Blue Cross MA CSF biomarkers Coverage Update

Coverage Criteria and Clinical Indications

Covered and investigational biomarker uses

Policy coverage statements

CSF testing for adjunct diagnosis in MCI: Cerebrospinal fluid biomarker testing (amyloid beta peptides, tau protein, neural thread proteins) as an adjunct to clinical diagnosis in individuals with mild cognitive impairment is considered INVESTIGATIONAL.

From policy Diagnosis section; neural thread proteins included.

CSF testing as adjunct in mild dementia due to AD: Cerebrospinal fluid biomarker testing as an adjunct to clinical diagnosis in individuals with mild dementia due to Alzheimer disease is considered INVESTIGATIONAL.

From policy Diagnosis section.

CSF amyloid beta and tau testing for initiation of amyloid-targeting therapy: CSF biomarker testing of amyloid beta peptides and tau protein as part of 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.

Policy specifies this covered therapy-related use; see policy guidelines for trial-based confirmation methods.

CSF neural thread proteins for initiation of therapy: Cerebrospinal fluid testing of neural thread proteins as part of evaluation for the initiation of amyloid beta–targeting therapy is considered INVESTIGATIONAL.

Neural thread proteins are listed separately as investigational despite other CSF biomarkers being covered for therapy initiation.

CSF/blood/urinary biomarkers for continuation of therapy: Cerebrospinal fluid biomarker testing (amyloid beta, tau, neural thread proteins) as part of an evaluation for continuation of amyloid beta–targeting therapy in individuals with MCI or mild dementia due to Alzheimer disease is considered INVESTIGATIONAL.

Policy labels continuation testing investigational.

Blood and urinary biomarker testing for diagnosis or evaluation: 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.

Reflects policy summary and investigational CPT code listings for blood tests.

Initial therapy selection with CSF biomarkers

Covered when ALL of the following are met

CSF selection for initiation: Use of CSF biomarkers to select individuals for initiation of FDA‑approved amyloid beta plaque targeting therapies is considered MEDICALLY NECESSARY when used to confirm presence of amyloid beta pathology as required by the therapy's FDA label (e.g., confirmation by CSF t‑tau/Aβ1‑42 or positive amyloid PET per pivotal trial protocols).

Derived from Therapy section and Policy Guidelines noting pivotal trial eligibility criteria for lecanemab and donanemab.

Investigational or Not Medically Necessary Indications

Investigational/Not established when ANY of the following are true

General diagnostic/prognostic use: Use of CSF, blood, or urinary biomarkers for diagnosis of Alzheimer disease or for prediction of progression from mild cognitive impairment to Alzheimer disease is considered INVESTIGATIONAL/NOT MEDICALLY NECESSARY because evidence is insufficient to demonstrate improvement in net health outcomes; many studies derive cutoffs from select samples without validation.

Reflects Summary of Evidence regarding insufficient evidence for general diagnostic or prognostic use.

Continuation of therapy: Use of CSF biomarkers alone (or in lieu of amyloid PET) to determine continuation of amyloid beta–targeting therapy is considered INVESTIGATIONAL/NOT MEDICALLY NECESSARY; further research is required to establish clinical utility for therapy continuation decisions.

Based on Summary of Evidence indicating insufficient evidence to support use of CSF biomarkers alone for continuation decisions.

Cerebrospinal fluid (CSF) biomarker testing performed solely to determine whether to continue an FDA‑approved amyloid beta–targeting therapy is considered investigational. The policy specifies that CSF measurements of amyloid beta peptides, total or phosphorylated tau, or neural thread proteins for the purpose of continuation decisions are not established as having demonstrated clinical utility to guide ongoing treatment.

Evidence from longitudinal and cohort studies has not shown that CSF biomarker results alone reliably inform continuation decisions compared with amyloid PET, and further research is required to determine whether CSF testing can improve net health outcomes when used for this purpose.

The policy considers widespread use of urinary biomarkers and many blood biomarkers as adjuncts to routine diagnostic or prognostic evaluation in individuals with mild cognitive impairment or mild dementia due to Alzheimer disease to be investigational. Clinical validity for many urinary and blood assays is uncertain because studies have often been performed in selected samples and optimal cutoffs have not been validated in general populations.

Because available evidence does not demonstrate that these tests improve important health outcomes (for example, by altering management to delay progression or improve quality of life), routine use for diagnosis or prognosis is not supported.

A number of newer plasma and investigational assays are specifically listed in the policy as investigational (not covered for Commercial Members). Examples include CPT codes for tests such as 0361U, 0412U, 0443U, 0503U, 0551U, 0568U, and 0596U, which describe assays for plasma neurofilament light, plasma Aβ42/40 with algorithmic reporting, plasma NfL, multiplex plasma amyloid/tau panels, and APOE isoform–specific plasma peptides.

These assays are considered investigational because their clinical validity and utility for routine diagnosis, prognosis, or therapy selection have not been established in the settings and populations relevant to coverage decisions.

Overall, CSF, blood, and urinary biomarker testing for general diagnostic or prognostic use in Alzheimer disease — including testing to predict conversion from mild cognitive impairment to Alzheimer dementia — is considered insufficient or investigational. Many clinical validity studies used select samples and derived optimal cutoffs without adequate external validation, limiting generalizability.

Although some biomarkers (for example, plasma pTau measures or CSF Aβ and tau) may correlate with disease or increased risk of progression, the evidence does not yet demonstrate that routine application of these tests leads to improved net health outcomes such as changes in management that delay onset or improve quality of life.

Billing and Code Lists

Covered CPT/HCPCS codes for Medicare PPO Blue when medical necessity criteria metmixedCovered

82233	Beta-amyloid; 1-40 (Abeta 40)
82234	Beta-amyloid; 1-42 (Abeta 42)
84393	Tau_phosphorylated (eg pTau 181,pTau 217) each
84394	Tau, total (tTau)
0358U	Neurology (mild cognitive impairment), analysis of B-amyloid 1-42 and 1-40, chemiluminescence enzyme immunoassay, cerebral spinal fluid, reported as positive, likely positive; or negative
0445U	B-amyloid (Abeta42) and Phospho Tau (181P) (pTau181), electrochemiluminescence immunoassay (ECLIA); cerebral spinal fluid, ratio reported as positive or negative for amyloid pathology
0459U	B-amyloid (Abeta42) and total tau (tTau), electrochemiluminescent immunoassay (ECLIA); cerebral spinal fluid, ratio reported as positive or negative for amyloid pathology
0479U

CPT codes considered investigational for Commercial MembersCPTNot Covered

0361U	Neurofilament light chain, digital immunoassay, plasma, quantitative
0412U	Beta amyloid, Aβ42/40 ratio, immunoprecipitation with quantitation by liquid chromatography with tandem mass spectrometry (LC-MS/MS) and qualitative ApoE isoform-specific proteotyping; plasma combined with age, algorithm reported as presence or absence of brain amyloid pathology
0443U	Neurofilament light chain (NfL), ultra-sensitive immunoassay, serum or cerebrospinal fluid
0503U	Neurology (Alzheimer disease), beta amyloid (AB40, AB42, AB42/40 ratio) and tau-protein (pTau217, np-tau217, pTau217/np-tau217 ratio), blood, immunoprecipitation with quantitation by liquid chromatography with tandem mass spectrometry (LC-MS/MS)
0551U	Tau, phosphorylated, pTau217, by single-molecule array (ultrasensitive digital protein detection) using plasma
0568U	Neurology (dementia) beta amyloid (AB40, AB42, AB42/40 ratio), tau-protein phosphorylated at residue (eg, pTau217), Neurofilament light chain (Nf-L), and glial fibrillary acidic protein (GFAP), by ultra-high sensitivity molecule array detection, plasma, algorithm reported as positive, intermediate or negative for Alzheimer pathology
0596U	Neurology (Alzheimer disease), plasma, 3 distinct isoform-specific peptides (APOE2, APOE3, and APOE4) by liquid chromatography with tandem mass spectrometry (LC-MS/MS)

ICD Diagnosis codes considered medically necessary when submitted with CPT codesICD-10

G30.0	Alzheimer's disease with early onset
G30.1	Alzheimer's disease with late onset
G30.8	Other Alzheimer's disease
G30.9	Alzheimer's disease, unspecified
G31.84	Mild cognitive impairment of uncertain or unknown etiology
R41.81	Age-related cognitive decline

Coding clarifications referencedmixed

No codes listed

Clinical trial eligibility confirmation (amyloid pathology confirmation)

Eligibility criterion used in lecanemab trialPresence of amyloid pathology confirmed by either positive amyloid PET or CSF t-tau/Aβ1-42 (per Clarity AD protocol).

Donanemab trial eligibilityTRAILBLAZER-ALZ 2 used PET assessment (flortaucipir F18 and florbetapir F18) rather than CSF.

Purpose for confirmationConfirmation of amyloid pathology is required prior to initiating FDA-approved amyloid beta–targeting therapies.

None specified

Specified contentNone specified.

References section

Provider Requirements and Operational Notes

Prior Authorization

Prior Authorization Required

Precertification/prior authorization is required for services described in this policy when performed inpatient. For outpatient procedures, consult product-specific rules below; many outpatient CSF or blood biomarker tests do not require prior authorization for several commercial and Medicare products, but providers should verify member-specific benefits.

Inpatient procedures: precertification/prior authorization IS REQUIRED for all products when performed inpatient.
Outpatient procedures: prior authorization generally NOT required for outpatient CSF/blood biomarker testing for most Commercial Managed Care, Commercial PPO/Indemnity, and Medicare products — verify member contract.

Documentation Required

Therapy-Related Biomarker Confirmation Required

FDA-approved amyloid-targeting therapies require confirmation of amyloid beta pathology prior to initiating treatment. Confirmation may be documented by an amyloid PET scan or by CSF biomarkers consistent with amyloid pathology per the therapies' prescribing information and pivotal trial eligibility criteria.

Clinical Background

Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized pathologically by extracellular amyloid beta plaques and intracellular neurofibrillary tau tangles. Biochemical biomarkers measured in cerebrospinal fluid (CSF) — including CSF amyloid beta 1‑42 and measures of total and phosphorylated tau — and emerging blood biomarkers (for example, plasma phosphorylated tau and neurofilament light) are being evaluated to assist with diagnosis, prognosis, and identification of patients likely to benefit from amyloid‑targeting therapies.

CSF biomarkers have demonstrated diagnostic correlations with amyloid PET in research settings, but test performance can vary across laboratories and many studies have been performed in selected populations using unvalidated cutoffs. Plasma biomarkers are promising for less invasive screening and selection, but validation and demonstration of improved clinical outcomes are still evolving. For FDA‑approved amyloid‑targeting therapies, confirmation of amyloid pathology (by amyloid PET or CSF measures) is expected per product labeling to identify appropriate candidates for treatment.

Key Definitions and Biomarker Groups

A/T/N biomarker groups — definitions

A (Amyloid)Aggregated amyloid beta or associated pathologic state (CSF Aβ42, Aβ42/Aβ40 ratio, or amyloid PET).

T (Tau)Aggregated tau/neurofibrillary tangles or associated pathologic state (CSF phosphorylated tau or tau PET).

N (Neurodegeneration)Neurodegeneration or neuronal injury (anatomic MRI, FDG PET, or CSF total tau).

CSF biomarkers — description

Analytes measuredCerebrospinal fluid measurements include amyloid beta 1-42 and total or phosphorylated tau proteins used to assess AD-related pathology.

Clinical roleCSF biomarkers correlate with amyloid PET and can be used to select patients for initiation of amyloid-targeting therapies.

OpenPayer

Cerebrospinal fluid and blood biomarkers for Alzheimer disease

Coverage Criteria and Clinical Indications

Billing and Code Lists

Provider Requirements and Operational Notes

Clinical Background

Key Definitions and Biomarker Groups