark pathological processes of AD

  • Biomarker testing may be performed following an initial workup if a clinician suspects a patient has symptoms caused by AD pathology

    1. 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

    2. THEN biomarker testing may be performed to determine whether the patient has AD pathology

Alzheimer’s Disease (AD) Pathology

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    • 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 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

    • 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

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  • DMTs 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

  • PET and CSF impose significant burden on patients and health systems

    • Limitations for PET and CSF testing include capacity constraints (i.e., limited availability of specialized equipment and personnel) and potential financial burden

    • Although lumbar punctures required for CSF testing are generally very well-tolerated, some patients perceive the procedure as invasive or uncomfortable

    • 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

  • High accuracy and well validated BBM tests offer unique advantages over 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

What to Know About Validated BBM Tests

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  • Empower patients to make more informed decisions about BBM testing

    • 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.)

  • 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 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 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

Interpretation of BBM Test Results

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Minimum thresholds for BBMs

Tests eligible for triaging and confirmation should meet the following criteria.

  • Minimum acceptable BBM thresholds in patient care determine how the test should be used

    • Interpretation of BBM test results are 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

  • 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.

  • 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

For use as a confirmatory test, a BBM test should have performance equivalent to CSF tests, which is a sensitivity and specificity of approximately 90% for amyloid PET status.

For use as a triaging test, a BBM test should have a sensitivity of 90% for amyloid PET status with a specificity >75% - 85%. High sensitivity is needed to minimize false-negative results so that most individuals with amyloid pathology are identified, especially because individuals with a negative result are not expected to have a follow-up test (e.g., amyloid PET or CSF test). The minimum acceptable specificity depends on the availability of follow-up testing because a positive result on a triaging test is expected to prompt a follow-up test in most patients. If the capacity to perform amyloid PET and/or CSF tests is limited as in primary care, a triaging test with a higher specificity (e.g., ≥85%) would be necessary or the number of individuals with positive BBM results (both true positive and false positive) may exceed the number of follow-up tests that can be performed. If the capacity at a secondary care center to perform amyloid PET and/or CSF tests is not limited, a triaging test with a lower specificity (e.g., ≥75%) may be acceptable.

Additional Resources: