Modifiedblue cross blue shield - louisianaPolicy AHS - G2048 - Biochemical Markers of Alzheimer Disease and Dementia

Biochemical Markers of Alzheimer Disease and Dementia

This policy governs coverage of biochemical biomarker tests for suspected Alzheimer disease (AD) and mild cognitive impairment (MCI) for Blue Cross and Blue Shield of Louisiana members; it specifies which CSF and plasma assays meet coverage criteria and which specimen types or tests do not.

Policy Summary

Payerblue cross blue shield - louisiana

PolicyBiochemical Markers of Alzheimer Disease and Dementia

Policy CodePolicy AHS - G2048 - Biochemical Markers of Alzheimer Disease and Dementia

Change TypeCoverage criteria revised and plasma allowance added

Effective DateFeb 1, 2026

Next Review Date

Key ActionObtain and document indication for covered CSF biomarkers or an FDA-approved plasma p-tau217/Aβ42 test and secure any required prior authorization per payer process.

SourceLink

POLICY UPDATE CHANGES

CC1 edited to allow p-tau/Aβ42 and t-tau/Aβ42 ratios in CSF.

New CC2 allows measurement of the ratio of p-tau217 to Aβ42 in plasma using an FDA-approved test.

Former CC2 and CC3 renumbered (now CC3 and CC4) and edited for consistency with new allowances.

Client requested variance: addition of 'other' to CC4 to read 'Measurement of other plasma and/or serum biomarkers... DOES NOT MEET COVERAGE CRITERIA.'

Multiple CPT codes were added across prior updates (e.g., 0596U, 0568U, 0547U/0548U/0551U and others).

3CSF biomarker types that meet coverage criteria

1FDA-approved plasma ratio tests covered

Trek Health ingests and normalizes Transparency in Coverage data and payer policy updates to give provider organizations a clear view of how commercial reimbursement behaves across markets, payers, and services. Our platform transforms raw payer disclosures into structured intelligence that supports contract evaluation, payer negotiations, and service line strategy. By combining market benchmarks with ongoing policy visibility, Trek helps teams identify variability, risk, and opportunity in commercial reimbursement. The result is faster insight, stronger negotiating positions, and more informed financial decisions.

Specimen/test categories not covered

20+CPT/HCPCS and proprietary codes listed

17Clinical scenarios rated for PET appropriateness

Coverage Criteria for Biochemical Biomarkers of Alzheimer Disease and Dementia

Covered biomarker testing

Covered when ALL of the following apply for individuals with suspected Alzheimer disease or mild cognitive impairment:

Covered CSF biomarkers: Measurement in cerebrospinal fluid of: (a) amyloid beta peptides; (b) the ratio of total tau (t-tau) to amyloid beta 1-42 (Aβ42); (c) the ratio of phosphorylated tau 181 (p-tau181) to Aβ42.

These CSF biomarkers meet coverage criteria for suspected AD or MCI.

Use and diagnostic thresholds for BBMs and CSF biomarkers

Covered when meeting guideline-based context-specific criteria

Specialist clinic symptomatic patients: BBMs (with established thresholds) may be used in symptomatic patients seen at specialist memory clinicsconfirmatory testing when possible

Results should be confirmed with CSF or PET whenever possible; BBMs are not yet recommended as standalone diagnostics in general practice

Core 1 diagnostic criteria: An abnormal result on a validated Core 1 biomarker (amyloid PET; CSF Aβ42/40, CSF p-tau181/Aβ42, CSF t-tau/Aβ42; or an 'accurate' plasma assay with equivalent accuracy to CSF in intended population) can be diagnostic of ADaccuracy equivalent to approved CSF assays for plasma tests

Not all available Core 1 tests meet sufficient accuracy; only those validated to detect abnormal amyloid PET are considered diagnostic

Primary care restriction: BBMs should not be used as primary diagnostic tests in primary care until additional data are availablespecialist confirmation recommended

Implementation in primary care will likely require further prospective validation

Amyloid/Tau PET Appropriate Use Criteria

Appropriateness of amyloid and tau PET across clinical scenarios

Clinical scenario ratings: Seventeen clinical scenarios were rated with appropriateness scores (1-9) for amyloid and tau PET; high scores (7-9) indicate appropriate use in specific symptomatic contexts such as younger-onset MCI/dementia and to determine eligibility for amyloid-targeting therapiesscore 7-9 considered appropriate

Examples: amyloid PET scored 9 for MCI/dementia <65 to evaluate suspected AD; amyloid PET scored 9 for determining eligibility for amyloid-targeting therapy

Appropriate use scenarios and limits

Use of amyloid and tau biomarkers is considered appropriate or inappropriate depending on clinical presentation, age, available CSF results, and purpose:

Determine eligibility for approved amyloid-targeting therapy: Use of amyloid PET is appropriate when used to determine eligibility for an approved amyloid-targeting therapy

High confidence (SNMMI/Alzheimer's Association)

Evaluate MCI or dementia with suspected AD pathology: Patients with MCI or dementia whose clinical syndrome is consistent with AD (amnestic presentations, onset <65 or >=65) — amyloid PET is rated appropriate or moderately appropriate depending on age and typical vs atypical presentation

Consensus ratings vary: high confidence for younger (<65) patients; moderate for typical onset >=65; consider tau PET also depending on question

Equivocal CSF results: In patients with MCI or dementia and equivocal or inconclusive recent CSF biomarkers, amyloid PET is moderately appropriate to clarify diagnosis

SNMMI/Alzheimer's Association consensus

Guideline-informed coverage criteria

Covered when ALL of the following guideline-informed conditions are met:

Guideline-concordant use: Testing is used to clarify diagnosis in patients with suspected dementia or cognitive impairment when results would change clinical management

Derived from NICE, CCCDTD, EFNS guidance

Appropriate test selection: Consider CSF amyloid/tau assessment or PET (amyloid or tau) when diagnosis is uncertain; consider CSF in early-onset (<65) or atypical/variant presentations

From NICE and CCCDTD

Interpretation and integration: Biomarker results must be interpreted with clinical assessment and other diagnostic testing; plasma tests are adjunctive and not standalone screening tools

Per FDA statements and NICE caution

Initial/Allowed Biomarker Tests

Covered when the following are met for individuals with suspected Alzheimer disease or mild cognitive impairment/dementia:

CC1: Measurement in cerebrospinal fluid of: (a) amyloid beta peptides; (b) the ratio of total tau (t-tau) to amyloid beta 1-42 (Aβ42); (c) the ratio of phosphorylated tau 181 (p-tau181) to Aβ42N/A

Meets coverage criteria for CSF biomarkers as specified.

CC2: Measurement in plasma of the ratio of p-tau217 to Aβ42 using an FDA-approved test (e.g., Lumipulse G pTau217/ß-Amyloid 1-42 Plasma Ratio)Must be FDA-approved assay

Meets coverage criteria for this specific plasma ratio test.

Not Medically Necessary / Excluded Tests

Not covered / does not meet coverage criteria:

CC3: Measurement of cerebrospinal fluid biomarkers of Alzheimer disease or dementia not mentioned in CC1 (examples given: α-synuclein, neural thread proteins) DOES NOT MEET COVERAGE CRITERIA.N/A

Explicit exclusion for CSF biomarkers not listed in allowed CC1.

CC4: Measurement of other plasma and/or serum biomarkers of Alzheimer disease or dementia (examples: p-tau217 or Aβ42 as individual markers, total tau protein, amyloid beta 1-40, neural thread proteins, ApoE, ApoE4) DOES NOT MEET COVERAGE CRITERIA.N/A

Client-requested insertion of the word 'other' clarifies exclusion.

Measurement of cerebrospinal fluid biomarkers not specified among the policy's allowed CSF measures does not meet coverage criteria. Examples of CSF tests that are excluded include assays for α-synuclein and neural thread proteins. Requests for these CSF biomarkers will be denied because they are not listed in the policy's allowed CSF biomarker group (CC1).

Clinical guidelines do not endorse routine, population-level use of Alzheimer disease biomarkers for general diagnostic screening. Biomarker testing is generally reserved for situations where results would influence diagnosis or management (for example, persistent or progressive MCI, atypical presentations, or younger-onset disease). Use of biomarkers in cognitively unimpaired individuals without risk factors is rated Inappropriate by guideline panels and consensus groups.

Biomarker testing for nonmedical purposes (such as legal, insurance, or employment screening) is not supported and is rated as rarely appropriate. Likewise, routine testing of individuals without established cognitive impairment or substituting biomarker tests for genetic testing in suspected autosomal dominant cases is not appropriate and will not meet coverage criteria.

Use of CSF or blood biomarker tests solely for population screening or as a stand-alone diagnostic without integration of clinical assessment is not supported. NICE and FDA guidance emphasize that biomarker results must be interpreted in the context of clinical evaluation and that certain plasma assays are not intended as screening or standalone diagnostics.

Measurement of CSF biomarkers that are not listed in the policy's allowed CSF group (CC1) does not meet coverage criteria (examples: α-synuclein, neural thread proteins). Measurement of other plasma and/or serum biomarkers not authorized by the policy (for example individual analytes such as p-tau217 or Aβ42 measured alone, total tau protein, Aβ40, ApoE/ApoE4) also DOES NOT MEET COVERAGE CRITERIA.

The use of multianalyte panels, algorithmic scoring methods, or any proprietary or composite tests that are not expressly identified as covered in the policy is considered not medically necessary. Such tests and analytic algorithms are excluded unless specifically enumerated among the policy's allowed assays.

Consensus guidance rates the use of amyloid or tau PET to determine disease severity or to monitor treatment response as generally discouraged except in narrow, well-justified circumstances. Using tracers for staging or routine monitoring in patients without a clear, guideline-supported indication is typically rated as rarely appropriate or uncertain and is not supported for broad clinical use.

Routine CSF analysis for all patients with dementia is not recommended. CSF testing should be considered selectively when there is diagnostic uncertainty—particularly in early-onset (<65) or atypical presentations—because CSF provides simultaneous amyloid and tau information and can inform diagnosis when results will change management.

Measurement of plasma or serum biomarkers used as single, isolated markers (for example p‑tau217 alone or Aβ42 alone), total tau alone, or other individual analytes such as Aβ40, neural thread proteins, ApoE/ApoE4 is not covered. The policy restricts plasma coverage to the p‑tau217/Aβ42 ratio measured using an FDA‑approved test (example: Lumipulse G), and individual plasma/serum analytes are excluded.

Coding and Billing

Applicable CPT Codes (amyloid peptides)CPT

82233	Beta-amyloid; 1-40 (Abeta 40)
82234	Beta-amyloid; 1-42 (Abeta 42)

Applicable CPT/HCPCS and Proprietary Codes (CSF/plasma assays)mixed

83520	Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified
83884	Neurofilament light chain (NfL)
84393	Tau, phosphorylated (eg, pTau 181, pTau 217), each
84394	Tau, total (tTau)
0206U	DISCERN™ proprietary test (PKCe response) for Alzheimer disease
0207U	DISCERN™ proprietary test (phospho-ERK imaging) for Alzheimer disease
0358U	Lumipulse® G β-Amyloid Ratio (1-42/1-40) test, CSF
0393U	SYNTap® detection of misfolded α-synuclein in CSF
0412U	PrecivityAD® blood test: Aβ42/40 ratio and ApoE proteotyping (plasma)

Additional Proprietary and Assay Codesmixed

0443U	Neurofilament light chain (nfl), ultra-sensitive immunoassay, serum or CSF
0445U	β-amyloid (abeta42) and phospho tau (181p) (ptau181), ECLIA, CSF; ratio reported
0459U	β-amyloid (Abeta42) and total tau (tTau), ECLIA, CSF; ratio reported
0479U	Tau, phosphorylated, pTau217
0503U	PrecivityAD2™ plasma assay (Aβ40, Aβ42, pTau217, algorithm score)
0547U	Neurofilament light chain (NfL), chemiluminescent enzyme immunoassay, plasma
0548U	Glial fibrillary acidic protein (GFAP), chemiluminescent enzyme immunoassay, plasma
0551U	pTau217 by single-molecule array, plasma (LucentAD p-Tau 217)
0568U	LucentAD™ Complete panel (Aβ, pTau217, NfL, GFAP), plasma
0596U	Precivity-ApoE™ APOE isoform peptides by LC-MS/MS, plasma

Policy-related CPT/HCPCS codes (added/removed in revision history)mixed

0596U	CPT code added 10/01/2025 (off-cycle)
0568U	CPT code added 07/01/2025 (off-cycle)
0547U	CPT code added 04/01/2025 (off-cycle)
0548U	CPT code added 04/01/2025 (off-cycle)
0551U	CPT code added 04/01/2025 (off-cycle)
82233	Added 01/01/2025
82234	Added 01/01/2025
83884	Added 01/01/2025
84393	Added 01/01/2025
84394	Added 01/01/2025

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WHO clinical performance — Minimum sensitivity and specificity

Minimum clinical performanceWHO recommends minimum sensitivity and specificity of 90% compared with a valid reference standard (e.g., neuropathology, amyloid PET, or approved CSF assays).

Intended diagnostic usePerformance target applies to diagnostic use in the target population (individuals with cognitive impairment consistent with ICD-11).

Reference standard examplesValid reference standards include neuropathology, amyloid PET, or approved CSF assays as comparators for accuracy assessment.

Validation settingValidation and assessment must be conducted in the intended-use setting and populations, including low- and middle-income countries when applicable.

Age for plasma test intended use

Provider Actions, Prior Authorization, and Documentation

Prior Authorization

Provider action: Biomarker tests requiring verification of indication

Measurement of specified CSF biomarkers and measurement of the plasma p-tau217/Aβ42 ratio using an FDA‑approved test meet coverage criteria when clinically indicated. Specifically, CSF amyloid beta peptides, CSF t‑tau/Aβ42 ratio, and CSF p‑tau181/Aβ42 ratio MEET COVERAGE CRITERIA for individuals with suspected Alzheimer disease or mild cognitive impairment. Measurement of the p‑tau217/Aβ42 ratio in plasma using an FDA‑approved test (e.g., Lumipulse G pTau217/ß‑Amyloid 1‑42 Plasma Ratio) MEETS COVERAGE CRITERIA for symptomatic patients over the indicated age range.

Prior authorization: Amyloid PET or tau PET when used to determine eligibility for an approved amyloid‑targeting therapy (e.g., lecanemab) may require prior authorization. Documentation must support clinical necessity and show that confirmation of elevated brain beta‑amyloid is required to consider therapy.
Prior authorization: Certain proprietary/plasma biomarker tests and listed CPT/HCPCS/proprietary codes may require prior authorization. Providers should include clinical indication, relevant prior testing, and rationale for the chosen test when submitting requests.

Prior Authorization

Provider action: Prior authorization for PET to determine therapy eligibility

Background and Evidence Summary

Alzheimer disease is a progressive neurodegenerative disorder characterized pathologically by extracellular amyloid plaques composed of beta‑amyloid and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. It is the most common cause of dementia, typically presenting after age 65, with mild cognitive impairment representing an intermediate state that may precede dementia.

Definitions and Key Terms

CSF — Cerebrospinal fluid

Specimen typeCerebrospinal fluid (CSF) — specimen used for measurement of amyloid beta, total tau, and phosphorylated tau biomarkers.

Collection method noteCSF is obtained via lumbar puncture; provide clinical rationale and document when CSF is preferred or when LP is contraindicated.

Diagnostic roleCSF provides simultaneous amyloid and tau information and is prioritized in many guidelines because it is less expensive than PET and informative for diagnosis.

p-tau — Phosphorylated tau protein

DefinitionPhosphorylated tau (p-tau) — tau protein phosphorylated at disease-relevant residues (e.g., p-tau181, p-tau217) used as a biomarker of tau pathology in Alzheimer disease.

Common isoformsExamples include p-tau181 and p-tau217, which are measured in CSF or plasma assays to infer tau pathology.

Policy Summary

Payerblue cross blue shield - louisiana

PolicyBiochemical Markers of Alzheimer Disease and Dementia

Policy CodePolicy AHS - G2048 - Biochemical Markers of Alzheimer Disease and Dementia

Change TypeCoverage criteria revised and plasma allowance added

Effective DateFeb 1, 2026

Next Review Date

Key ActionObtain and document indication for covered CSF biomarkers or an FDA-approved plasma p-tau217/Aβ42 test and secure any required prior authorization per payer process.

SourceLink

On This Page

Monitoring or staging established AD: Use of amyloid PET to determine disease severity or track progression in patients with an established biomarker-supported diagnosis of AD is rarely appropriate

Consensus: amyloid PET rarely appropriate for progression tracking

Nonmedical use: Biomarker testing for legal, insurance, employment screening or as a substitute for genotyping is rarely appropriate

Consensus high confidence

Age restriction (FDA)Plasma p-tau217/Aβ42 ratio test is intended for patients over the age of 50 (per FDA marketing authorization).

Clinical presentation requirementTest is designed for patients who present with signs or symptoms of cognitive decline, not for screening or standalone diagnosis.

Analysis requirementsResults must be analyzed in combination with other clinical information about the patient.

Test authorization requirement

FDA-approved assay requirementThe plasma p-tau217/Aβ42 ratio must be measured using an FDA-approved test (example named: Lumipulse G pTau217/ß-Amyloid 1-42 Plasma Ratio).

Coverage linkagePolicy coverage for plasma p-tau217/Aβ42 ratio is contingent on use of an FDA-authorized assay as specified in CC2 of the policy revision.

Example proprietary testsLumipulse G pTau217/ß-Amyloid 1-42 is provided as an example of an FDA-permitted plasma ratio test; other FDA-cleared/authorized assays may qualify if equivalent and authorized.

Amyloid PET or tau PET performed to determine eligibility for an approved amyloid‑targeting therapy is considered appropriate when documentation supports the clinical necessity to confirm elevated brain beta‑amyloid. Acceptable confirmation methods include CSF testing or PET per FDA and guideline statements; clinicians must document why the modality chosen is necessary (e.g., lumbar puncture contraindication).

Documentation should indicate how the PET result will affect treatment decisions (e.g., eligibility for anti‑amyloid therapy).
If lumbar puncture is contraindicated or not feasible, PET is an accepted alternative to CSF for amyloid confirmation.

Prior Authorization

Provider action: Prior authorization for covered biomarker tests

Prior authorization is recommended/required for covered biomarker tests listed in the procedure code section when indicated by medical necessity. When prior authorization is requested, include: clinical indication, relevant clinical phenotype, prior diagnostic workup (cognitive testing, imaging, prior biomarker results if any), reason for test selection (CSF vs plasma vs PET), and how results will impact management.

Include the specific proprietary test name (if applicable) and the performing laboratory when known.
When requesting coverage for FDA‑cleared plasma ratio tests, specify that an FDA‑approved assay is being used and the intended use (diagnostic support in symptomatic patients, not screening).

Denial Risk

Provider action: Denial triggers

Tests that DO NOT MEET COVERAGE CRITERIA will be denied. Requests for measurement of CSF, plasma/serum, urine, or multianalyte methods not included in the policy's allowed lists are subject to denial.

Examples of denied/unallowed biomarkers include: CSF analytes not listed in CC1 (e.g., α‑synuclein, neural thread proteins) and plasma/serum markers other than the specified FDA‑approved p‑tau217/Aβ42 ratio (e.g., isolated p‑tau217, Aβ42 alone, total tau, Aβ40 alone, ApoE, neural thread proteins).
Multianalyte algorithms or proprietary panels not explicitly listed as meeting coverage criteria will be denied.
Non‑covered specimen types (e.g., urine biomarkers) will be denied.

Note

Provider action: Routine use discouraged may limit coverage

Routine use of biomarker testing for Alzheimer disease is discouraged. Guideline groups note that biomarkers should not be used routinely for all patients because of limited standardization, variable availability across settings, and that core clinical criteria provide good diagnostic accuracy in most patients. Biomarker testing should be selected when results are likely to change management.

Tests should be considered primarily for symptomatic patients where knowing the subtype will change management, for investigational studies or clinical trials, or when results will meaningfully affect treatment decisions.
Widespread use in primary care is not currently recommended; BBMs should not be used as stand‑alone diagnostic tests in community settings.

Denial Risk

Provider action: Nonmedical use and substitution for genotyping

Use of amyloid or tau PET tracers for nonmedical purposes (for example, legal, insurance, or employment screening) or as a substitute for genetic testing (genotyping) in suspected autosomal dominant mutation carriers is inappropriate and will not be supported.

Requests for PET with nonmedical intent will be considered inappropriate and are subject to denial.
Do not use PET in lieu of genotyping for evaluation of autosomal dominant Alzheimer disease risk.

Note

Provider action: Appropriate use guidance

Follow appropriate use guidance: biomarker testing should be performed when it will aid diagnosis of a dementia subtype and when knowing the subtype will change management. Use clinical judgment to evaluate added value for the symptomatic patient based on age, phenotype, comorbidities, patient preferences, trial eligibility, and how results will change management.

Consider CSF testing (preferred where available) or PET when diagnosis is uncertain and results would affect treatment or trial eligibility.
Per IWG and NICE, avoid biomarker testing in cognitively unimpaired individuals unless participation in a trial or other specific justification exists.

Documentation Required

Provider action: Required clinical documentation

Documentation must support medical necessity: document suspected Alzheimer disease or mild cognitive impairment, the clinical phenotype, the intended use of the biomarker test (how results will change management), prior diagnostic testing, and the chosen specimen/modality. When applicable, specify that an FDA‑approved plasma ratio test will be used.

Clinical phenotype: describe cognitive presentation (amnestic vs atypical), age, comorbidities, and relevance to management.
Intended use: state whether test is to confirm amyloid pathology for treatment eligibility, to clarify diagnosis, or for prognostic purposes.
Specimen choice: provide rationale for CSF vs plasma vs PET (e.g., LP contraindication, availability, cost).
Provide prior test results if available (neuroimaging, prior CSF or plasma biomarkers, cognitive testing).

Note

Provider action: Preanalytical and analytical variability

Preanalytical and analytical variability may affect plasma biomarker levels and lead to misclassification (false‑negative or false‑positive). Providers should be aware of handling requirements, assay performance characteristics, and that some plasma assays require FDA approval for coverage.

When ordering plasma assays, ensure the laboratory uses an FDA‑approved method if coverage is being sought (e.g., approved p‑tau217/Aβ42 plasma ratio).
Document specimen handling and assay used when relevant, and interpret plasma results in the context of clinical evaluation and confirmatory testing when indicated.

Documentation Required

Provider action: Clinical rationale and specimen choice

Clinical rationale and specimen choice must be recorded: indicate the clinical phenotype, why biomarker testing is expected to add diagnostic or management value, and why the selected specimen (CSF, plasma, or PET) was chosen.

CSF is prioritized when both amyloid and tau information is needed and is generally less expensive than PET.
If lumbar puncture is contraindicated, document reason and rationale for selecting PET.
BBMs (blood‑based biomarkers) should currently be used primarily in symptomatic patients at specialist memory clinics and corroborated with CSF or PET when possible.

Documentation Required

Provider action: Clinical justification and intended use

Clinical justification and intended use: document that testing is intended to assist diagnosis in patients with suspected dementia or cognitive decline and that results will be interpreted with other clinical information. For therapy decisions, confirmatory testing of amyloid pathology is required prior to initiating an amyloid‑targeting therapy.

Prior to initiating anti‑amyloid therapy, confirmation of elevated brain beta‑amyloid by CSF or PET is required and must be documented.
State explicitly whether the test result will be used for treatment eligibility, prognosis, diagnostic clarification, or trial enrollment.

Documentation Required

Provider action: Documentation expectations

Documentation expectations: provide evidence that the individual is symptomatic (suspected AD or MCI/dementia), include the specific biomarker test name and method (CSF assay, PET tracer, or FDA‑approved plasma ratio), and explain how the test result will affect patient management.

For FDA‑approved plasma ratio tests, document that an FDA‑cleared assay will be used and that results will not be used as a standalone screen.
Include prior cognitive testing, imaging, and any prior biomarker results to contextualize the request.

Prior Authorization

Provider action: Biomarker confirmation prior to therapy

Biomarker confirmation prior to therapy: Before considering anti‑amyloid therapies (such as lecanemab), clinicians must confirm elevated brain beta‑amyloid using accepted tools (CSF amyloid biomarkers or amyloid PET). The FDA does not mandate a single diagnostic tool, but documentation must show use of an accepted confirmatory method.

When CSF is used for confirmation, document which CSF analytes/ratios were measured and their interpretation relative to assay cutoffs.
If PET is used, document tracer, indication, and how PET results fulfill therapy eligibility criteria.

Note

Provider action: BBMs restricted to specialist settings

BBMs restricted to specialist settings: Current guidance recommends blood‑based biomarkers only be used in symptomatic patients at specialist memory clinics; results should be confirmed with CSF or PET when possible and correlated with specialized clinical evaluation.

Do not rely on BBMs as standalone diagnostics in primary care; additional validation and appropriate use criteria are needed before broader implementation.
When BBMs are used, include documentation of specialist clinic evaluation and plan for confirmatory testing if indicated.

Note

Provider action: Testing sequence preference

Testing sequence preference: CSF biomarkers are prioritized over PET because they are less expensive and provide both amyloid and tau information. If lumbar puncture is contraindicated or not feasible, PET is a reasonable alternative. Consider established imaging (FDG‑PET or perfusion SPECT) or CSF testing when diagnosis is uncertain.

When multiple modalities are considered, document rationale for sequence chosen (cost, contraindication, expected information yield).
No mandatory stepwise testing sequence is imposed, but clinicians should prioritize CSF when both amyloid and tau data are needed and PET when LP is contraindicated.

Interpretation contextElevated p-tau concentrations, especially when combined with low Aβ42, increase confidence in AD diagnosis; interpret with clinical phenotype.

FDA-approved plasma p-tau217/Aß42 ratio

What it isAn FDA-approved plasma p-tau217/Aβ42 ratio is a plasma-based biomarker ratio measured by an FDA-authorized test to assess amyloid pathology associated with Alzheimer disease (example: Lumipulse G pTau217/ß-Amyloid 1-42 Plasma Ratio).

Intended useIntended to identify patients with amyloid pathology associated with AD who present with signs or symptoms of cognitive decline; not intended as a screening or standalone diagnostic test.

Coverage linkagePolicy CC2 specifies coverage only when the ratio is measured using an FDA-approved test; test-specific authorization and documentation are required.

Core 1 biomarkers

Timing relative to amyloid PETCore 1 biomarkers become abnormal around the same time as amyloid PET and can be sufficient to establish a diagnosis of AD when validated (e.g., amyloid PET, CSF Aβ42/40, CSF p-tau181/Aβ42, CSF t-tau/Aβ42, or accurate plasma assays).

ExamplesExamples of Core 1 include amyloid PET and CSF analytes such as Aβ42/40 and p-tau181/Aβ42.

Diagnostic implicationAn abnormal Core 1 biomarker result can be diagnostic of AD and inform clinical decision-making throughout the disease continuum per 2024 guideline definitions.

Core 2 biomarkers

What they areCore 2 biomarkers are later-changing biomarkers (fluid analytes or tau PET) that typically provide prognostic information and increase confidence that AD contributes to the clinical syndrome.

ExamplesCore 2 includes tau PET and certain fluid analytes (e.g., MTBR-tau243, p-tau205) that have not undergone the same validation as Core 1 markers.

Use in diagnosisCore 2 biomarkers are usually not used as standalone diagnostic tests but support prognosis and disease characterization.

CSF AD signature

DefinitionCSF AD signature — biochemical pattern combining low CSF Aβ1-42 and high CSF total tau or phosphorylated tau consistent with Alzheimer's pathology.

Diagnostic performanceCombination of low Aβ1-42 and high T-tau or P-tau in CSF increases diagnostic accuracy for AD (reported sensitivity ~90-95% and specificity ~90% in IWG reports).

Interpretation cautionCSF biomarkers should be interpreted in the broader clinical context due to inter-laboratory variability and lack of universal cutoffs.

In-vivo evidence of Alzheimer's pathology (IWG)

Definition (IWG)In-vivo evidence of Alzheimer’s pathology (IWG): one of decreased CSF Aβ1-42 with increased CSF T-tau or P-tau; increased tracer retention on amyloid PET; or presence of an AD autosomal dominant mutation (PSEN1, PSEN2, APP).

Role in diagnosisIWG requires both a specific clinical phenotype and biomarker evidence (amyloid-positive and tau-positive) to establish AD diagnosis.

Testing priorityIWG prioritizes CSF because it provides simultaneous amyloid and tau information and is less expensive than PET; PET is alternative when LP contraindicated.

Amyloid/tau biomarkers

ScopeAmyloid/tau biomarkers encompass laboratory assays (CSF or plasma) that quantify Aβ42, Aβ40, pTau (e.g., pTau181, pTau217), total tau, and derived ratios (Aβ42/40, pTau/Aβ42) to infer amyloid plaque and tau pathology.

Specimen typesMeasured in CSF or plasma depending on the assay; CSF provides both amyloid and tau concurrently while plasma assays are emerging adjuncts.

Clinical interpretationBiomarker results must be integrated with clinical assessment; plasma assays are adjunctive and not standalone screening tools per FDA and guideline cautions.

NfL and GFAP

Markers describedNfL (neurofilament light chain) and GFAP (glial fibrillary acidic protein) are fluid biomarkers used as indicators of neuroaxonal injury and astroglial activation, respectively.

Specimen and assaysMeasured in plasma or CSF using immunoassays (examples: codes 83884 for NfL, 0548U for GFAP).

Clinical roleThese markers are supportive rather than diagnostic for AD and may complement amyloid/tau biomarker assessment in certain contexts.

p-tau/Aβ42 ratio

Definitionp-tau/Aβ42 ratio — the ratio of phosphorylated tau (e.g., p-tau181 or p-tau217) to amyloid beta 1-42 measured in CSF or plasma; specific ratios (p-tau181/Aβ42, p-tau217/Aβ42, t-tau/Aβ42) are operationalized in the policy.

Policy applicationPolicy CC1 allows CSF t-tau/Aβ42 and p-tau181/Aβ42 ratios; CC2 allows plasma p-tau217/Aβ42 ratio when measured with an FDA-approved test.

Diagnostic significanceElevated p-tau/Aβ42 ratios increase confidence in AD diagnosis and are part of Core 1 biomarker definitions when validated.