Blue Cross Blue Shield - Tennessee Alzheimer Biomarkers Coverage

Coverage Criteria

Not Medically Necessary / Not Covered Tests

Not covered when ANY of the following are requested

Non-covered biomarker categories: Measurement of cerebrospinal fluid biomarkers of Alzheimer disease or dementia (e.g., tau protein, amyloid beta peptides, α-synuclein, or neural thread proteins) DOES NOT MEET COVERAGE CRITERIA.

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Non-covered plasma/serum biomarkers: Measurement of plasma and/or serum biomarkers of Alzheimer disease or dementia (e.g., tau protein, amyloid beta peptides, neural thread proteins, ApoE, and ApoE4) DOES NOT MEET COVERAGE CRITERIA.

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Non-covered urinary biomarkers: Measurement of urinary biomarkers of Alzheimer disease or dementia (e.g., neural thread proteins, amyloid beta peptides, and urinary extracellular vesicle analysis) DOES NOT MEET COVERAGE CRITERIA.

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Non-covered multianalyte/algorithmic tests: 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.

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Appropriate Use

CSF biomarker testing is supported as appropriate in the following clinical contexts according to the Alzheimer's Association and specialty workgroups when results would inform diagnosis or management:

Appropriate Indications: Patients with persistent, progressive, and unexplained mild cognitive impairment (MCI)

Appropriate (Shaw et al., 2018)

Appropriate Indications: Patients with symptoms that suggest possible Alzheimer disease

Appropriate (Shaw et al., 2018)

Appropriate Indications: Early-onset MCI or dementia (onset <65 years)

Appropriate (Shaw et al., 2018)

Appropriate Indications: Patients meeting core clinical criteria for probable Alzheimer disease with typical age of onset when biomarker confirmation would affect care or management

Inappropriate Use

Biomarker testing is considered inappropriate in these scenarios:

Inappropriate Indications: Cognitively unimpaired individuals without risk factors or subjective cognitive decline

Inappropriate (Shaw et al., 2018)

Inappropriate Indications: Unselected cognitively unimpaired individuals, including asymptomatic APOE ɛ4 carriers

Inappropriate (Shaw et al., 2018)

Inappropriate Indications: Use of lumbar puncture or biomarker testing solely to determine disease severity in patients already diagnosed with Alzheimer disease

Inappropriate (Shaw et al., 2018)

Evidence considerations

Evidence summaries and assay performance that inform coverage decisions:

Plasma Aβ performance: Plasma Aβ42 and Aβ40 measured with Elecsys immunoassays predicted Aβ PET status with AUC in the range 0.80–0.86; adding APOE genotype increased AUC to ~0.85 (Palmqvist et al., 2019).AUC 0.80–0.86

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P-tau181 utility: Plasma phosphorylated-tau181 (P-tau181) outperformed other plasma markers in differentiating AD from cognitively unimpaired and was associated with cognitive decline and regional gray matter loss (Simrén et al., 2021).

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Analytic variability caution: Plasma and CSF biomarker measurements may be affected by preanalytical handling and assay performance, which can lead to misclassification (false-negative or false-positive) and limit clinical reliability without standardization (Nojima et al., 2022).

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Appropriate use criteria (per IWG and consensus statements)

Use of biomarkers to support an AD diagnosis is recommended when clinical phenotype and context warrant confirmation and when results will impact management.

IWG diagnostic framework: Both a specific clinical phenotype of Alzheimer disease (phenotype positive) AND biomarker evidence of Alzheimer's pathology (amyloid-positive and tau-positive) are required to establish an AD diagnosis; CSF is prioritized because it provides simultaneous information on both amyloid β and tau.

IWG; CSF preferred when lumbar puncture is not contraindicated; PET alternative (Dubois et al., 2014; Dubois et al., 2021)

When to consider biomarkers: Consider biomarker testing in symptomatic patients with typical AD phenotypes (e.g., amnestic variant, logopenic primary progressive aphasia, posterior cortical atrophy), in cases of diagnostic uncertainty, early-onset disease (<65 years), atypical presentations, or when results would alter management or trial eligibility; plasma biomarkers are not currently recommended for routine clinical practice pending further validation.

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Measurement of cerebrospinal fluid (CSF), plasma/serum, urinary, or multianalyte/algorithmic biomarker tests for the diagnosis, prognosis, or management of Alzheimer disease or dementia DOES NOT MEET COVERAGE CRITERIA. The policy lists CSF biomarkers (e.g., tau protein, amyloid beta peptides, α-synuclein, neuronal thread proteins), plasma/serum analytes (e.g., tau, amyloid beta peptides, ApoE), urinary markers (e.g., neuronal thread proteins, amyloid peptides, urinary extracellular vesicle analysis), and multianalyte or algorithmic analyses as not meeting coverage due to insufficient published evidence that these tests are required and beneficial for diagnosis or treatment.

Professional guideline panels have concluded that biomarker testing should not be used routinely for all patients with suspected Alzheimer disease. The 2011 diagnostic workgroup and subsequent specialty guidance note that core clinical criteria provide good diagnostic accuracy, that biomarker-based criteria require further validation and standardization, and that biomarkers should be considered in limited circumstances (e.g., investigational studies, trials, or when clinically appropriate) rather than as routine first-line testing.

Investigating pathophysiological biomarkers in cognitively unimpaired individuals for screening is not recommended at this time. Consensus guidance states plasma and CSF biomarkers cannot reliably predict clinical trajectories in asymptomatic, biomarker‑positive people, and the USPSTF finds current evidence insufficient to recommend screening for cognitive impairment in older adults.

Procedure and proprietary test codes listed in this policy are provided solely as a general reference tool and may not be all‑inclusive. Providers should confirm the appropriate billing code for the specific test and laboratory prior to submission.

The bibliographic references included in this policy provide supporting literature on biomarker research and guidelines but do not themselves establish coverage decisions, medical necessity criteria, or exclusions. Coverage determinations are set by the policy language and applicable benefit terms.

The policy addresses measurements from multiple specimen types including cerebrospinal fluid (CSF), plasma/serum, and urine, and refers to specific biomarkers such as amyloid‑β (Aβ1‑42, Aβ1‑40 and the Aβ42/40 ratio), total tau (T‑tau), phosphorylated tau (P‑tau), α‑synuclein, and neuronal thread proteins, as well as proprietary assay tests reported under assigned U‑codes.

Guidance from specialty bodies recommends against routine use of CSF or blood biomarkers as standard first‑line diagnostic tests in unselected patients. Biomarker testing is generally advised only when the clinical context (for example, persistent or progressive MCI, early‑onset symptoms, atypical phenotype, or when results will change management) supports its use.

CSF and other biomarkers are not recommended for routine use in the general evaluation of suspected Alzheimer disease absent a clear clinical justification; specialty guidance emphasizes standard clinical assessment first and reserves biomarker testing for select indications where results will inform diagnosis, prognosis, management, or trial eligibility.

This portion of the document does not contain separate explicit 'not medically necessary' statements beyond the coverage criteria set forth elsewhere in the policy; the references listed are citations supporting the scientific context and do not change the coverage stance.

Summary coverage decision for providers: measurement of CSF, plasma/serum, urinary, or multianalyte/algorithmic biomarkers for Alzheimer disease or dementia does not meet coverage criteria under this policy and therefore is not covered unless the request meets a documented appropriate indication per the policy and applicable benefit provisions.

Coding and Test Identifiers

Proprietary assays mentionedmixed

Elecsys® beta-Amyloid (1-42) CSF II (Abeta42)	Roche Elecsys assay for CSF Abeta42 (FDA 510(k) clearance mentioned)
Elecsys® Phospho-Tau (181P) CSF (pTau181)	Roche Elecsys assay for CSF pTau181 (FDA 510(k) clearance mentioned)
Elecsys® Total-Tau CSF (tTau)	Roche Elecsys total tau CSF assay (FDA 510(k) clearance mentioned)
Lumipulse® G β-Amyloid Ratio (1-42/1-40)	Fujirebio Lumipulse CSF beta-amyloid 1-42/1-40 ratio assay (Breakthrough Device Designation cited)
PrecivityAD (C2N Diagnostics)	Blood test measuring Aß42/Aß40 ratio and ApoE detection (Breakthrough Device Designation cited)
LucentAD (Quanterix)	Serum p-tau181 assay (launched July 2023; not FDA approved at time of text)

Listed Proprietary Biomarker CPT/HCPCS U-codesCPT/HCPCS

0206U	Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified = 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; Proprietary test: DISCERN™; Lab/Manufacturer: NeuroDiagnostics.
0207U	Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified = 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; Proprietary test: DISCERN™; Lab/Manufacturer: NeuroDiagnostics.
0289U	Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified = Neurology (Alzheimer disease), mRNA, gene expression profiling by RNA sequencing of 24 genes, whole blood, algorithm reported as predictive risk score; Proprietary test: MindX Blood Test™ - Memory/Alzheimer's; Lab/Manufacturer: MindX Sciences™ Laboratory/MindX Sciences™ Inc.
0346U	Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified = Beta amyloid, Aβ40 and Aβ42 by liquid chromatography with tandem mass spectrometry (LC-MS/MS), ratio, plasma; Proprietary test: QUEST AD-Detect™; Beta-Amyloid 42/40 Ratio, Plasma; Lab/Manufacturer: Quest Diagnostics.
0358U	Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified = Neurology (mild cognitive impairment), analysis of β-amyloid 1-42 and 1-40, chemiluminescence enzyme immunoassay, cerebrospinal fluid, reported as positive, likely positive, or negative; Proprietary test: Lumipulse® G β-Amyloid Ratio (1-42/1-40) Test; Lab/Manufacturer: Fujirebio Diagnostics, Inc.
0393U	Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified = Neurology (e.g., Parkinson disease, dementia with Lewy bodies), cerebrospinal fluid (CSF), detection of misfolded α-synuclein protein by seed amplification assay, qualitative; Proprietary test: SYNTap® Biomarker Test; Lab/Manufacturer: Amprion Clinical Laboratory.

Proprietary assay U-codes listedCPT

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; Proprietary test: DISCERN™; Lab/Manufacturer: NeuroDiagnostics.
0207U	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; Proprietary test: DISCERN™; Lab/Manufacturer: NeuroDiagnostics.
0289U	Neurology (Alzheimer disease), mRNA, gene expression profiling by RNA sequencing of 24 genes, whole blood, algorithm reported as predictive risk score; Proprietary test: MindX Blood Test™ - Memory/Alzheimer's; Lab/Manufacturer: MindX Sciences™ Laboratory/MindX Sciences™ Inc.
0346U	Beta amyloid, Aβ40 and Aβ42 by liquid chromatography with tandem mass spectrometry (LC-MS/MS), ratio, plasma; Proprietary test: QUEST AD-Detect™; Beta-Amyloid 42/40 Ratio, Plasma; Lab/Manufacturer: Quest Diagnostics.
0358U	Neurology (mild cognitive impairment), analysis of β-amyloid 1-42 and 1-40, chemiluminescence enzyme immunoassay, cerebrospinal fluid, reported as positive, likely positive, or negative; Proprietary test: Lumipulse® G β-Amyloid Ratio (1-42/1-40) Test; Lab/Manufacturer: Fujirebio Diagnostics, Inc.
0393U	Neurology (e.g., Parkinson disease, dementia with Lewy bodies), cerebrospinal fluid (CSF), detection of misfolded α-synuclein protein by seed amplification assay, qualitative; Proprietary test: SYNTap® Biomarker Test; Lab/Manufacturer: Amprion Clinical Laboratory.

CSF Aß42/40 concordance — Aß42/40 ratio vs Aß42 alone

Concordance with amyloid PETCSF Aß42/40 ratio: 89.4% concordance with PET; Aß42 alone: 74.9% concordance.

AUC comparisonAß42/40 ratio AUC 0.936 vs Aß42 alone AUC 0.814 (Lewczuk et al., 2017).

Study populationStudy compared 200 patients (150 PET-negative, 50 PET-positive) against PET results.

IWG reported diagnostic performance — CSF combination sensitivity/specificity

Sensitivity of combined CSF Aβ and tauReported sensitivity 90–95% for combination of Aβ1-42 and tau (T-tau or P-tau).

Specificity of combined CSF Aβ and tau

Provider Actions, Documentation & Authorization

Denial Risk

Measurement of CSF, plasma/serum, or urinary biomarkers — Coverage status

Measurement of cerebrospinal fluid (CSF), plasma/serum, or urinary biomarkers for Alzheimer disease or dementia does not meet coverage criteria due to insufficient evidence of clinical benefit. Requests for such testing should include clinical justification and documentation supporting the relevant clinical phenotype and rationale (e.g., to resolve diagnostic uncertainty or inform management). Coverage determinations depend on the individual's benefit plan and applicable Medicare/Medicaid specifications; proprietary assays may have separate coverage rules.

CSF biomarkers (e.g., tau, phosphorylated tau, Aβ42, Aβ40, Aβ42/Aβ40 ratio, α-synuclein) — NOT COVERED (does not meet coverage criteria).
Plasma/serum biomarkers (e.g., p-tau181, Aβ42/40, neurofilament light, ApoE) — NOT COVERED (does not meet coverage criteria).
Urinary biomarkers (e.g., neural thread proteins, urinary extracellular vesicle analysis) — NOT COVERED (does not meet coverage criteria).
Multianalyte/algorithmic assays and other novel tests for prognosis, diagnosis, or management of AD/dementia — NOT COVERED (does not meet coverage criteria).
Include clinical justification and documentation of the clinical phenotype when ordering (see documentation callout).

Background and Scope

Background: Alzheimer disease is a progressive neurodegenerative disorder characterized by cognitive decline associated with amyloid plaques and neurofibrillary tangles. This policy covers laboratory tests that measure biochemical biomarkers (CSF Aβ1‑42, Aβ1‑40, Aβ42/40 ratio, total tau, phosphorylated tau, α‑synuclein, neuronal thread proteins, plasma phosphorylated tau and other blood biomarkers, urinary markers, extracellular vesicle analyses, and proprietary multianalyte assays) when ordered for diagnosis, prognosis, or management of Alzheimer's disease.

Definitions and Key Terms

CSF — cerebrospinal fluid definition and biomarkers measured

Definition of CSFCerebrospinal fluid (CSF): fluid analyzed for biomarkers such as Aß42, Aß40, total tau (T-tau), and phosphorylated tau (P-tau).

SourceTerminology and definitions listed in the policy Table of Terminology and reimbursement policy sections.

Sample sourceObtained via lumbar puncture (LP) for biochemical biomarker analysis.

Aß42/40 ratio — definition and rationale

DefinitionAß42/40 ratio = ratio of amyloid beta 1-42 to amyloid beta 1-40 measured in CSF; preferred to Aß42 alone for amyloid PET concordance.

Rationale for useLewczuk et al. (2017) concluded the CSF Aß42/40 ratio is superior to Aß42 alone as a marker of amyloid-positivity by PET (higher concordance and AUC).

References and Bibliography

The bibliography lists primary studies, systematic reviews, and guideline statements that inform the policy (for example, recommendations on CSF biomarkers, studies of plasma and urinary markers, and reviews of genetic biomarkers). These citations provide scientific context but do not by themselves define coverage or guarantee reimbursement.

OpenPayer

Biochemical Markers of Alzheimer Disease

Coverage Criteria

Coding and Test Identifiers

Provider Actions, Documentation & Authorization

Background and Scope

Definitions and Key Terms

References and Bibliography