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Cerebrospinal Fluid and Urinary Biomarkers of Alzheimer Disease

Policy Number: MP-200

Latest Review Date: December 2020

Category: Laboratory

Policy Grade: A

POLICY:

Measurement of cerebrospinal fluid biomarkers of Alzheimer disease, including but not limited to tau protein, amyloid beta peptides, or neural thread proteins, is considered not medically necessary and investigational.

Measurement of urinary biomarkers of Alzheimer disease, including but not limited to neural thread proteins, is considered not medically necessary and investigational.

DESCRIPTION OF PROCEDURE OR SERVICE:

Biochemical changes associated with the pathophysiology of Alzheimer disease (AD) are being evaluated to aid in the diagnosis of AD. Some of the most commonly studied biomarkers are amyloid-β peptide 1-42 (AB-42) and total or phosphorylated tau protein (T-tau or P-tau) in cerebrospinal fluid (CSF).

Biomarkers

Several potential biomarkers of AD are associated with AD pathophysiology (e.g., β-amyloid plaques, neurofibrillary tangles). Elevated CSF levels of specific proteins have been found in patients with AD. These include tau protein, phosphorylated at AD-specific epitopes such as threonine 181 (P-tau) or total tau protein (T-tau), or an amyloid-β peptide such as AB-42. Other potential CSF and serum peptide markers also 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. AB-42 is a subtype of amyloid-β peptide that is produced from metabolism of amyloid precursor protein. AB-42 is the key peptide deposited in amyloid plaques characteristic of AD. Low levels of AB-42 in the CSF have been associated with AD, perhaps because AB-42 is deposited in amyloid plaques instead of remaining in fluid. Investigators have suggested that the tau/AB-42 ratio may be a more accurate diagnostic marker than either alone. A variety of kits are commercially available to measure AB-42 and tau proteins. Between-laboratory variability in CSF biomarker measurement is large. 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.

KEY POINTS:

The most recent literature review was updated through October 21, 2020.

Summary of Evidence

For individuals who have AD or mild cognitive impairment (MCI) who receive cerebrospinal fluid (CSF) biomarker testing for AD, the evidence includes systematic reviews and prospective and retrospective studies. These studies assess using CSF biomarkers for diagnosis of AD or for the prognosis of progression of MCI to AD. Relevant outcomes include diagnosis accuracy, 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 the effects of the technology on health outcomes.

For individuals who have AD or MCI who receive urinary biomarker testing for AD, the evidence includes a systematic review and prospective and retrospective studies. Relevant outcomes include diagnosis accuracy, 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 the effects of the technology on health outcomes.

Practice Guidelines and Position Statements

National Institute of Aging

2011 Revised Diagnostic Criteria

As of 2011, probable Alzheimer disease (AD) was defined by the National Institute on Aging and the Alzheimer’s Association workgroup according to the following diagnostic criteria:

“Meets criteria for dementia described ... and in addition, have the following characteristics:

  • Insidious onset. Symptoms have a gradual onset over months to years, not sudden over hours or days;
  • Clear-cut history of worsening of cognition by report or observation; and
  • The initial and most prominent cognitive deficits are evident on history and examination in one of the following categories:
    • 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 one other cognitive domain, as defined earlier in the text.
    • 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.
  • The diagnosis of probable AD dementia should not be applied when there is evidence of:
    • 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
    • core features of Dementia with Lewy bodies other than dementia itself; or
    • prominent features of behavioral variant frontotemporal dementia; or
    • prominent features of semantic variant primary progressive aphasia or nonfluent/agrammatic variant primary progressive aphasia; or
    • 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 follow criteria:

  • 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
  • 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 CSF AB-42, positive positron emission tomography (PET) amyloid imaging, or elevated CSF tau, and decreased 18-F fluorodeoxyglucose uptake on PET in the temporo-parietal cortex with accompanying atrophy by magnetic resonance imaging (MRI) in relevant structures. Detection of the “pathophysiological process” is further divided according to 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 AD Criteria and Biomarkers

The biomarkers reviewed in this policy are included in a category among revisions to AD diagnostic criteria—“probable AD dementia with evidence of the AD pathophysiological process”. 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 one 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 three circumstances: investigational studies, clinical trials, and as optional clinical tools for use where available and when deemed appropriate by the clinician.”

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.” In 2012, the Alzheimer's Biomarkers Standardization Initiative published consensus recommendations for standardization of preanalytical aspects (e.g., fasting, tube types, centrifugation, storage time, temperature) of CSF biomarker testing.

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. The recommended algorithm for cognitive assessment was based on “current validated tools and commonly used rule-out assessments.” Guideline authors noted that use of biomarkers (e.g., 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 (2018) published appropriate use criteria for lumbar puncture and CSF testing for AD. The table below summarizes the indications for these practices.

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

Appropriate Indications

Patients with SCD who are considered at increased risk for AD

MCI that is persistent, progressing, and unexplained

Patients with symptoms that suggest possible AD

MCI or dementia with an onset at an early age (<65 y)

Meeting core clinical criteria for probable AD with typical age of onset

Patients whose dominant symptom is a change in behavior where AD diagnosis is being considered

Inappropriate Indications

Cognitively unimpaired and within normal range functioning for age as established by objective testing; no conditions suggesting high risk and no SCD or expressed concern about developing AD

Cognitively unimpaired patient based on objective testing, but considered by patient, family informant and/or clinician to be at risk for AD based on family history.

Patients with SCD who are not considered to be at increased risk for AD

Individuals who are apolipoprotein E (APOE) Ɛ4 carriers with no cognitive impairment

Use of lumbar puncture in lieu of genotyping for suspected ADAD mutation carriers

ADAD mutation carriers, with or without symptoms

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

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. The statement discusses that screening tests are not intended to diagnose mild cognitive impairment or dementia, but a positive screening test result should prompt additional testing consisting of blood tests, radiology examinations, and/or medical and neuropsychologic evaluation.

KEY WORDS:

Biochemical marker, amyloid beta peptides, AB-42 Protein, Alzheimer’s Disease, ADmark ProfileAD7C, Alzheimer’s Disease, Beta-amyloid Protein, Neural thread Protein, Tau Protein, Alzheimer, Innotest, AlzheimAlert, MCI, mild cognitive impairment, AD, Alzheimer Disease

APPROVED BY GOVERNING BODIES:

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 CLIA. AlzheimAlert™ and AdMark® CSF analysis are available under the auspices of the CLIA. Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing. To date, the FDA has chosen not to require any regulatory review of this test.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits.  Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP contracts: FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

CURRENT CODING: 

CPT Codes:

81099

Unlisted urinalysis procedure

83520

Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative; not otherwise specified

86849

Unlisted immunology procedure

0206U

Neurology (Alzheimer disease); cell aggregation using morphometric imaging and protein kinase C-epsilon (PKCe) concentration in response to amylospheroid treatment by ELISA, cultured skin fibroblasts, each reported as positive or negative for Alzheimer disease (DISCERN™) (Effective 10/1/2020)

0207U

imaging of  quantitative phosphorylated ERK1 and ERK2 in response to bradykinin treatment by in situ immunofluorescence, using cultured skin fibroblasts, reported as a probability index for Alzheimer disease (List separately in addition to code for primary procedure) (Use 0207U in conjunction with 0206U) (DISCERN™) (Effective 10/1/2020)

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POLICY HISTORY:

Medical Policy Group, August 2004 (4)

Medical Policy Administration Committee, August 2004

Available for comment August 24-October 7, 2004

Medical Policy Group, August 2006 (1)

Medical Policy Group, August 2008 (1)

Medical Policy Group, August 2010 (1): 2010 Description and Key Points Updated, No change in policy coverage

Medical Policy Group, May 2011 (1): 2011 Update to Description, Key Points and References

Medical Policy Panel, September 2012

Medical Policy Group, September 2012 (1): 2012 Update to Key Points and References; no change to policy statement

Medical Policy Group, December 2012 (3): 2013 Code Updates – Deleted 83912

Medical Policy Panel, August 2013

Medical Policy Group, September 2013 (1): 2013 Update to Key Points and References; removed codes 83912 and G0452, unlisted codes 81099 and 86849 added to policy; no change to policy statement

Medical Policy Panel, August 2014

Medical Policy Group, August 2014 (1): 2014 Update to Key Points, Key Words, Governing Bodies and References; no change to policy statement

Medical Policy Panel, August 2015

Medical Policy Group, August 2015 (3):  2015 Update to Description & Key Points; no change in policy statement

Medical Policy Panel, December 2016

Medical Policy Group, December 2016 (3): 2016 Updates to Title, Key Points, Approved by Governing Bodies & References; no change to policy statement.

Medical Policy Panel, December 2017

Medical Policy Group, December 2017 (3): 2017 Updates to Description, Key Points, Practice Guidelines and References; no change to policy statement.

Medical Policy Panel, December 2018

Medical Policy Group, January 2019 (3): Updates to Key Points and References. No change in policy statement.

Medical Policy Panel, December 2019

Medical Policy Group, December 2019 (9): 2019 Updates to Description, Key Points, References. Added key words: MCI, mild cognitive impairment, AD, Alzheimer Disease. No change to policy statement.

Medical Policy Group, September 2020 (9): Added CPT codes 0206U and 0207U due to 10/1/2020 Coding Update.

Medical Policy Panel, December 2020

Medical Policy Group, December 2020 (9): 2020 Updates to Key Points, Description, References. Title changed to "Evaluation of Biomarkers for Alzheimer Disease" to accommodate two new PLA codes 0206U and 0207U that were added effective 10/1/2020. No change to policy statement.


This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.