Currentblue cross blue shield - tennesseePolicy N/A

Biochemical Markers of Alzheimer Disease and Dementia

Defines coverage stance for laboratory measurement of biochemical biomarkers (CSF, plasma/serum, urine, and multianalyte assays) for diagnosis, prognosis, or management of Alzheimer disease and dementia for Blue Cross Blue Shield - Tennessee members.

Policy Summary

Payerblue cross blue shield - tennessee

PolicyBiochemical Markers of Alzheimer Disease and Dementia

Policy CodePolicy N/A

Change TypeNo material changes

Effective DateN/A

Next Review DateN/A

Key ActionDo not submit claims for CSF, plasma/serum, urine biomarkers, or multianalyte assays for Alzheimer disease as they do not meet coverage criteria.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

4categories not covered

up to 0.86plasma biomarker AUC

≈90-95%IWG CSF sensitivity

concernbetween-lab variability

13-150systematic reviews size

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Coverage Determinations and Rationale

Not Covered Biomarker Tests

Tests that do not meet coverage criteria due to insufficient evidence:

Not covered biomarker categories: Measurement of cerebrospinal fluid biomarkers of Alzheimer disease (including, but not limited to, tau protein, amyloid beta peptides, α-synuclein, and neural thread proteins) DOES NOT MEET COVERAGE CRITERIA; Measurement of plasma and/or serum biomarkers of Alzheimer disease (including, but not limited to, tau protein, amyloid beta peptides, neural thread proteins, ApoE, and ApoE4) DOES NOT MEET COVERAGE CRITERIA; Measurement of urinary biomarkers of Alzheimer disease (including, but not limited to, neural thread proteins, amyloid beta peptides, and urinary extracellular vesicle analysis) DOES NOT MEET COVERAGE CRITERIA; The use of multianalyte assays, algorithmic analysis, and/or any other tests not mentioned above for the prognosis, diagnosis, and/or management of Alzheimer disease or dementia DOES NOT MEET COVERAGE CRITERIA.

Policy lists these four explicit categories as not meeting coverage.

Guideline-based appropriate use and predictive utility

Recommendations summarized from professional organizations and expert groups regarding appropriate use of CSF and blood biomarkers:

Alzheimer's Association appropriate indications: CSF (lumbar puncture) biomarker testing is considered appropriate for: cognitively unimpaired individuals with subjective cognitive decline who are at increased risk for AD; patients with persistent, progressing, unexplained mild cognitive impairment (MCI); patients with symptoms that suggest possible AD; MCI or dementia with early onset (<65 years); and individuals meeting core clinical criteria for probable AD with typical onset.

Derived from Shaw et al., 2018 table of indications

Alzheimer's Association inappropriate indications: CSF testing is considered inappropriate for: cognitively unimpaired individuals with normal objective testing and no risk factors; cognitively unimpaired individuals at risk based only on family history; cognitively unimpaired individuals not at increased risk; and for purposes such as determining disease severity after diagnosis or routine testing in asymptomatic persons.

Derived from Shaw et al., 2018

JPND BIOMARKAPD on MCI: For patients with MCI, CSF biomarkers are recommended as an add-on to clinical evaluation to predict conversion to AD dementia and to predict functional or cognitive decline (strong recommendation for prediction of conversion/decline), but evidence was insufficient to recommend CSF biomarkers as an alternative to FDG‑PET or amyloid‑PET for predicting future decline.

Simonsen et al., 2017: strong recommendation for prediction but not as replacement for imaging

NIA‑AA guidance indicates combinations of biomarker abnormalities (for example, low CSF Aβ42 together with elevated CSF tau measures) increase the likelihood of progression to AD in MCI and are useful for staging the Alzheimer continuum; these guidelines are intended primarily for observational and interventional research rather than routine clinical care.

Jack et al., 2018; Albert et al., 2011

Measurement of biochemical biomarkers for Alzheimer disease in the following specimen types DOES NOT MEET COVERAGE CRITERIA and are explicitly excluded from coverage: (1) cerebrospinal fluid (CSF) biomarkers (e.g., tau proteins, amyloid beta peptides, α-synuclein, neural thread proteins); (2) plasma and/or serum biomarkers (e.g., tau, amyloid beta peptides, neural thread proteins, ApoE/ApoE4); (3) urinary biomarkers (e.g., neural thread proteins, amyloid beta peptides, urinary extracellular vesicle analysis); and (4) the use of multianalyte assays, algorithmic analysis, or other tests not specifically listed for diagnosis, prognosis, or management of Alzheimer disease or dementia.

Guideline authors do not advocate routine use of Alzheimer disease biomarker tests for all patients. Reasons cited include that core clinical criteria already provide good diagnostic accuracy in most patients, and that biomarker-based approaches require further study and validation. In addition, CSF biomarkers currently show large between-laboratory variability and limited availability, and some operational guidance states these measures are not approved or widely available for routine clinical use.

Routine CSF analysis is not recommended for all patients. CSF testing may be considered in select situations where the diagnosis remains uncertain or presentation is atypical — for example, patients with diagnostic uncertainty, early-onset dementia (onset <65 years), or predominant language, visuospatial, dysexecutive, or behavioral features — to help evaluate for Alzheimer disease pathophysiology.

The policy cites a number of bibliographic references and consensus documents used to inform these statements, and several of those references present guidance or evidence summaries rather than explicit payer coverage exclusions.

Consistent with the evidence review summarized in this policy, measurement of CSF, plasma/serum, and urinary biomarkers, as well as the use of multianalyte or algorithmic tests for Alzheimer disease, DO NOT MEET COVERAGE CRITERIA for diagnosis, prognosis, or management.

The American Academy of Neurology states that, as of their review, there are no accepted biomarkers for routine use to predict progression in patients with mild cognitive impairment (MCI). Clinicians should counsel patients and families that biomarkers are not established for routine prognostication and that the evidence base remains evolving.

The United States Preventive Services Task Force concluded that current evidence is insufficient to assess the balance of benefits and harms of screening for cognitive impairment in older adults, and therefore does not support routine population screening using biomarkers or other means at this time.

Several cited bibliographic entries provide background, methodological discussion, or consensus recommendations but do not themselves state explicit Not Medically Necessary or coverage-denial determinations; the policy synthesizes these sources to reach coverage conclusions.

Provider Requirements, Authorization, and Documentation

Prior Authorization

Prior Authorization for Biomarker Testing

Prior authorization may be required for biomarker testing. Note that this policy indicates CSF, plasma/serum, urine, and multianalyte/algorithmic tests for Alzheimer disease do not meet coverage criteria; providers should obtain prior authorization when required by the member's benefit plan and submit documentation supporting medical necessity and clinical context.

Excluded tests: CSF biomarkers (tau, amyloid beta, α‑synuclein, neural thread proteins)
Excluded tests: Plasma/serum biomarkers (tau, amyloid beta, ApoE/ApoE4, neural thread proteins)
Excluded tests: Urinary biomarkers and extracellular vesicle analysis
Excluded tests: Multianalyte assays/algorithmic tests

Prior Authorization

CSF Testing Indicated for Select Clinical Scenarios

CSF biomarker testing is indicated only for select clinical scenarios per specialty guidance. The Alzheimer's Association recommends CSF testing as appropriate for specific indications (eg, persistent/progressing unexplained MCI, suspected AD symptoms, early-onset onset <65, and certain SCD or high‑risk situations) and inappropriate for routine use in cognitively unimpaired individuals or certain other scenarios. Use CSF testing as an add‑on to clinical evaluation rather than as a standalone diagnostic test.

Appropriate indications include: persistent/progressive unexplained MCI, symptoms suggestive of AD, MCI or dementia with early onset (<65), meeting core clinical criteria for probable AD with typical onset
Inappropriate: routine testing in cognitively unimpaired individuals, APOE ɛ4 carriers without impairment, using LP solely to determine disease severity

Note

Confirm Coverage and Prior Authorization per Government and Payer Rules

Confirm coverage and prior authorization requirements per applicable government and payer rules. If there is any conflict between this policy and an applicable government determination (LCD/NCD) or state Medicaid rule, the government policy governs the coverage decision.

Verify Medicare LCDs/NCDs and state Medicaid policies prior to ordering
Follow payer-specific prior authorization processes when required

Note

Prior Authorization Not Specified in References

The references cited in this policy do not by themselves specify prior authorization procedures. Providers should not assume lack of a stated prior authorization requirement in the bibliography means prior authorization is not required by the payer or by applicable government programs.

Bibliographic references (guidelines, systematic reviews) generally do not include payer-specific prior authorization directives
Check the member's benefit plan and payer portals for operational prior authorization instructions

Documentation Required

Use CSF Biomarkers Only with Clinical Context

Do not use CSF or other biomarker assays as standalone diagnostic tests. CSF biomarkers must be interpreted within the full clinical context (clinical evaluation, imaging, comorbidities) due to between‑laboratory variability and lack of universally accepted cutoffs.

CSF Aβ1‑42 with elevated T‑tau or P‑tau supports AD pathology but must be integrated with clinical findings
Large between‑laboratory variability and absent standard cutoffs limits standalone interpretation

Documentation Required

Documentation Expectations

Document clinical rationale and laboratory method when ordering or submitting claims for biomarker tests. Include clinical presentation, objective testing results, specific indication (per specialty criteria), expected impact on management, and whether the assay is a laboratory‑developed test (LDT) or FDA‑cleared/approved.

Clinical documentation: symptoms, objective cognitive testing results, differential diagnosis, and how results will influence management
Laboratory documentation: test method, vendor/assay name, LDT status (if applicable), and quality control participation

Documentation Required

Need for Standardization and Quality Control

Address standardization and quality control concerns: confirm that laboratories participate in quality control or standardization programs (eg, Alzheimer's Association CSF QC initiatives) and be aware of between‑laboratory variability that can affect interpretation.

Prefer labs participating in recognized QC/standardization efforts
Note potential variability and request method‑specific reference ranges or cutoffs

Note

Consider Less Invasive Blood‑Based Biomarkers First

Consider using less invasive blood‑based biomarkers as an initial step in a multi‑stage diagnostic process, reserving CSF testing or PET confirmation for when blood biomarkers are positive or when additional confirmation is needed.

Blood biomarkers can serve as first‑step screening in a multi‑stage process
CSF or PET may be used to confirm results when clinically necessary

Step Therapy

No Step Therapy Directives in References

There are no step‑therapy directives or required prior diagnostic steps specified in the cited references. Payers may still impose step edits or clinical prerequisites; verify payer rules before ordering.

Guidelines/reviews do not mandate step therapy for biomarker testing
Check the member's benefit plan for any payer‑level step edits or prerequisites

Terms and Abbreviations

Selected terminology — CSF, Aβ42/40 ratio, P-tau and related terms

CSFCerebrospinal fluid (CSF)

Aβ42/40 ratioRatio of amyloid beta 42 to 40 peptides used to assess amyloid (Aβ) pathology

P-tauPhosphorylated tau protein (P-tau), a tau species measured to evaluate neurofibrillary pathology

T-tauTotal tau (T-tau), a measure of overall tau protein in CSF

NfLNeurofilament light chain (NfL), a marker of axonal injury noted in terminology list

Neurogranin (Ng) — definition and context

DefinitionNeurogranin (Ng): a postsynaptic protein measured in CSF studied as a prognostic biomarker in Alzheimer disease

Prognostic evidenceCSF Ng has been shown to predict MMSE decline and memory/executive decline in Aβ+ MCI patients

Clinical statusMay help predict progression from MCI to AD dementia but requires further validation before routine clinical use

Plasma p-tau181 — definition and diagnostic performance context

DefinitionPlasma p-tau181: phosphorylated-tau181 measured in blood as a noninvasive biomarker for Alzheimer disease

Diagnostic performancePlasma P-tau181 significantly outperformed other plasma biomarkers in differentiating AD dementia from cognitively unimpaired individuals

Prognostic associationHigher plasma P-tau181 values associated with increased cognitive decline and temporal gray matter loss

CSF AD signature — decreased Aβ1-42 with increased T-tau or P-tau

DefinitionCSF AD signature: decreased Aβ1-42 together with increased total tau (T-tau) or phosphorylated tau (P-tau) in CSF

InterpretationConsidered in-vivo biochemical evidence of Alzheimer pathology per IWG definitions

Alternative evidenceOther in-vivo evidence includes increased amyloid PET retention or presence of AD autosomal dominant mutation

Laboratory-developed test (LDT) — definition and CLIA '88 regulatory note

DefinitionLaboratory-developed test (LDT): a test developed and validated in-house by a laboratory

Regulatory noteLDTs are regulated by CMS as high-complexity tests under CLIA '88

FDA statusLDTs are not FDA-cleared or approved; FDA clearance is not currently required for clinical use

CSF biomarkers — examples used in diagnostic evaluation

Core CSF biomarkersAβ42 (amyloid beta 42) measured in cerebrospinal fluid

Aβ42/40 ratioAβ42/40 ratio, noted to correspond better than Aβ42 alone with amyloid PET

Total tau (T-tau)Measure of overall tau protein in CSF used in diagnostic evaluation

Phosphorylated tau (P-tau)Phosphorylated tau species in CSF used to assess neurofibrillary tangle pathology

Billing and Code Considerations

Not covered - Biomarker categoriesmixedNot Covered

	Measurement of cerebrospinal fluid biomarkers (e.g., tau, amyloid beta peptides, α-synuclein, neuronal thread proteins) DOES NOT MEET COVERAGE CRITERIA
	Measurement of plasma and/or serum biomarkers (e.g., tau, amyloid beta peptides, neural thread proteins, ApoE/ApoE4) DOES NOT MEET COVERAGE CRITERIA
	Measurement of urinary biomarkers (e.g., neuronal thread proteins, amyloid beta peptides, urinary extracellular vesicle analysis) DOES NOT MEET COVERAGE CRITERIA
	Use of multianalyte assays, algorithmic analysis, and other tests not specifically listed DOES NOT MEET COVERAGE CRITERIA

Guidance / Recommended appropriate use (not coverage)mixed

	Alzheimer's Association: CSF biomarker testing recommended for selected clinical indications (e.g., subjective cognitive decline at increased risk, persistent/progressive unexplained MCI, symptoms suggesting possible AD, early-onset <65, meeting core clinical criteria for probable AD with typical onset) — guidance only
	Alzheimer's Association: CSF testing inappropriate for cognitively unimpaired individuals with normal testing and no risk, unimpaired at risk based only on family history, for determining disease severity after AD diagnosis, APOE ɛ4 carriers without impairment, and use of LP in lieu of genotyping for ADAD mutation carriers
	JPND BIOMARKAPD: In MCI, CSF biomarkers may be used as an add-on to clinical evaluation to predict progression to AD dementia (recommendation for predictive use, not routine clinical replacement)

OpenPayer

Biochemical Markers of Alzheimer Disease and Dementia

Coverage Determinations and Rationale

Provider Requirements, Authorization, and Documentation

Clinical and Evidence Background

Terms and Abbreviations

Billing and Code Considerations

Document Revision History