Premera Bluecross Alzheimer biomarkers Coverage Update

Coverage Criteria

Medical necessity — CSF biomarkers for therapy initiation

Covered when ALL of the following are met

CSF testing for initiation: 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.

Examples: lecanemab (Leqembi), donanemab (Kisunla); presence of amyloid pathology should be confirmed prior to initiating labeled amyloid‑targeting therapies.

Investigational / Not medically necessary

Not covered / Investigational

Investigational biomarker uses: Measurement of biochemical markers of Alzheimer disease is considered investigational in any of the following: (1) cerebrospinal fluid biomarker testing of neural thread proteins as part of an evaluation for the initiation of amyloid beta–targeting therapy; (2) CSF biomarker testing (including but not limited to amyloid beta peptides, tau protein, neural thread proteins) as an adjunct to clinical diagnosis in individuals with MCI or mild dementia; (3) CSF biomarker testing (including but not limited to amyloid beta peptides, tau protein, neural thread proteins) as part of an evaluation for continuation of amyloid beta–targeting therapy; (4) measurement of plasma and/or serum biomarkers (including tau, amyloid beta peptides, neural thread proteins) as adjuncts to clinical diagnosis in MCI or mild dementia; (5) measurement of urinary biomarkers (including neural thread proteins, amyloid beta peptides, urinary extracellular vesicle analysis) as adjuncts to clinical diagnosis; (6) multianalyte assays, algorithmic analyses, skin biopsies, or CSF testing for alpha‑synuclein, or other tests not specified above used as adjuncts to clinical diagnosis.

These uses are considered investigational due to insufficient evidence of improved health outcomes.

Biomarker testing for therapy continuation

Covered when ALL of the following are met

Therapy continuation context: Patient has mild cognitive impairment or mild dementia due to Alzheimer disease, is receiving an amyloid beta plaque–targeting therapy, and is being evaluated for continuation of that therapy.

Diagnostic accuracy of CSF biomarkers and amyloid PET are similar; evidence is insufficient to determine whether CSF biomarkers alone inform continuation decisions to improve net health outcome.

Role of blood-based biomarkers

Recommended use

Blood-based biomarkers as prescreen: Blood-based markers may be used as prescreeners to identify individuals likely to have Alzheimer disease pathological changes, but positive prescreens should be confirmed with PET or CSF testing and not used as standalone diagnostic evidence.

Workgroup recommended against using blood markers as primary endpoints or as standalone diagnostic tests; use primarily to select individuals for confirmatory testing.

CSF assay interpretation and limitations

Interpretation guidance for FDA-cleared CSF assays

Assay interpretation: Results from FDA‑cleared CSF assays must be interpreted in conjunction with other clinical information; specific numerical cutoffs are provided by cleared assays (e.g., Lumipulse G amyloid ratio and Elecsys pTau181/Abeta42 and tTau/Abeta42) but do not establish a diagnosis when used alone.see thresholds module

Performance for predicting dementia development or monitoring therapy response has not been established; compare results to manufacturer‑provided cutoffs.

Investigational and adjunct-use criteria

Policy statements and investigational determinations (as recorded in History):

Investigational - general: Measurement of biochemical markers of Alzheimer disease is considered investigational.

Original policy statement (effective 05/01/24).

Investigational - CSF neural thread proteins: Measurement of cerebrospinal fluid biomarker testing of neural thread proteins as part of an evaluation for the initiation or continuation of amyloid beta–targeting therapy in individuals with MCI or mild dementia due to Alzheimer disease is considered investigational.

Added effective April 6, 2025 per policy history.

Regulatory-cleared assay adjunct use: Specific FDA‑cleared assays (e.g., Elecsys, Lumipulse) are indicated as adjuncts to clinical evaluation and are not intended as screening or standalone diagnostic tests; manufacturers provide numeric cutoffs and intended‑use language.

See regulatory indication language and numeric cutoffs in Regulatory Status.

The policy explicitly designates several specimen types and test classes as investigational when used as adjuncts to clinical diagnosis or for therapy continuation. Use of blood, urine, multianalyte algorithms, skin fibroblast tests (e.g., Discern), urinary extracellular vesicle analyses, CSF neural thread protein testing, and other non‑specified assays for adjunctive diagnostic evaluation or for evaluating continuation of amyloid‑targeting therapy are considered investigational and may be denied.

The policy follows evidence‑based recommendations that biomarker testing should not be applied routinely to all individuals and should not be used as a standalone diagnostic in most clinical settings. The 2011 revised diagnostic criteria workgroup noted that biomarker tests are not recommended for routine diagnostic purposes because of limited standardization and access; biomarkers may be useful in selected circumstances such as investigational studies or trials. Workgroups also recommend that blood‑based markers be used as prescreeners only and that any positive prescreen result be confirmed with CSF or PET testing.

Regulatory‑cleared assays (for example, Lumipulse and Elecsys products) are cleared with intended‑use language that frames results as adjuncts to clinical evaluation rather than screening or standalone diagnostics. The policy notes that these assays’ instructions state results must be interpreted in conjunction with other clinical information and are not intended as screening or stand‑alone diagnostic tests.

Given limitations in clinical validity and uncertainty about impact on health outcomes, the policy considers many urinary and blood biomarker tests investigational and not medically necessary. Urinary biomarker testing and numerous blood/plasma assays (including multianalyte/algorithmic analyses and other non‑specified serum/plasma biomarkers) are listed as investigational because existing studies have limited generalizability and do not demonstrate improved net health outcomes.

The policy does not support use of blood‑based biomarkers as a standalone diagnostic for Alzheimer disease. While plasma assays (e.g., p‑tau measures) may have utility as prescreeners, the policy requires confirmatory testing with CSF or amyloid PET before diagnosing or before initiating labeled amyloid‑targeting therapies; the FDA‑approved drug labels cited in the evidence require confirmation of amyloid pathology prior to treatment initiation.

Policy history entries record a general investigational stance for biochemical markers of Alzheimer disease. The policy creation and subsequent updates state that measurement of biochemical markers of Alzheimer disease is considered investigational, and later history entries (effective April 6, 2025) specifically added investigational determinations for CSF testing of neural thread proteins and expanded investigational language covering CSF and other biomarker uses as adjuncts or for therapy continuation.

Coding and Test Identifiers

Listed CPT/CodesCPT

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 (use to report: DISCERN).
0207U	Neurology (Alzheimer disease); quantitative imaging of 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 (use to report: DISCERN).
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 (Lumipulse).
0361U	Neurofilament light chain, digital immunoassay, plasma, quantitative (use to report: Neurofilament Light Chain/Mayo Clinic) (code termed 01/01/26).
0393U	Cerebrospinal fluid (CSF), detection of misfolded α-synuclein protein by seed amplification assay, qualitative (use to report: SYNTap Biomarker Test).
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 (use to report: PrecivityAD).
0443U	Neurofilament light chain (NfL), ultra-sensitive immunoassay, serum or cerebrospinal fluid (use to report: Neurofilament Light Chain/Washington University Neuromuscular Clinical Laboratory).
0445U	B-amyloid (Abeta42) and phospho tau (181P) (pTau181), electrochemiluminescent immunoassay (ECLIA), cerebral spinal fluid, ratio reported as positive or negative for amyloid pathology (Elecsys Phospho-Tau CSF and B-Amyloid CSF II Ratio).
0459U	B-amyloid (Abeta42) and total tau (tTau), electrochemiluminescent immunoassay (ECLIA), cerebral spinal fluid, ratio reported as positive or negative for amyloid pathology (Elecsys Total Tau CSF and B-Amyloid CSF II Ratio).
0479U	Tau, phosphorylated, pTau217.

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Regulatory/product codes mentionedmixed

QSE (product code)

FDA product code referenced for cleared AD biomarker tests.

Biomarker CPT/HCPCS codes mentioned in historymixed

0206U	Added per History
0207U	Added per History
0346U	Removed/termed per History
0361U	Added per History; later noted termed 01/01/26
0393U	Added per History
0412U	Added per History
0443U	Added per History
81099	Added per History
86849	Added per History
0479U	Coding update added 10/01/24

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inv-16: Lumipulse G amyloid ratio — numeric interpretation categories

Lumipulse G amyloid ratio - Positive≤0.058 (consistent with a positive amyloid PET scan) — does not by itself establish a diagnosis of AD

Lumipulse G amyloid ratio - Likely positive0.059–0.072 (more likely consistent with a positive amyloid PET scan) — increased uncertainty

Lumipulse G amyloid ratio - Negative≥0.073 (consistent with a negative amyloid PET scan) — reduces likelihood that cognitive impairment is due to AD

inv-17: Elecsys pTau181/Abeta42 ratio — adjusted ratio cutoff

Elecsys pTau181/Abeta42 ratio — Adjusted cutoffAdjusted ratio cutoff = 0.023; values above cutoff are consistent with a positive amyloid PET scan (adjunct to clinical evaluation)

Provider Actions and Operational Requirements

Prior Authorization

Prior Authorization Required

Prior authorization is required for CSF biomarker testing when used to evaluate initiation of an FDA‑approved amyloid‑targeting therapy. Providers must verify prior authorization has been obtained and that the requested biomarker assay CPT/HCPCS codes match the approved authorization.

Affected codes: verify current CPT/HCPCS list (policy history contains multiple coding updates).
Confirm PA for assays used to document amyloid pathology before treatment initiation.

Denial Risk

Documentation and Denial Risk for Plasma/Serum/Urine Biomarkers

Requests for measurement of plasma, serum, or urinary biomarkers for adjunctive clinical use should be accompanied by documentation of medical necessity. Such requests may be denied when used solely as adjuncts to clinical diagnosis or for therapy continuation decisions unless otherwise supported by the policy.

Background

Alzheimer disease is a progressive neurodegenerative disorder characterized by extracellular amyloid beta plaques and intracellular neurofibrillary tangles. Biomarkers in cerebrospinal fluid, blood, and urine — including CSF Aβ42 (or Aβ42/Aβ40), total tau (t‑tau), and phosphorylated tau (p‑tau) — have been developed to detect amyloid and tau pathology. CSF biomarkers have diagnostic parity with amyloid PET in many studies and were used in randomized controlled trials supporting amyloid‑targeting therapies. However, limitations in standardization, generalizability, and demonstrated impact on net health outcomes mean many non‑CSF biomarkers remain under evaluation; blood‑based markers are currently positioned as prescreeners requiring confirmatory CSF or PET testing.

Definitions and Frameworks

inv-35: A/T/N framework — definitions of biomarker categories

A (Amyloid)Aggregated Aβ or associated pathologic state (examples: low CSF Aβ42, low CSF Aβ42/Aβ40 ratio, or positive amyloid PET)

T (Tau)Aggregated tau or associated pathologic state (examples: elevated CSF phosphorylated tau or positive tau PET)

N (Neurodegeneration)Neurodegeneration/neuronal injury (examples: anatomic MRI atrophy, FDG PET hypometabolism, or elevated CSF total tau)

inv-36: Core CSF biomarkers — Aβ42, t-tau, p-tau definitions

Aβ42 (CSF)Cerebrospinal fluid amyloid beta‑42 (Aβ42) — low CSF Aβ42 associated with amyloid plaque deposition in AD

Total tau (t‑tau)CSF total tau — reflects neurodegeneration/neuronal injury and is typically elevated in AD

OpenPayer

Evaluation of Biomarkers for Alzheimer Disease

Coverage Criteria

Coding and Test Identifiers

Provider Actions and Operational Requirements

Background

Definitions and Frameworks