Biochemical Markers of Alzheimer Disease and Dementia
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This policy describes coverage determinations for measurement of biochemical biomarkers (CSF, plasma/serum, urine, and multi-analyte tests) used in diagnosis or management of Alzheimer disease and related dementias for BlueCross BlueShield of Tennessee members.
No material clinical or coverage changes in this revision.
Coverage Determinations
inv-01: CSF amyloid beta peptides
Covered when ALL of the following are met
Applies to CSF amyloid beta peptide assays (e.g., ratios) per policy.
inv-02: Not medically necessary / not covered biomarker types
Not covered when ANY of the following are present
Policy explicitly lists these CSF biomarkers as not meeting coverage criteria.
Policy explicitly lists plasma/serum biomarkers as not meeting coverage criteria.
Policy explicitly lists urinary biomarkers as not meeting coverage criteria.
Policy explicitly lists multianalyte/algorithmic tests as not meeting coverage criteria.
Measurement of cerebrospinal fluid (CSF) biomarkers beyond amyloid beta peptides is not encompassed by the covered indications in this policy. Examples explicitly called out in the policy include CSF tau protein, α‑synuclein, and neural thread proteins, which the policy states DOES NOT MEET COVERAGE CRITERIA due to insufficient published evidence demonstrating benefit for diagnosis or treatment. Requests for measurement of other CSF analytes not specifically listed as covered should be expected to be denied as not meeting coverage criteria.
The policy emphasizes use of validated assays when measuring biomarkers for Alzheimer disease. FDA marketing authorizations and clearances for specific CSF assay platforms are cited in the policy bibliography as supporting clinical diagnostic use; documentation submitted for coverage should reference the assay and method. Conversely, assays that lack demonstrated analytic or clinical validity in the peer‑reviewed literature or that are described as unvalidated or experimental are not supported by this policy and are at increased risk for denial.
Non‑CSF amyloid biomarker tests listed in the policy — including plasma/serum biomarkers (e.g., tau, amyloid beta peptides, ApoE), urinary biomarkers, and multianalyte or algorithmic assays — are stated to DOES NOT MEET COVERAGE CRITERIA. The policy attributes this stance to a lack of published scientific literature showing these tests are required and beneficial in the diagnosis or treatment of Alzheimer disease or related dementias.
Tests described in the literature as investigational — for example, certain urinary extracellular vesicle analyses, novel peripheral blood panels, or emerging skin/biopsy markers — are considered investigational in this policy context and therefore may be considered not medically necessary when submitted for coverage. The policy references the need for robust, published evidence before peripheral or novel specimen assays are accepted for clinical coverage.
Procedure, Test, and Coding Information
| 83520 | Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified. |
| 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™) |
| 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 (DISCERN™) |
| 0289U | Neurology (Alzheimer disease), mRNA, gene expression profiling by RNA sequencing of 24 genes, whole blood, algorithm reported as predictive risk score (MindX Blood Test™) |
| 0346U | Beta amyloid, Aβ40 and Aβ42 by liquid chromatography with tandem mass spectrometry (LC-MS/MS), ratio, plasma (QUEST AD-Detect™) |
| 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 (Lumipulse® G β-Amyloid Ratio) |
| 0393U | Neurology (eg, Parkinson disease, dementia with Lewy bodies), CSF, detection of misfolded α-synuclein protein by seed amplification assay, qualitative (SYNTap®) |
| 0412U | Beta amyloid, Aβ42/40 ratio, immunoprecipitation with LC-MS/MS and qualitative ApoE isoform-specific proteotyping, plasma with algorithm (PrecivityAD®) |
| 0443U | Neurofilament light chain (NfL), ultra-sensitive immunoassay, serum or CSF (Neuromuscular Clinical Laboratory at Washington University) |
| 0445U | B-amyloid (abeta42) and phospho tau (181p) (ptau181), electrochemiluminescent immunoassay (ECLIA), CSF, ratio reported as positive or negative for amyloid pathology (Elecsys® pTau181/Abeta42 Ratio) |
| No codes listed |
Provider Responsibilities and Billing Guidance
Coding and claim submission — Use listed CPT/HCPCS and proprietary test codes
Use the specific CPT/HCPCS and proprietary test codes listed when requesting coverage or submitting claims. Include the appropriate procedure codes (for example: 83520; vaccine/proprietary codes such as 0206U, 0207U, 0289U, 0346U, 0358U, 0393U, 0412U, 0443U, 0445U, 0459U, 0479U, 0503U) on claims and prior authorization requests so the service is identified accurately.
- Include the listed proprietary test codes (e.g., Lumipulse®, Elecsys®, PrecivityAD®, SYNTap®, DISCERN™, QUEST AD-Detect™) when applicable.
- Use CPT/HCPCS codes per the policy's coding section; codes shown are for reference and may not be all-inclusive.
Laboratory requirements — LDT validation and CLIA compliance
Laboratory-developed tests (LDTs) must be validated and performed in-house under CLIA '88 as high-complexity tests. LDTs are not FDA-cleared or approved; document validation and CLIA status when submitting claims or prior authorization.
- Ensure the performing laboratory is CLIA-certified for high-complexity testing.
- If an LDT is used, include evidence of in-house validation and the laboratory's CLIA certification number in the record or prior authorization documentation.
Documentation should reference assay type, method, and specimen source
Documentation submitted with the request should explicitly reference the assay type, method, and specimen source (for example, LUMIPULSE, Roche Elecsys CSF assays; CSF, plasma, urine, skin). Include the assay name, whether it is FDA-cleared or an LDT, and specimen site.
- State the assay name and manufacturer (e.g., Elecsys® PhosphoTau (181P) CSF, Lumipulse® G β-Amyloid Ratio).
- Report specimen source (CSF, plasma, serum, urine, skin fibroblasts) and the analytic method (e.g., ECLIA, LC-MS/MS, seed amplification).
- If available, include the specific reported metric (e.g., Aβ42/40 ratio, pTau181/Abeta42 ratio, algorithm score).
Denial triggers — Tests outside covered biomarker scope are likely to be denied
Requests for measurement of CSF biomarkers other than amyloid beta peptides, plasma/serum/urine biomarkers, and certain multianalyte or proprietary tests lack sufficient evidence and are likely to be denied. Prior authorization and coverage are generally limited to CSF amyloid beta peptide measurement for Alzheimer disease or mild cognitive impairment.
- Tests measuring CSF biomarkers other than amyloid beta peptides (e.g., tau, α-synuclein) generally do NOT meet coverage criteria.
- Plasma, serum, or urine biomarker measurements (including blood-based amyloid or tau assays) DO NOT meet coverage criteria unless specifically addressed by updated policy or FDA clearance noted in the policy.
- Multianalyte algorithms or tests not listed in the policy are not covered due to insufficient evidence.
Denial risk — Tests lacking evidence, clearance, or appropriate indication
There is increased denial risk when testing uses assays that are not supported by evidence of clinical utility or that lack appropriate regulatory clearance/validation. FDA clearance (e.g., Roche Elecsys assays) reduces denial risk when the indication and patient population match the cleared use; LDTs without demonstrated clinical validity carry higher documentation burden.
- If using an FDA-cleared assay, provide documentation that the patient's indication and age match the cleared population.
- For LDTs or newer proprietary assays, submit validation data and clinical utility evidence to support medical necessity.
- Be aware that some proprietary blood tests listed in the coding section remain subject to coverage limitations and may be denied if clinical utility is not established.
Clinical guidance — Follow appropriate use criteria and document prior less-invasive evaluation
Clinical guidance recommends following appropriate use criteria for lumbar puncture and CSF testing, implying that less-invasive evaluation and guideline-based assessment should precede CSF biomarker testing. Document prior evaluations and adherence to guidelines when seeking coverage.
- Document prior cognitive assessment, imaging, and other less-invasive evaluations per guidelines before CSF testing.
- Reference guideline sources (e.g., Shaw et al. appropriate use criteria, Morris et al., NICE) in the clinical rationale.
- Ensure CSF testing is performed only when results will meaningfully influence diagnosis or management.
Clinical Background
Alzheimer disease is a progressive neurodegenerative disorder characterized by gradual decline in memory and other cognitive functions, associated with brain atrophy and accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles. Biomarker testing, particularly CSF amyloid beta peptide measurement, has been studied to support diagnosis and staging; however, the policy distinguishes which biomarkers and specimen types have sufficient evidence to meet coverage criteria.
Key Terms and Definitions
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