Medical Policy

Policy Num:      11.001.032
Policy Name:    Evaluation of Biomarkers for Alzheimer Disease
Policy ID:          [11.001.032]  [Ac / B / M + / P-]  [2.04.14]

Last Review:     December 10, 2024
Next Review:     November 20, 2025

BCBS Related Policies:

11.003.040 -Genetic Testing for Alzheimer Disease
06.001.053 Selected Positron Emission Tomography Technologies for Alzheimer Disease

            Evaluation of Biomarkers for Alzheimer Disease

Summary

Description

Biochemical changes associated with the pathophysiology of Alzheimer disease (AD) are being evaluated to aid in the diagnosis of AD. This includes the potential use of biomarkers, such as amyloid beta peptide 1-42 and total or phosphorylated tau protein, in cerebrospinal fluid (CSF) and urine. Additionally, the potential correlation between CSF biomarkers and positron emission tomography (PET) amyloid scans may assist in selecting appropriate patients for the initiation or discontinuation of amyloid beta plaque targeted therapy.

Summary of Evidence

For individuals who have mild cognitive impairment (MCI) or AD who receive CSF biomarker testing for AD, the evidence includes systematic reviews. These studies assess using CSF biomarkers for diagnosis of AD or for the prognosis of progression of MCI to AD. Relevant outcomes include test validity, correct treatment, avoiding unnecessary subsequent testing, harms of invasive testing, and quality of life (QOL). Most clinical validity studies have been derived from select patient samples and defined optimal test cutoffs without validation; thus, the generalizability of results is uncertain. For predicting conversion from MCI to AD, limited evidence has suggested that testing may define increased risk. Whether an earlier diagnosis leads to improved health outcomes through a delay of AD onset due to medical therapy or other interventions or improved QOL is unknown. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have MCI or AD who receive urinary biomarker testing for AD, the evidence includes a systematic review. Relevant outcomes include test validity, correct treatment, avoiding unnecessary subsequent testing, harms of invasive testing, and QOL. Clinical validity studies have included normal healthy controls and defined optimal test cutoffs without validation; thus, clinical validity is uncertain. Whether an earlier diagnosis leads to improved health outcomes through a delay of AD onset or improved QOL is unknown. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have MCI or AD who receive blood biomarker testing for AD, the evidence includes a systematic review and cohort studies. Relevant outcomes include test validity, correct treatment, avoiding unnecessary subsequent testing, harms of invasive testing, and QOL. Clinical validity studies have primarily focused on the biomarker, plasma pTau, and have shown that this biomarker may be beneficial in screening for and diagnosing AD. Whether an earlier diagnosis leads to improved health outcomes through a delay of AD onset or improved QOL is unknown. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have MCI or mild dementia due to AD who are being considered for initial treatment with an approved amyloid beta plaque targeting therapy, the evidence includes multisite longitudinal studies and an analysis of a mixed cohort. Two of these studies assess the correlation between CSF biomarkers and PET amyloid scans and another assesses the clinical utility of amyloid PET in cognitively impaired patients who met appropriate use criteria for clinical amyloid PET. Relevant outcomes include test validity, symptoms, change in disease status, functional outcomes, health status measures, and QOL. Overall, the diagnostic accuracy of CSF biomarkers versus amyloid PET scans to identify MCI-AD was found to be similar but there are no data to support the clinical utility of CSF biomarker use as a component of determining appropriate initiation of amyloid beta targeting therapy. Prior to the availability of amyloid beta targeting therapy, additional data exist suggesting that amyloid beta PET scan results impacted diagnosis of dementias and patient management including use of symptomatic treatment. Further research is required to determine whether use of CSF biomarkers alone or in conjunction with amyloid PET scans is associated with improved clinical outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have MCI or mild dementia due to AD, who are being treated with an amyloid beta plaque targeting therapy and are being evaluated for therapy continuation, the evidence includes multisite longitudinal studies and an analysis of a mixed cohort. Two of these studies assess the correlation between CSF biomarkers and PET amyloid scans and another assesses the clinical utility of amyloid PET in cognitively impaired patients who met appropriate use criteria for clinical amyloid PET. Relevant outcomes include test validity, symptoms, change in disease status, functional outcomes, health status measures, and QOL. The diagnostic accuracy of CSF biomarkers versus amyloid beta PET scans to identify MCI-AD was found to be similar. Prior to the availability of amyloid beta targeting therapy, additional data exist suggesting that amyloid beta PET scan results impacted diagnosis of dementias and patient management including use of symptomatic treatment. Further research is required to determine whether use of CSF biomarkers alone or in conjunction with amyloid beta PET scans are useful for determining whether or not amyloid beta targeting therapy should be continued. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

2024 Input

Clinical input was sought to help determine whether the use of cerebrospinal fluid biomarker testing for individuals who are being considered for an approved amyloid beta plaque targeting therapy would provide a clinically meaningful improvement in net health outcome. In response to requests, clinical input was received from 3 respondents; 1 physician-level response identified through a specialty society; 2 physician-level responses (joint response) identified through an academic medical center.

For individuals who have early AD who receive amyloid-beta targeting therapy, clinical input supports this use provides a clinically meaningful improvement in net health outcome with the criteria described.

Further details from clinical input are included in the Appendix.

Objective

The objective of this evidence review is to examine whether testing cerebrospinal fluid (CSF), urinary, and blood biomarkers improves the net health outcome in individuals with mild cognitive impairment or Alzheimer disease, with an additional focus on the correlation between CSF biomarkers and positron emission tomography (PET) amyloid scans in selecting patients for, and maintaining patients on, amyloid beta plaque targeted therapy.

POLICY statements

Cerebrospinal fluid biomarker testing, including but not limited to amyloid beta peptides, tau protein, or neural thread proteins, as an adjunct to clinical diagnosis in individuals with mild cognitive impairment is considered investigational.

Cerebrospinal fluid biomarker testing, including but not limited to amyloid beta peptides, tau protein, or neural thread proteins, as an adjunct to clinical diagnosis in individuals with mild dementia due to Alzheimer disease is considered investigational.

Cerebrospinal fluid biomarker testing of amyloid beta peptides and tau protein as part of an evaluation for the initiation of amyloid beta targeting therapy in individuals with mild cognitive impairment or mild dementia due to Alzheimer disease is considered medically necessary (see Policy Guidelines).

Cerebrospinal fluid biomarker testing of neural thread proteins as part of an evaluation for the initiation of amyloid beta targeting therapy in individuals with mild cognitive impairment or mild dementia due to Alzheimer disease is considered investigational.

Cerebrospinal fluid biomarker testing, including but not limited to amyloid beta peptides, tau protein, or neural thread proteins, as part of an evaluation for the continuation of amyloid beta targeting therapy in individuals with mild cognitive impairment or mild dementia due to Alzheimer disease is considered investigational.

Measurement of urinary and blood biomarkers as an adjunct to clinical diagnosis in individuals with mild cognitive impairment or mild dementia due to Alzheimer disease is considered investigational.

policy guidelines

The labels for FDA-approved, amyloid beta targeting therapies, LEQEMBI® (lecanemab) and Kisunla^TM (donanemab) state that the presence of amyloid beta pathology should be confirmed prior to initiating treatment. In the pivotal randomized controlled trial for lecanemab (Clarity AD), the protocol states that the eligibility criteria related to amyloid beta pathology required "confirmed amyloid pathology indicated by either 1) positive amyloid load confirmed by amyloid PET assessment, or 2) CSF assessment of t-tau / Aβ[1-42].'" \

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues :None.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage. 

Background

Alzheimer Disease

Alzheimer Disease (AD) is a fatal neurodegenerative disease that causes progressive loss in memory, language, and thinking, with the eventual loss of ability to perform social and functional activities in daily life. Survival after a diagnosis of dementia due to AD generally ranges between 4 and 8 years; however, life expectancy can be influenced by other factors, such as comorbid medical conditions. It is estimated that 6.2 million Americans aged 65 and older are currently living with AD dementia, and the number is projected to reach over 12 million by 2050.^1, Per the 2018 American Academy of Neurology practice guideline update on mild cognitive impairment (MCI), the prevalence of MCI was 6.7% for ages 60 to 64, 8.4% for ages 65 to 69, 10.1% for ages 70 to 74, 14.8% for ages 75 to 79, and 25.2% for ages 80 to 84.^2, The cumulative dementia incidence was 14.9% in individuals with MCI >65 years of age followed for 2 years.

Data from the National Institute on Aging have shown that Black Americans are approximately 1.5 to 2 times more likely to develop AD and related dementias as compared to Whites.^3, Additionally, Black participants in AD research studies were 35% less likely to be diagnosed with AD and related dementias and were found to have more risk factors for the disease as well as greater cognitive impairment and symptom severity than White participants. Findings from 2 national surveys conducted by the Alzheimer's Association also found that people of color face discrimination when seeking health care for AD and related dementias with the highest level of discrimination in dementia health care reported by Black Americans (50%) followed by Native (42%), Asian (34%), and Hispanic (33%) Americans.^4, Non-Hispanic White Americans reported a discrimination rate of 9%.

Pathophysiology

The pathologic hallmarks of AD are extracellular deposits of amyloid beta, referred to as amyloid plaques, and intracellular aggregates of hyperphosphorylated tau in the form of neurofibrillary tangles. There are different forms of amyloid such as plaques, oligomers, and monomers, and the roles of these different forms and their contributions to the pathophysiology of AD is not well understood. Generally referred to as the “amyloid hypothesis”, it is believed that aggregation of amyloid beta oligomers in the brain leads to amyloid plaques. Amyloid aggregation in addition to accumulation of tau pathology and neurodegeneration are thought to be the main drivers of the disease process. These changes in the brain result in widespread neurodegeneration and cell death, and ultimately cause the clinical signs and symptoms of dementia.^5,6,

The pathophysiological changes and clinical manifestations of AD are progressive and occur along a continuum, and accumulation of amyloid beta may begin 20 years or more before symptoms arise.^7, The National Institute on Aging-Alzheimer’s Association (NIA-AA) has created a “numeric clinical staging scheme” (Table 1) that avoids traditional syndromal labels and is applicable for only those in the Alzheimer continuum. This staging scheme is primarily used in the research setting and reflects the sequential evolution of AD from an initial stage characterized by the appearance of abnormal AD biomarkers in asymptomatic individuals. As biomarker abnormalities progress, the earliest subtle symptoms become detectable. Further progression of biomarker abnormalities is accompanied by progressive worsening of cognitive symptoms, culminating in dementia.

Table 1. National Institute on Aging-Alzheimer’s Association Numerical Clinical Staging for Individuals in the Alzheimer Continuum^a

      Adapted from Table 6, Jack et al (2018)8,

      aApplicable only to individuals in the Alzheimer continuum that fall into 1 of the 4 biomarker groups: 1) A+T+N+ 2) A+T-N- 3) A+T+N- 4) A+T-N+ where A: Aggregated Aβ or associated pathologic state (CSF Aβ42, or Aβ42/Aβ40 ratio or Amyloid PET), T: Aggregated tau (neurofibrillary tangles) or associated pathologic state (CSF phosphorylated tau or Tau PET) and N: Neurodegeneration or neuronal injury (anatomic MRI, FDG PET or CSF total tau) For stages 1 to 6: Cognitive test performance may be compared to normative data of the investigator's choice, with or without adjustment (choice of the investigators) for age, sex, education, etc.  For stages 2 to 6: Although cognition is the core feature, neurobehavioral changes—for example, changes in mood, anxiety, or motivation—may coexist.  For stages 3 to 6: Cognitive impairment may be characterized by presentations that are not primarily amnestic. CSF: cerebrospinal fluid; FDG: fluorodeoxyglucose; MCI: mild cognitive impairment; MRI: magnetic resonance imaging; PET: positron emission tomography. 

Biomarkers

Several potential biomarkers of AD are associated with AD pathophysiology (eg, amyloid beta plaques, neurofibrillary tangles). Altered cerebrospinal fluid (CSF) levels of specific proteins have been found in patients with AD. These include tau protein, phosphorylated at AD-specific epitopes such as phosphorylated threonine 181 or total tau protein, an amyloid beta peptide such as 1-42 (Aβ42), and the synaptic protein, neurogranin.^9, Other potential CSF^10,11,, urinary, and blood^12, peptide markers have been explored. Tau protein is a microtubule-associated molecule found in neurofibrillary tangles that are typical of AD. Tau protein is thought to be related to degenerating and dying neurons and high levels of tau protein in the CSF have been associated with AD. Amyloid beta-42 is a subtype of amyloid beta peptide produced from the metabolism of the amyloid precursor protein. Amyloid beta-42 is the key peptide deposited in amyloid plaques characteristic of AD. Low levels of amyloid beta-42 in the CSF have been associated with AD, perhaps because amyloid beta-42 is deposited in amyloid plaques instead of remaining in the fluid. Investigators have suggested the tau/amyloid beta-42 ratio may be a more accurate diagnostic marker than either alone.^13, Neurogranin is a dendritic protein and CSF measurement may serve as a biomarker for dendritic instability and synaptic degeneration.^9, Elevated CSF neurogranin may predict prodromal AD in MCI and has been confirmed in AD dementia and prodromal AD in several studies.

A variety of kits are commercially available to measure amyloid beta-42 and tau proteins. Between-laboratory variability in CSF biomarker measurement is large.^14,15, Neural thread protein is associated with neurofibrillary tangles of AD. Both CSF and urine levels of this protein have been investigated as a potential marker of AD. Urine and CSF tests for neural thread protein may be referred to as the AD7C test.

More recently, research has focused on blood as a new matrix for AD biomarkers that have already been validated in the CSF. As blood is more accessible than CSF, blood sampling would be preferable to CSF when taking samples to measure AD biomarkers, both for clinical diagnosis or screening.^9, However, developing blood AD biomarkers has proven complex. While the CSF is continuous with the brain extracellular fluid, with a free exchange of molecules from the brain to the CSF, only a fraction of brain proteins enter the bloodstream. Examples of blood biomarkers that are currently under examination for use in AD include amyloid beta, tau protein, and neurofilament light.^16, Results from initial studies show that these blood biomarkers may potentially assist in early and more precise diagnosis, prognosis, or monitoring of disease progression and treatment in AD. In 2019, the Geneva AD Biomarker Roadmap Initiative expert panel concluded that of the currently assessed blood biomarkers plasma pTau has shown analytical validity and initial evidence of clinical validity, whereas the maturity level for amyloid beta remains to be partially achieved.^17,

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer laboratory-developed tests (LDTs) must be certified by CLIA for high-complexity testing. To date, the FDA has chosen not to require any regulatory review of these tests. Several AD biomarker tests are available as LDTs.

The FDA has cleared AD biomarker tests for marketing via the De Novo and 510(k) pathways with product code QSE, see Table 2.

Table 2. FDA Cleared Biomarker Tests for Alzheimer Disease

      AD: Alzheimer disease; CSF: cerebral spinal fluid; FDA: Food and Drug Administration; PET: positron emission tomography.

RATIONALE

This evidence review was created in July 1999 and has been regularly updated with searches of the PubMed database. The most recent literature update was performed through May 15, 2024.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

Cerebrospinal Fluid, Urinary, or Blood Biomarker Testing for Alzheimer Disease

Clinical Context and Test Purpose

The purpose of cerebrospinal fluid (CSF), urinary, or blood biomarker testing for Alzheimer disease (AD) is to provide an alternative or superior method for diagnosis to inform a decision to proceed with appropriate treatment in patients with AD or mild cognitive impairment (MCI).

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with MCI or AD.

Interventions

The tests being considered are CSF, urinary, or blood biomarker testing for MCI or AD.

Comparators

Comparators of interest include a clinical diagnosis of AD.

A definitive diagnosis of AD requires histopathologic examination. Both the Diagnostic and Statistical Manual of Mental Disorders (DSM) and National Institute on Aging-Alzheimer’s Association (NIA-AA) have proposed criteria for diagnosis of probable AD.^18,19,20,

NIA-AA criteria for the diagnosis of probable AD requires the presence of dementia and the following:^19,20,

• Interference with ability to function at work or usual activities;

• Decline from previous level of functioning and performing;

• Not explained by delirium or major psychiatric disorder;

• Cognitive impairment established by history from the patient and informant and objective mental status examination or neuropsychologic testing;

• Cognitive impairment involving at least 2 of the following:

  • Impaired ability to acquire and remember new information;

  • Impaired reasoning and handing of complex tasks, poor judgment;

  • Impaired visuospatial abilities;

  • Impaired language functions;

  • Changes in personality, behavior, or comportment.

• Insidious onset;

• History of worsening;

• Most prominent cognitive deficits are: amnestic, nonamnestic with a language presentation; visuospatial; or dysexecutive;

• No evidence of another concurrent, active neurologic or non-neurologic disease or use of medication that could have a substantial effect on cognition.

The most common disorders considered in the differential diagnosis of AD are vascular dementia and other neurodegenerative dementias such as dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD).

Outcomes

The general outcomes of interest are test validity, correct treatment, avoiding unnecessary subsequent testing, harms of invasive testing, and quality of life (QOL) for testing to diagnose AD. For testing to predict progression of MCI, the outcomes of interest are correct treatment, avoiding unnecessary subsequent testing, harms of invasive testing, and QOL.

Follow-up is at months to years for CSF, urinary, or blood biomarker testing for the outcomes of interest.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• The study population represents the population of interest. Eligibility and selection are described;

• The test is compared with a credible reference standard;

• If the test is intended to replace or be an adjunct to an existing test; it should also be compared with that test;

• Studies should report sensitivity, specificity, and predictive values. Studies that completely report true- and false-positive results are ideal. Studies reporting other measures (eg, receiver operating characteristic, area under receiver operating characteristic, c-statistic, likelihood ratios) may be included but are less informative;

• Studies should also report reclassification of the diagnostic or risk category.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

Cerebrospinal Fluid Biomarker Testing

Diagnosis of Alzheimer Disease

Systematic Reviews

Most studies have relied on clinically diagnosed AD as the criterion standard. Results from the majority of systematic reviews are summarized in Table 2. Studies included in these systematic reviews are not individually reviewed.

Table 3. Systematic Reviews Assessing CSF Biomarkers Performance for Distinguishing Alzheimer Disease From Controls With Clinical Diagnosis as the Reference Standard

      Values in parentheses are 95% confidence intervals. Aβ42: amyloid-β peptide 1-42; CSF: cerebrospinal fluid; NR: not reported; pTau: phosphorylated tau protein; tTau: total tau protein. a Or unspecified.

Fink et al (2020) conducted a systematic review of biomarker accuracy for diagnosing neuropathologically defined AD in older patients with dementia.^22, The analysis included literature published between January 2012 and November 2019, with 9 cohort studies focusing on CSF biomarkers. Overall, CSF biomarkers and ratios had moderate sensitivity (range, 62% to 83%) and specificity (range, 53% to 69%). Biomarker accuracy was higher with amyloid beta-42/pTau ratio, tTau/amyloid beta-42 ratio, and pTau compared with tTau alone.

Cure et al (2014) conducted a systematic review with meta-analysis of CSF and imaging studies for the diagnosis of definite AD (autopsy-confirmed).^23, Literature was searched in January 2012, and 3 studies of CSF markers (pTau, tTau, amyloid beta-42, amyloid beta-40) were identified (N=337 patients). Pooled sensitivity of all CSF tests was 82% (95% confidence interval [CI], 72% to 92%), and pooled specificity was 75% (95% CI, 60% to 90%). Statistical heterogeneity was not reported, but studies varied by AD definitions, controls (patients without dementia or patients with dementia due to other causes), and test thresholds. The summary area under receiver operating characteristic curve, constructed using multiple test thresholds, was 0.84.

Subsection Summary: Clinical Validity of Cerebrospinal Fluid Biomarker Testing for Diagnosis of Alzheimer Disease

Several studies have examined the diagnostic performance of CSF biomarkers for distinguishing patients with probable AD from patients without dementia and from patients with other types of dementia. The range of reported sensitivities and specificities is broad compared with a clinical diagnosis reference standard. In systematic reviews with meta-analyses, sensitivity and specificity rates ranged from 80% to 82% and 82% to 90%, respectively, for differentiating AD from healthy controls, and were 73% and 67%, respectively, for differentiating AD from other dementias. Positive and negative likelihood ratios were 2 to 8 and 0.2 to 0.4, respectively, in either setting. There is limited evidence examining the incremental diagnostic accuracy of CSF biomarkers for AD diagnosis employing autopsy as a criterion standard. Cutoffs for a positive diagnosis are not standardized.

Prognosis for Progression of Mild Cognitive Impairment

Systematic Reviews

There are a variety of systematic reviews that have evaluated the prognostic value of CSF biomarkers for the progression of MCI and conversion to clinically manifest AD. These studies primarily include clinical diagnosis as a reference standard and varying cutoffs for predicting conversion. Tables 3 and 4 present the characteristics and results of key meta-analyses.

Table 4. Characteristics of Key Meta-Analyses That Evaluate the Prognostic Value of CSF Biomarkers for the Progression of MCI and Conversion to Clinically Manifest AD

      AD: Alzheimer disease; CSF: cerebrospinal fluid; MCI: mild cognitive impairment; mo: month(s); y: year(s).

Table 5. Results of Key Meta-Analyses

      Average ratio: Alzheimer disease to control ratio for cerebral spinal fluid biomarker concentration. Aβ42: amyloid-β peptide 1-42; CI: confidence interval; NR: not reported; pTau: phosphorylated tau protein; tTau: total tau protein.

Subsection Summary: Clinical Validity of Cerebrospinal Fluid Biomarker Testing for Prognosis for Progression of Mild Cognitive Impairment

Possible clinical uses of CSF biomarker testing could include confirming the diagnosis of AD to begin medications at an earlier stage or ruling out AD, which could lead to further diagnostic testing to determine the etiology of dementia and/or avoidance of unnecessary medication.

Testing for treatment of MCI and early AD using anti-amyloid therapies is discussed in another section. Outside of that indication, no other trials were identified that have reported health outcomes after CSF biomarker testing; thus, there is no direct evidence for clinical utility. Decision models can provide indirect evidence of utility if the likelihood of benefits and consequences are estimable. To evaluate the benefits and consequences of CSF biomarker interventions, models would need to describe disease progression, resources used, and QOL. Such estimates are scarce and highly variable.

Although not without controversy because of modest efficacy, cholinesterase inhibitors are used to treat symptoms of mild-to-moderate AD.^30,31, Memantine, an N-methyl-d-aspartate receptor antagonist, appears to provide a small benefit in treating symptoms in those with moderate-to-advanced disease.^30,32, Neither cholinesterase inhibitors nor memantine is disease-modifying. Clinical trial entry criteria and benefits for cholinesterase inhibitors and memantine have been based on clinical diagnosis. There is less evidence to support the use of cholinesterase inhibitors in other dementias, but they are still frequently used to treat cognitive symptoms. While the possibility that a more accurate differential diagnosis may lead to improved outcomes is plausible, it is not based on current evidence. Use of cholinesterase inhibitors and memantine for MCI have not demonstrated benefit in reducing progression to AD.^33,34,35,36, The chain of evidence of clinical utility is incomplete.

The evidence suggests that biomarker testing may identify an increased risk of conversion from MCI to AD. Studies primarily include clinical diagnosis as a reference standard and varying cutoffs for predicting conversion.

      Average ratio: Alzheimer disease to control ratio for cerebral spinal fluid biomarker concentration. Aβ42: amyloid-β peptide 1-42; CI: confidence interval; NR: not reported; pTau: phosphorylated tau protein; tTau: total tau protein.

Fink et al (2020) conducted a systematic review of biomarker accuracy for diagnosing neuropathologically defined AD in older patients with dementia.^25, The analysis included literature published between January 2012 and November 2019, with 9 cohort studies focusing on CSF biomarkers. Overall, CSF biomarkers and ratios had moderate sensitivity (range, 62% to 83%) and specificity (range, 53% to 69%). Biomarker accuracy was higher with amyloid beta-42/pTau ratio, tTau/amyloid beta-42 ratio, and pTau compared with tTau alone.

Cure et al (2014) conducted a systematic review with meta-analysis of CSF and imaging studies for the diagnosis of definite AD (autopsy-confirmed).^26, Literature was searched in January 2012, and 3 studies of CSF markers (pTau, tTau, amyloid beta-42, amyloid beta-40) were identified (N=337 patients). Pooled sensitivity of all CSF tests was 82% (95% confidence interval [CI], 72% to 92%), and pooled specificity was 75% (95% CI, 60% to 90%). Statistical heterogeneity was not reported, but studies varied by AD definitions, controls (patients without dementia or patients with dementia due to other causes), and test thresholds. The summary area under receiver operating characteristic curve, constructed using multiple test thresholds, was 0.84.

Subsection Summary: Clinical Validity of Cerebrospinal Fluid Biomarker Testing for Prognosis for Progression of Mild Cognitive Impairment

The evidence suggests that biomarker testing may identify an increased risk of conversion from MCI to AD. Studies primarily include clinical diagnosis as a reference standard and varying cutoffs for predicting conversion.

Clinically Useful

Possible clinical uses of CSF biomarker testing could include confirming the diagnosis of AD to begin medications at an earlier stage or ruling out AD, which could lead to further diagnostic testing to determine the etiology of dementia and/or avoidance of unnecessary medication.

No trials were identified that have reported health outcomes after CSF biomarker testing; thus, there is no direct evidence for clinical utility. Decision models can provide indirect evidence of utility if the likelihood of benefits and consequences are estimable. To evaluate the benefits and consequences of CSF biomarker interventions, models would need to describe disease progression, resources used, and QOL. Such estimates are scarce and highly variable.

Although not without controversy because of modest efficacy, cholinesterase inhibitors are used to treat mild-to-moderate AD.^27,28, Memantine, an N-methyl-d-aspartate receptor antagonist, appears to provide a small benefit in treating symptoms in those with the moderate-to-advanced disease.^27,29, Neither cholinesterase inhibitors nor memantine is disease-modifying.

Given available therapies, in principle, a more accurate diagnosis might allow targeting treatment to those most likely to benefit. However, clinical trial entry criteria and benefits have been based on clinical diagnosis. There is less evidence to support the use of cholinesterase inhibitors in other dementias, but they are still frequently used to treat cognitive symptoms. While the possibility that a more accurate differential diagnosis may lead to improved outcomes is plausible, it is not based on current evidence. Pharmacologic interventions for MCI have not demonstrated benefit in reducing progression to AD.^30,31,32,33, The chain of evidence of clinical utility is incomplete.

Section Summary: Cerebrospinal Fluid Biomarker Testing

Most clinical validity studies of both diagnosis of AD and prognosis for progression of MCI to AD use select patient samples and define optimal test cutoffs without validation. There is no evidence that improved diagnosis or prognosis leads to improved health outcomes or QOL.

For individuals who have mild cognitive impairment (MCI) or AD who receive CSF biomarker testing for AD, the evidence includes systematic reviews. These studies assess using CSF biomarkers for diagnosis of AD or for the prognosis of progression of MCI to AD. Relevant outcomes include test validity, correct treatment, avoiding unnecessary subsequent testing, harms of invasive testing, and quality of life (QOL). Most clinical validity studies have been derived from select patient samples and defined optimal test cutoffs without validation; thus, the generalizability of results is uncertain. For predicting conversion from MCI to AD, limited evidence has suggested that testing may define increased risk. Whether an earlier diagnosis leads to improved health outcomes through a delay of AD onset due to medical therapy or other interventions or improved QOL is unknown. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2

Urinary Biomarker Testing

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Zhang et al (2014) conducted a systematic review and meta-analysis of urinary AD-associated neural thread protein (NTP) for diagnosing AD in patients with suspected AD.^37, Nine studies were included (n=841 patients with probable or possible AD; 37 patients with MCI, 992 with non-AD dementia or controls without dementia). The reference standard was a clinical diagnosis in 8 studies and not described in another. Varying cutoffs for positive diagnosis were used across included studies. Controls were both healthy volunteers and patients with other dementias. For probable AD, pooled sensitivity and specificity were 89% (95% CI, 86% to 92%) and 90% (95% CI, 88% to 92%), respectively. Pooled positive and negative likelihood ratios were 8.9 (95% CI, 7.1 to 11.1) and 0.12 (95% CI, 0.09 to 0.16), respectively.

Clinically Useful

There is no direct evidence to support the clinical utility of urinary markers for diagnosing AD and the chain of evidence is incomplete.

Section Summary: Urinary Marker Testing

A systematic review and meta-analysis that evaluated urinary AD-associated NTP with regard to diagnosing AD in patients with suspected AD concluded that, for probable AD, pooled sensitivity and specificity were 89% (95% CI, 86% to 92%) and 90% (95% CI, 88% to 92%), respectively. Pooled positive and negative likelihood ratios were 8.9 (95% CI, 7.1 to 11.1) and 0.12 (95% CI, 0.09 to 0.16), respectively.

For individuals who have MCI or AD who receive urinary biomarker testing for AD, the evidence includes a systematic review. Relevant outcomes include test validity, correct treatment, avoiding unnecessary subsequent testing, harms of invasive testing, and QOL. Clinical validity studies have included normal healthy controls and defined optimal test cutoffs without validation; thus, clinical validity is uncertain. Whether an earlier diagnosis leads to improved health outcomes through a delay of AD onset or improved QOL is unknown. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 3

Blood Biomarker Testing

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Screening and Diagnosis of Alzheimer Disease

Systematic Reviews

Olsson et al (2016) conducted a systematic review of the 15 most promising biomarkers in both CSF and blood to evaluate which may be useful to distinguish patients with AD from controls and patients with MCI due to AD from those with stable MCI.^24, In total, 231 articles comprising 15,699 patients with AD and 13,018 controls were included in the analysis. Among blood biomarkers, plasma T-tau was the only biomarker found to discriminate patients with AD from controls (p=.02). No differences in plasma concentrations of amyloid beta-42 and amyloid beta-40 biomarkers in individuals with AD as compared to controls were seen in this systematic review; however, these results were reported before the development of more highly sensitive assays and technologies.^16,

Cohort Studies

Krishna et al (2024) reported results of a cross-sectional study of a single molecule array (Simoa) analysis of Aβ1–42, total tau (t-tau), phospho-tau (p-tau 181), and neurofilament L (NfL) in the plasma samples of AD patients (n=35), healthy controls (n=35), and non-AD (n=33) patients from a tertiary care center in India.^38, The non-AD dementia patients included those with frontotemporal dementia (n=12), vascular dementia (n=5), Lewy body dementia (n=4), and mixed dementia (n=12). The cutoffs used for calculating sensitivity and specificity were unclear. A model including all 4 biomarkers had sensitivity of 94% and specificity of 96% for distinguishing AD versus healthy controls. The model including all 4 biomarkers had sensitivity of 40% and specificity of 93% for distinguishing AD from non-AD dementia.

Schraen-Maschke et al (2024) reported results from a subgroup (n=106) of the BALTAZAR study evaluating whether plasma levels of the free amyloid peptides Aβ1–42 and Aβ1–40 and the free plasma Aβ1–42/Aβ1–40 ratio are associated with the conversion of MCI to dementia over three years of follow-up.^39, A total of 50 participants converted to dementia during follow-up. The risk of conversion was lower for participants in the highest quartile of free plasma Aβ1–42/ Aβ1–40 compared to those in the three lower quartiles: adjusted hazard ratio = 0.36; 95% CI, 0.15 to 0.87; p=.02. The risk of conversion in the highest quartile of total plasma Aβ1–42/Aβ1–40 compared to the lower quartiles was similar: adjusted hazard ratio = 0.37; 95% CI, 0.16 to 0.89, p=.03).

Thijssen et al (2020) evaluated whether plasma phosphorylated tau at residue 181 (pTau181) could differentiate between clinically diagnosed or autopsy-confirmed AD and frontotemporal lobar degeneration (N=362).^40, Results revealed that plasma pTau181 concentrations were increased by 3.5-fold in patients with AD compared to controls and differentiated AD from both clinically diagnosed and autopsy-confirmed frontotemporal lobar degeneration. Plasma pTau181 also identified individuals who were amyloid beta-PET-positive regardless of clinical diagnosis and was reported to be a potentially useful screening test for AD.

Janelidze et al (2020) evaluated the diagnostic and prognostic usefulness of plasma pTau181 in 3 cohorts totaling 589 individuals (patients with MCI, AD dementia, non-AD neurodegenerative diseases, and cognitively unimpaired individuals).^41, Results revealed plasma pTau181 to be increased in patients with preclinical AD and further elevated in the MCI and dementia disease stages. Plasma pTau181 also differentiated AD dementia from non-AD neurodegenerative diseases with an accuracy similar to PET Tau and CSF pTau181 and detected AD neuropathology in an autopsy-confirmed cohort.

Palmqvist et al (2020) examined the feasibility of plasma phosphorylated tau at residue 217 (pTau217) as a diagnostic biomarker for AD among 1402 participants from 3 selected cohorts.^42, Results revealed that plasma pTau217 discriminated AD from other neurodegenerative diseases, with significantly higher accuracy than established plasma- and MRI-based biomarkers, and its performance was not significantly different from key CSF- or PET-based measures.

Clinically Useful

There is currently no direct evidence to support the clinical utility of blood markers for diagnosing AD and the chain of evidence is incomplete.

Section Summary: Blood Biomarker Testing

Results from a systematic review and various cohort studies have shown that plasma pTau may be beneficial for the early screening and differential diagnosis of AD; however, currently, there is no evidence that improved diagnosis with blood biomarker testing leads to improved health outcomes or QOL.

For individuals who have MCI or AD who receive blood biomarker testing for AD, the evidence includes a systematic review and cohort studies. Relevant outcomes include test validity, correct treatment, avoiding unnecessary subsequent testing, harms of invasive testing, and QOL. Clinical validity studies have primarily focused on the biomarker, plasma pTau, and have shown that this biomarker may be beneficial in screening for and diagnosing AD. Whether an earlier diagnosis leads to improved health outcomes through a delay of AD onset or improved QOL is unknown. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 4

Cerebrospinal Fluid Biomarkers and Targeted Therapy for Mild Cognitive Impairment or Mild Dementia due to Alzheimer Disease

Clinical Context and Test Purpose

The purpose of CSF biomarkers or PET amyloid scans for individuals with MCI or mild dementia due to AD is to select appropriate patients for initiation or discontinuation of treatment with an amyloid beta plaque targeting therapy (eg, aducanumab).

The question addressed in this evidence review is: Does testing with CSF biomarkers as an adjunct, or alternative to, amyloid beta PET imaging in individuals with MCI or mild dementia due to AD who are being evaluated for initiation or continuation with an amyloid beta plaque targeting therapy improve the net health outcome?

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with a clinical diagnosis of MCI or mild dementia due to AD, who are being evaluated for an FDA approved amyloid beta plaque targeting therapy or are being evaluated for continuing or discontinuing such therapy.

In the pivotal trials for the amyloid beta plaque targeting therapy aducanumab, enrolled patients had an early stage of AD; MCI due to AD; or mild AD dementia based on an entry criteria of baseline Mini-Mental State Examination (MMSE) score of 24 to 30, baseline Clinical Dementia Rating (CDR) global score of 0.5 and Repeatable Battery for the Assessment of Neurological Status (RBANS) delayed memory index score ≤85. Patients were also clinically staged based on the National Institute on Aging-Alzheimer's criteria (Table 1). The National Institute on Aging-Alzheimer's Association has provided guidance on the clinical diagnosis of MCI and dementia due to AD.^38,39,40, This includes utilizing a battery of cognitive tests versus a single test to identify individuals with MCI due to AD (stage 3) or mild dementia due to AD (stage 4). The tests should evaluate multiple domains such as cognition and function and specific tests may vary.

Interventions

The test being considered is the CSF biomarker amyloid beta-42/40 ratio. The amyloid beta-42/40 ratio test quantifies the amount of amyloid beta-42 and 40 proteins in a CSF sample (collected via lumbar puncture) and computes the ratio of those proteins, intended to be an indication of AD pathology. Ratios <0.058 indicate a higher likelihood of a patient having a clinical diagnosis of AD. The ratio, as compared with CSF amyloid beta-42 alone, corrects for interindividual variability in the overall amyloid beta production and CSF turnover, changes in global levels of all amyloid beta isoforms owing to non-AD-related abnormal findings, and variability owing to preanalytical factors.^41, This concentration ratio has also been suggested to be superior to the concentration of amyloid beta-42 alone when identifying patients with AD.^42, The test is indicated for patients being evaluated for MCI or mild dementia clinical stages of AD who are under consideration for targeted therapy.

Comparators

Comparators of interest include the amyloid beta PET scan. Amyloid beta PET imaging is a neuroimaging technique with standardized tracer-specific visual reading procedures and documented high reproducibility across PET centers.^43, It allows non-invasive, in-vivo detection of amyloid plaques with very high sensitivity (96%; 95% CI, 80 to 100) and specificity (100%, 95% CI, 78 to 100) as determined by correlation in patients with confirmed AD who had an autopsy within 1 year of PET imaging. Trials of amyloid beta targeting therapy have traditionally used clinical criteria along with amyloid beta PET imaging to select appropriate patients for participation.

Outcomes

The general outcomes of interest are test validity, symptoms, change in disease status, functional outcomes, health status measures, and QOL. Specific measures of cognitive and functional health outcomes that may be relevant to early AD include the Clinical Dementia Rating-Sum of Boxes (CDR-SOB), MMSE, Alzheimer's Disease Assessment Scale - Cognitive 13-Item Scale (ADAS-Cog 13), Alzheimer's Disease Cooperative Study - Activities of Daily Living - Mild Cognitive Impairment (ADCS-ADL-MCI), and the Neuropsychiatric Inventory-10 (NPI-10).

Follow-up is at months to years for CSF biomarkers or PET amyloid scans for the outcomes of interest.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• The study population represents the population of interest. Eligibility and selection are described;

• The test is compared with a credible reference standard;

• If the test is intended to replace or be an adjunct to an existing test; it should also be compared with that test;

• Studies should report sensitivity, specificity, and predictive values. Studies that completely report true- and false-positive results are ideal. Studies reporting other measures (eg, receiver operating characteristic, area under receiver operating characteristic, c-statistic, likelihood ratios) may be included but are less informative;

• Studies should also report reclassification of the diagnostic or risk category.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

Overall, both PET imaging and CSF biomarkers provide overlapping, and in part complementary, diagnostic information with agreement between CSF and PET amyloid results usually good.^50, There are various studies that evaluate concordance between CSF biomarkers and PET imaging.

The diagnostic accuracy of CSF biomarkers and amyloid beta PET for diagnosing early-stage AD were compared using data from the prospective, longitudinal Swedish BioFINDER study that consecutively enrolled patients without dementia with mild cognitive symptoms.^51, This was the first study to compare the accuracy of regional amyloid beta PET (using the [¹⁸F]-flutemetamol) and different CSF assays or ratios of CSF biomarkers, including amyloid beta-42/40, for this diagnostic purpose. The study included 34 patients with MCI who developed AD dementia within 3 years and 122 healthy elderly controls. Overall, the best CSF measures for the identification of MCI-AD were amyloid-beta 42/total tau (t-tau) and amyloid beta-42/hyperphosphorylated tau (p-tau), with an area under the curve (AUC) of 0.93 to 0.94. The best PET measures (ie, anterior cingulate, posterior cingulate/percuneus, and global neocortical uptake) performed similarly (AUC 0.92 to 0.93). The AUC for CSF amyloid beta-42/40 was numerically poorer as compared to the majority of PET variables; however, the differences were nonsiginficant (p=.09 to.40). The combination of CSF and PET was not better than using either biomarker separately. The results were replicated in 146 controls and 64 patients with MCI-AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study that utilized another CSF assay (amyloid beta-42, t-tau and p-tau) and PET (¹⁸F-florbetapir) tracer. In the ADNI cohort, amyloid-beta 42/t-tau and amyloid beta-42/p-tau ratios similarly had higher AUCs than amyloid beta-42 alone.

Lewczuk et al (2017) evaluated whether amyloid beta-42 alone or the amyloid beta-42/40 ratio corresponded better with amyloid beta PET status.^52, The investigators collected CSF from a mixed cohort (N=200) of cognitively normal and abnormal subjects who had undergone amyloid beta PET within 12 months. Of these, 150 were PET-negative and 50 were PET-positive according to a previously published cutoff. The collected CSF was assayed for amyloid beta-42 alone and the amyloid beta-42/40 ratio. Results revealed that the amyloid beta-42/40 ratio corresponded better than amyloid beta-42 alone with PET results, with a higher proportion of concordant cases (89.4% vs. 74.9%; p<.0001) and a larger AUC (0.936 vs. 0.814; p<.0001) associated with the ratio.

Nisenbaum et al (2022) compared CSF biomarkers to amyloid PET in the EMERGE and ENGAGE phase 3 randomized controlled trials (RCTs) of anti-amyloid therapy, aducanumab.^53, EMERGE and ENGAGE participants had MCI due to AD or mild AD with confirmed amyloid-beta pathology by amyloid PET scan. A population of 350 participants who were screened for the RCTs (EMERGE; n=208; ENGAGE; n=142) were included in a CSF substudy. Amyloid PET imaging was performed using any of the FDA-approved amyloid PET tracers. Expert central readers classified the amyloid PET scans as positive or negative. CSF samples were tested for p-tau, t-tau, amyloid beta-42 and amyloid beta-40 via the Lumipulse system. The mean age for participants in the substudy was 70 years (SD=7). 46% of the participants were female, 93% of participants were White, 1% were Black and 1% were Asian, 37% of participants were ApoE ε4 noncarriers, 47% were heterozygous and 17% were homozygous. The AUC (95% CI) for the amyloid beta-42/40 ratio was 0.90 (0.83 to 0.97; p<.001) with Positive Percent Agreement of 94% (91 to 97) and Negative Percent Agreement of 88% (74 to 96). The AUC of t-tau/amyloid beta-42 ratio was 0.92 (0.86 to 0.97; p<0.001) with Positive Percent Agreement of 92% (89 to 95) and Negative Percent Agreement of 82% (66 to 92).

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The clinical use of CSF biomarkersreviewed in this section is to select individuals who can begin anti-amyloid targeted medications at an l early stage of AD.

Treatment Initiation

CSF biomarkers have demonstrated usefulness for identifying patients who will benefit from anti-amyloid therapy. CSF biomarkers have been used as an alternative to amyloid PET for the purposes of establishing eligibility in terms of amyloid beta pathology in trials that have established the efficacy of anti-amyloid therapies. In brief, lecanemab has been evaluated in 2 double-blind RCTs (Study 201 and Study 301/Clarity AD) with samples sizes of 390 and 1795, respectively. The trials included individuals with MCI due to AD or mild AD dementia with confirmed amyloid beta pathology. In Clarity AD, the protocol states that amyloid beta pathology was confirmed by either 1) positive amyloid load confirmed by amyloid PET assessment, or 2) CSF assessment of t-tau / Aβ[1-42]. Both trials reported an approximately 27% statistically significantly slower rate of decline for the primary cognitive and functional outcome (ADCOMS for Study 201; CDR-SB for Study 301) for lecanemab versus placebo.^54,47, Lecanemab received traditional FDA approval based on results of these RCTs and the label for lecanemab states that the presence of amyloid beta pathology should be confirmed prior to initiating treatment.^55,

Treatment Continuation

There are no data on the serial use of these tests to determine if there are changes in biomarker results that correlate with clinical cognitive and functional status and/or amyloid beta imaging to inform continuation of amyloid beta plaque targeting therapy.

Section Summary: Cerebrospinal Fluid Biomarkers and Positron Emission Tomography Amyloid Scans for Mild Cognitive Impairment or Mild Dementia due to Alzheimer Disease

The evidence supporting a correlation between CSF biomarkers, including amyloid beta-42/40 and t-tau/amyloid beta-42, and PET amyloid scans indicates that the diagnostic accuracy of CSF and amyloid PET biomarkers to identify MCI-AD was similar and that the amyloid beta-42/40 ratio and total tau to amyloid beta-42 ratio corresponded better with PET results compared to single CSF biomarker, alone such as amyloid beta-42. CSF biomarkers have been used as an alternative to PET amyloid scans to establish eligibility regarding the presence of amyloid beta pathology in RCTs that showed the efficacy of anti-amyloid therapies, which in turn demonstrates that the CSF biomarkers can identify patients who would benefit from therapy. The FDA-approved labels for lecanemab and donanemab state that the presence of amyloid beta pathology should be confirmed prior to initiating treatment.

For individuals who have MCI or mild dementia due to AD who are being considered for initial treatment with an approved amyloid beta plaque targeting therapy, the evidence includes multisite longitudinal studies and an analysis of a mixed cohort. Two of these studies assess the correlation between CSF biomarkers and PET amyloid scans and another assesses the clinical utility of amyloid PET in cognitively impaired patients who met appropriate use criteria for clinical amyloid PET. Relevant outcomes include test validity, symptoms, change in disease status, functional outcomes, health status measures, and QOL. Overall, the diagnostic accuracy of CSF biomarkers versus amyloid PET scans to identify MCI-AD was found to be similar but there are no data to support the clinical utility of CSF biomarker use as a component of determining appropriate initiation of amyloid beta targeting therapy. Prior to the availability of amyloid beta targeting therapy, additional data exist suggesting that amyloid beta PET scan results impacted diagnosis of dementias and patient management including use of symptomatic treatment. Further research is required to determine whether use of CSF biomarkers alone or in conjunction with amyloid PET scans is associated with improved clinical outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. 

2024 Input

Clinical input was sought to help determine whether the use of cerebrospinal fluid biomarker testing for individuals who are being considered for an approved amyloid beta plaque targeting therapy would provide a clinically meaningful improvement in net health outcome. In response to requests, clinical input was received from 3 respondents; 1 physician-level response identified through a specialty society; 2 physician-level responses (joint response) identified through an academic medical center.

For individuals who have early AD who receive amyloid-beta targeting therapy, clinical input supports this use provides a clinically meaningful improvement in net health outcome with the criteria described.

Cerebrospinal fluid biomarker testing of amyloid beta peptides and tau protein as part of an evaluation for the initiation of amyloid beta targeting therapy in individuals with mild cognitive impairment or mild dementia due to Alzheimer disease is considered medically necessary (see Policy Guidelines).

Population Reference No. 5

Who are being treated with an amyloid beta plaque targeting therapy and are being evaluated for therapy continuation

For individuals who have MCI or mild dementia due to AD, who are being treated with an amyloid beta plaque targeting therapy and are being evaluated for therapy continuation, the evidence includes multisite longitudinal studies and an analysis of a mixed cohort. Two of these studies assess the correlation between CSF biomarkers and PET amyloid scans and another assesses the clinical utility of amyloid PET in cognitively impaired patients who met appropriate use criteria for clinical amyloid PET. Relevant outcomes include test validity, symptoms, change in disease status, functional outcomes, health status measures, and QOL. The diagnostic accuracy of CSF biomarkers versus amyloid beta PET scans to identify MCI-AD was found to be similar. Prior to the availability of amyloid beta targeting therapy, additional data exist suggesting that amyloid beta PET scan results impacted diagnosis of dementias and patient management including use of symptomatic treatment. Further research is required to determine whether use of CSF biomarkers alone or in conjunction with amyloid beta PET scans are useful for determining whether or not amyloid beta targeting therapy should be continued. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

National Institute of Aging

2011 Revised Diagnostic Criteria

In 2011, probable Alzheimer disease (AD) was defined by the National Institute on Aging and the Alzheimer's Association workgroup using the following diagnostic criteria:^20,

"Meets criteria for dementia…and in addition has the following characteristics:

1. Insidious onset. Symptoms have a gradual onset over months to years, not sudden over hours or days;

2. Clear-cut history of worsening of cognition by report or observation; and

3. The initial and most prominent cognitive deficits are evident on history and examination in 1 of the following categories.

   1. Amnestic presentation: It is the most common syndromic presentation of AD dementia. The deficits should include impairment in learning and recall of recently learned information. There should also be evidence of cognitive dysfunction in at least 1 other cognitive domain, as defined earlier in the text.

   2. Nonamnestic presentations: Language presentation: The most prominent deficits are in word-finding, but deficits in other cognitive domains should be present. Visuospatial presentation: The most prominent deficits are in spatial cognition, including object agnosia, impaired face recognition, simultanagnosia, and alexia. Deficits in other cognitive domains should be present. Executive dysfunction: The most prominent deficits are impaired reasoning, judgment, and problem-solving. Deficits in other cognitive domains should be present.

4. The diagnosis of probable AD dementia should not be applied when there is evidence of:

   1. Substantial concomitant cerebrovascular disease, defined by a history of a stroke temporally related to the onset or worsening of cognitive impairment; or the presence of multiple or extensive infarcts or severe white matter hyperintensity burden; or

   2. Core features of dementia with Lewy bodies other than dementia itself; or

   3. Prominent features of behavioral variant frontotemporal dementia; or

   4. Prominent features of semantic variant primary progressive aphasia or nonfluent/agrammatic variant primary progressive aphasia; or

   5. Evidence for another concurrent, active neurological disease, or a non-neurological medical comorbidity or use of medication that could have a substantial effect on cognition."

The diagnosis for possible AD dementia should meet the following criteria:

A. Core criteria for the nature of cognitive deficits for AD dementia but is marked by sudden onset of cognitive impairment or insufficient history or documentation describing progressive decline; or

B. All core clinical criteria for AD dementia but presents with concomitant cerebrovascular disease, features of dementia with Lewy bodies, or evidence of another neurological disease or any condition that could affect cognition.

Additionally, a category "Probable AD dementia with evidence of the AD pathophysiological process" has been added. Evidence of the AD pathophysiologic process is supported by detection of low cerebrospinal fluid (CSF) amyloid beta peptide 1-42 (Aβ42), positive positron emission tomography amyloid imaging, or elevated CSF tau, and decreased fluorine 18 fluorodeoxyglucose uptake on positron emission tomography in the temporoparietal cortex with accompanying atrophy by magnetic resonance imaging in relevant structures. Detection of the "pathophysiological process" is further divided by when in the disease natural history markers are expected to be detectable. Biomarker evidence in cases of probable AD may increase the certainty that the dementia is due to AD pathophysiological process.

Note on the 2011 Revised Criteria and Biomarkers

Some of the biomarkers considered in this evidence review are in a category among the 2011 revisions to AD diagnostic criteria, "probable AD dementia with evidence of the AD pathophysiological process."^20, However, the diagnostic criteria workgroup noted the following:

"[We] do not advocate the use of AD biomarker tests for routine diagnostic purposes at the present time. There are several reasons for this limitation: 1) the core clinical criteria provide very good diagnostic accuracy and utility in most patients; 2) more research needs to be done to ensure that criteria that include the use of biomarkers have been appropriately designed, 3) there is limited standardization of biomarkers from 1 locale to another, and 4) access to biomarkers is limited to varying degrees in community settings. Presently, the use of biomarkers to enhance certainty of AD pathophysiological process may be useful in 3 circumstances: investigational studies, clinical trials, and as optional clinical tools for use where available and when deemed appropriate by the clinician."^20,

Alzheimer's Association

In 2009, the Alzheimer's Association initiated a quality control program for CSF markers, noting that "Measurements of CSF AD biomarkers show large between laboratory variability, likely caused by factors related to analytical procedures and the analytical kits. Standardization of laboratory procedures and efforts by kit vendors to increase kit performance might lower variability, and will likely increase the usefulness of CSF AD biomarkers."^22, In 2012, the Alzheimer's Biomarkers Standardization Initiative published consensus recommendations for standardization of preanalytical aspects (eg, fasting, tube types, centrifugation, storage time, temperature) of CSF biomarker testing.^56,

In 2013, the Alzheimer's Association published recommendations for operationalizing the detection of cognitive impairment during the Medicare annual wellness visit in primary care settings.^57, The recommended algorithm for cognitive assessment was based on "current validated tools and commonly used rule-out assessments." Guidelines noted that the use of biomarkers (eg, CSF tau and β-amyloid proteins) "was not considered as these measures are not currently approved or widely available for clinical use."

In 2018, the Alzheimer’s Association published appropriate use criteria for lumbar puncture and CSF testing for AD.^58,Table 6 summarizes the indications for these practices. In 2021, the Alzheimer's Association also published international guidelines for the appropriate handling of CSF for routine clinical measurements of amyloid beta and tau.^59,

Table 6. Indications for Appropriate Use of Lumbar Puncture and CSF Testing in Diagnosing AD

      AD: Alzheimer disease; ADAD: autosomal-dominant Alzheimer disease; CSF: cerebrospinal fluid; MCI: mild cognitive impairment; SCD: subjective cognitive decline.

In 2022, the Alzheimer's Association Global Workgroup released appropriate use recommendations for blood biomarkers in AD.^60, The Workgroup recommended "use of blood-based markers as (pre-)screeners to identify individuals likely to have AD pathological changes for inclusion in trials evaluating disease-modifying therapies, provided the AD status is confirmed with PET or CSF testing." The Workgroup also encouraged "studying longitudinal blood-based marker changes in ongoing as well as future interventional trials" but cautioned that these markers "should not yet be used as primary endpoints in pivotal trials." Further, the Workgroup also recommended cautiously starting to use blood-based biomarkers "in specialized memory clinics as part of the diagnostic work-up of patients with cognitive symptoms" with the results confirmed with CSF or PET whenever possible. Additional data are needed before the use of blood-based biomarkers as stand-alone diagnostic AD markers, or before considering use in primary care.

National Institute for Health and Care Excellence

In 2018, the National Institute for Health and Care Excellence (NICE) released a guideline on assessment, management, and support for people living with dementia and their caregivers.^61, The guideline states that in cases of uncertain diagnosis, but highly suspicious for AD, providers can consider examining CSF for total tau or total tau and phosphorylated-tau 181 and either beta amyloid 42 or beta amyloid 42 and beta amyloid 40. People who are older are more likely to receive a false positive with a CSF analysis.

U.S. Preventive Services Task Force Recommendations

In 2020, the U.S. Preventive Services Task Force released recommendations for screening cognitive impairment in older adults, concluding that the current evidence is insufficient to determine benefits versus harms of screening for cognitive impairment in older adults.^53, The statement discusses that screening tests are not intended to diagnose MCI or dementia, but a positive screening test result should prompt additional testing consisting of blood tests, radiology examinations, and/or medical and neuropsychologic evaluation.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinal Trials

Some currently ongoing and unpublished trials that might influence this review are listed in Table 6.

Table 7. Summary of Key Trials

      NCT: national clinical trial.

References

1. 2021 Alzheimer's disease facts and figures. Alzheimers Dement. Mar 2021; 17(3): 327-406. PMID 33756057
2. Petersen RC, Lopez O, Armstrong MJ, et al. Practice guideline update summary: Mild cognitive impairment: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. Jan 16 2018; 90(3): 126-135. PMID 29282327
3. National Institutes on Aging. Data shows racial disparities in Alzheimer's disease diagnosis between Black and white research study participants. December 16, 2021. https://www.nia.nih.gov/news/data-shows-racial-disparities-alzheimers-disease-diagnosis-between-black-and-white-research. Accessed August 23, 2023.
4. Centers for Disease Control and Prevention. Barriers to equity in Alzheimer's and dementia care. June 2, 2021. https://www.cdc.gov/aging/publications/features/barriers-to-equity-in-alzheimers-dementia-care/index.html. Accessed August 23, 2023.
5. Alzheimer's Association. 2022 Alzheimer's disease facts and figures. https://www.alz.org/media/documents/alzheimers-facts-and-figures.pdf. Accessed August 23, 2023.
6. Roberts RO, Aakre JA, Kremers WK, et al. Prevalence and Outcomes of Amyloid Positivity Among Persons Without Dementia in a Longitudinal, Population-Based Setting. JAMA Neurol. Aug 01 2018; 75(8): 970-979. PMID 29710225
7. Vermunt L, Sikkes SAM, van den Hout A, et al. Duration of preclinical, prodromal, and dementia stages of Alzheimer's disease in relation to age, sex, and APOE genotype. Alzheimers Dement. Jul 2019; 15(7): 888-898. PMID 31164314
8. Jack CR, Bennett DA, Blennow K, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. Apr 2018; 14(4): 535-562. PMID 29653606
9. Blennow K, Zetterberg H. Biomarkers for Alzheimer's disease: current status and prospects for the future. J Intern Med. Dec 2018; 284(6): 643-663. PMID 30051512
10. Galasko D, Clark C, Chang L, et al. Assessment of CSF levels of tau protein in mildly demented patients with Alzheimer's disease. Neurology. Mar 1997; 48(3): 632-5. PMID 9065538
11. Motter R, Vigo-Pelfrey C, Kholodenko D, et al. Reduction of beta-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer's disease. Ann Neurol. Oct 1995; 38(4): 643-8. PMID 7574461
12. Zhang J, Peng M, Jia J. Plasma amyloid-β oligomers and soluble tumor necrosis factor receptors as potential biomarkers of AD. Curr Alzheimer Res. May 2014; 11(4): 325-31. PMID 24635842
13. Maddalena A, Papassotiropoulos A, Müller-Tillmanns B, et al. Biochemical diagnosis of Alzheimer disease by measuring the cerebrospinal fluid ratio of phosphorylated tau protein to beta-amyloid peptide42. Arch Neurol. Sep 2003; 60(9): 1202-6. PMID 12975284
14. Dumurgier J, Vercruysse O, Paquet C, et al. Intersite variability of CSF Alzheimer's disease biomarkers in clinical setting. Alzheimers Dement. Jul 2013; 9(4): 406-13. PMID 23141384
15. Mattsson N, Andreasson U, Persson S, et al. The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers. Alzheimers Dement. Jul 2011; 7(4): 386-395.e6. PMID 21784349
16. Teunissen CE, Verberk IMW, Thijssen EH, et al. Blood-based biomarkers for Alzheimer's disease: towards clinical implementation. Lancet Neurol. Jan 2022; 21(1): 66-77. PMID 34838239
17. Ashton NJ, Leuzy A, Karikari TK, et al. The validation status of blood biomarkers of amyloid and phospho-tau assessed with the 5-phase development framework for AD biomarkers. Eur J Nucl Med Mol Imaging. Jul 2021; 48(7): 2140-2156. PMID 33677733
18. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), American Psychiatric Association, Arlington, VA 2013.
19. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. Jul 1984; 34(7): 939-44. PMID 6610841
20. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. May 2011; 7(3): 263-9. PMID 21514250
21. Rosa MI, Perucchi J, Medeiros LR, et al. Accuracy of cerebrospinal fluid Aβ(1-42) for Alzheimer's disease diagnosis: a systematic review and meta-analysis. J Alzheimers Dis. 2014; 40(2): 443-54. PMID 24448789
22. Bloudek LM, Spackman DE, Blankenburg M, et al. Review and meta-analysis of biomarkers and diagnostic imaging in Alzheimer's disease. J Alzheimers Dis. 2011; 26(4): 627-45. PMID 21694448
23. Formichi P, Battisti C, Radi E, et al. Cerebrospinal fluid tau, A beta, and phosphorylated tau protein for the diagnosis of Alzheimer's disease. J Cell Physiol. Jul 2006; 208(1): 39-46. PMID 16447254
24. Ferreira D, Perestelo-Pérez L, Westman E, et al. Meta-Review of CSF Core Biomarkers in Alzheimer's Disease: The State-of-the-Art after the New Revised Diagnostic Criteria. Front Aging Neurosci. 2014; 6: 47. PMID 24715863
25. Fink HA, Linskens EJ, Silverman PC, et al. Accuracy of Biomarker Testing for Neuropathologically Defined Alzheimer Disease in Older Adults With Dementia. Ann Intern Med. May 19 2020; 172(10): 669-677. PMID 32340038
26. Cure S, Abrams K, Belger M, et al. Systematic literature review and meta-analysis of diagnostic test accuracy in Alzheimer's disease and other dementia using autopsy as standard of truth. J Alzheimers Dis. 2014; 42(1): 169-82. PMID 24840572
27. Olsson B, Lautner R, Andreasson U, et al. CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis. Lancet Neurol. Jun 2016; 15(7): 673-684. PMID 27068280
28. Ritchie C, Smailagic N, Noel-Storr AH, et al. CSF tau and the CSF tau/ABeta ratio for the diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev. Mar 22 2017; 3(3): CD010803. PMID 28328043
29. Ritchie C, Smailagic N, Noel-Storr AH, et al. Plasma and cerebrospinal fluid amyloid beta for the diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev. Jun 10 2014; 2014(6): CD008782. PMID 24913723
30. Raina P, Santaguida P, Ismaila A, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med. Mar 04 2008; 148(5): 379-97. PMID 18316756
31. Kaduszkiewicz H, Zimmermann T, Beck-Bornholdt HP, et al. Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials. BMJ. Aug 06 2005; 331(7512): 321-7. PMID 16081444
32. McShane R, Areosa Sastre A, Minakaran N. Memantine for dementia. Cochrane Database Syst Rev. Apr 19 2006; (2): CD003154. PMID 16625572
33. Schneider LS, Mangialasche F, Andreasen N, et al. Clinical trials and late-stage drug development for Alzheimer's disease: an appraisal from 1984 to 2014. J Intern Med. Mar 2014; 275(3): 251-83. PMID 24605808
34. Feldman HH, Ferris S, Winblad B, et al. Effect of rivastigmine on delay to diagnosis of Alzheimer's disease from mild cognitive impairment: the InDDEx study. Lancet Neurol. Jun 2007; 6(6): 501-12. PMID 17509485
35. Winblad B, Gauthier S, Scinto L, et al. Safety and efficacy of galantamine in subjects with mild cognitive impairment. Neurology. May 27 2008; 70(22): 2024-35. PMID 18322263
36. Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. Jun 09 2005; 352(23): 2379-88. PMID 15829527
37. Zhang J, Zhang CH, Li RJ, et al. Accuracy of urinary AD7c-NTP for diagnosing Alzheimer's disease: a systematic review and meta-analysis. J Alzheimers Dis. 2014; 40(1): 153-9. PMID 24346218
38. Krishna G, Thangaraju Sivakumar P, Dahale AB, et al. Potential Utility of Plasma Biomarker Panels in Differential Diagnosis of Alzheimer's Disease. J Alzheimers Dis Rep. 2024; 8(1): 1-7. PMID 38229828
39. Schraen-Maschke S, Duhamel A, Vidal JS, et al. The free plasma amyloid Aβ 1 - 42 /Aβ 1 - 40 ratio predicts conversion to dementia for subjects with mild cognitive impairment with performance equivalent to that of the total plasma Aβ 1 - 42 /Aβ 1 - 40 ratio. The BALTAZAR study. Neurobiol Dis. Apr 2024; 193: 106459. PMID 38423192
40. Thijssen EH, La Joie R, Wolf A, et al. Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobar degeneration. Nat Med. Mar 2020; 26(3): 387-397. PMID 32123386
41. Janelidze S, Mattsson N, Palmqvist S, et al. Plasma P-tau181 in Alzheimer's disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer's dementia. Nat Med. Mar 2020; 26(3): 379-386. PMID 32123385
42. Palmqvist S, Janelidze S, Quiroz YT, et al. Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders. JAMA. Aug 25 2020; 324(8): 772-781. PMID 32722745
43. Jack CR, Albert MS, Knopman DS, et al. Introduction to the recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. May 2011; 7(3): 257-62. PMID 21514247
44. Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. May 2011; 7(3): 270-9. PMID 21514249
45. Budd Haeberlein S, Aisen PS, Barkhof F, et al. Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer's Disease. J Prev Alzheimers Dis. 2022; 9(2): 197-210. PMID 35542991
46. Salloway S, Chalkias S, Barkhof F, et al. Amyloid-Related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients With Early Alzheimer Disease. JAMA Neurol. Jan 01 2022; 79(1): 13-21. PMID 34807243
47. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in Early Alzheimer's Disease. N Engl J Med. Jan 05 2023; 388(1): 9-21. PMID 36449413
48. Janelidze S, Pannee J, Mikulskis A, et al. Concordance Between Different Amyloid Immunoassays and Visual Amyloid Positron Emission Tomographic Assessment. JAMA Neurol. Dec 01 2017; 74(12): 1492-1501. PMID 29114726
49. Hansson O, Lehmann S, Otto M, et al. Advantages and disadvantages of the use of the CSF Amyloid β (Aβ) 42/40 ratio in the diagnosis of Alzheimer's Disease. Alzheimers Res Ther. Apr 22 2019; 11(1): 34. PMID 31010420
50. Chételat G, Arbizu J, Barthel H, et al. Amyloid-PET and 18 F-FDG-PET in the diagnostic investigation of Alzheimer's disease and other dementias. Lancet Neurol. Nov 2020; 19(11): 951-962. PMID 33098804
51. Palmqvist S, Zetterberg H, Mattsson N, et al. Detailed comparison of amyloid PET and CSF biomarkers for identifying early Alzheimer disease. Neurology. Oct 06 2015; 85(14): 1240-9. PMID 26354982
52. Lewczuk P, Matzen A, Blennow K, et al. Cerebrospinal Fluid Aβ42/40 Corresponds Better than Aβ42 to Amyloid PET in Alzheimer's Disease. J Alzheimers Dis. 2017; 55(2): 813-822. PMID 27792012
53. Nisenbaum L, Martone R, Chen T, et al. CSF biomarker concordance with amyloid PET in Phase 3 studies of aducanumab. Alzheimers Dement. Aug 2023; 19(8): 3379-3388. PMID 36795603
54. Summary Review for Leqembi (lecanemab) Application Number: 761269Orig1s000. Center for Drug Evaluation and Research. Available at https://www.accessdata.fda.gov/drugsatfda_docs/summary_review/2023/761269Orig1s000SumR.pdf. Accessed on August 23, 2023.
55. Prescribing Label for LEQEMBI (lecanemab-irmb) injection, for intravenous use. Available at https://www.leqembi.com/-/media/Files/Leqembi/Prescribing-Information.pdf?hash=3d7bf1a2-5db2-4990-8388-81086f415676. Accessed on August 23, 2023.
56. Vanderstichele H, Bibl M, Engelborghs S, et al. Standardization of preanalytical aspects of cerebrospinal fluid biomarker testing for Alzheimer's disease diagnosis: a consensus paper from the Alzheimer's Biomarkers Standardization Initiative. Alzheimers Dement. Jan 2012; 8(1): 65-73. PMID 22047631
57. Cordell CB, Borson S, Boustani M, et al. Alzheimer's Association recommendations for operationalizing the detection of cognitive impairment during the Medicare Annual Wellness Visit in a primary care setting. Alzheimers Dement. Mar 2013; 9(2): 141-50. PMID 23265826
58. Shaw LM, Arias J, Blennow K, et al. Appropriate use criteria for lumbar puncture and cerebrospinal fluid testing in the diagnosis of Alzheimer's disease. Alzheimers Dement. Nov 2018; 14(11): 1505-1521. PMID 30316776
59. Hansson O, Batrla R, Brix B, et al. The Alzheimer's Association international guidelines for handling of cerebrospinal fluid for routine clinical measurements of amyloid β and tau. Alzheimers Dement. Sep 2021; 17(9): 1575-1582. PMID 33788410
60. Hansson O, Edelmayer RM, Boxer AL, et al. The Alzheimer's Association appropriate use recommendations for blood biomarkers in Alzheimer's disease. Alzheimers Dement. Dec 2022; 18(12): 2669-2686. PMID 35908251
61. Dementia: assessment, management and support for people living with dementia and their carers. National Institute for Health and Care Excellence. Published June 20, 2018. https://www.nice.org.uk/guidance/ng97. Accessed August 23, 2023.
62. Cognitive impairment in older adults: screening. U.S. Preventative Task Force. Published February 25, 2020. https://uspreventiveservicestaskforce.org/uspstf/recommendation/cognitive-impairment-in-older-adults-screening. Accessed August 23, 2023.

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