Currentblue cross blue shield - tennesseePolicy N/A

Biochemical Markers of Alzheimer Disease and Dementia

Defines coverage stance and limitations for biochemical biomarker testing (CSF, plasma/serum, urine, multianalyte assays) for diagnosis, prognosis, or management of Alzheimer disease and dementia for Blue Cross Blue Shield - Tennessee members. Specifies that coverage decisions depend on individual benefits and references Medicare/Medicaid specifications in a later section.

Policy Summary

Payerblue cross blue shield - tennessee

PolicyBiochemical Markers of Alzheimer Disease and Dementia

Policy CodePolicy N/A

Change TypeClarified (adoption effective date noted)

Effective DateJul 1, 2023

Next Review Date

Key ActionVerify member benefits and applicable Medicare/Medicaid specifications at time of request.

SourceLink

POLICY UPDATE CHANGES

Policy adopted Avalon policy recommendation effective 7/1/2023.

4Explicit not-covered test categories listed

Guideline summaries citedEvidence Sources

LDTs regulated by CLIARegulatory note

Coverage Summary

This policy, effective 2023-07-01, addresses biochemical biomarker testing for Alzheimer disease and dementia and states that such testing is not covered (cosmetic) for the listed indications. The categories explicitly listed as not meeting coverage criteria include testing of CSF biomarkers (e.g., tau, amyloid beta peptides, α-synuclein, neural thread proteins), plasma/serum biomarkers (e.g., tau, amyloid beta peptides, ApoE/ApoE4), urine biomarkers (e.g., AD7c-NTP, amyloid peptides, urinary extracellular vesicle analysis), and the use of multianalyte/algorithmic assays for diagnosis, prognosis, or management.

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Medical Necessity and Diagnostic Criteria

Not meeting coverage criteria

The following tests DO NOT MEET COVERAGE CRITERIA due to lack of sufficient published evidence:

Measurement of cerebrospinal fluid (CSF) biomarkers of Alzheimer disease including, but not limited to, tau protein, amyloid beta peptides, α-synuclein, or neural thread proteins

Explicitly listed as not meeting coverage criteria

Measurement of plasma and/or serum biomarkers of Alzheimer disease including, but not limited to, tau protein, amyloid beta peptides, neural thread proteins, ApoE, and ApoE4

Explicitly listed as not meeting coverage criteria

Measurement of urinary biomarkers of Alzheimer disease including, but not limited to, neural thread proteins, amyloid beta peptides, and urinary extracellular vesicle analysis

Explicitly listed as not meeting coverage criteria

The use of multianalyte assays, algorithmic analysis, and/or any other tests not mentioned above for prognosis, diagnosis, and/or management of Alzheimer disease or dementia

Explicitly listed as not meeting coverage criteria

Definitions and evidence for in-vivo AD pathology (IWG)

The IWG describes specific biochemical evidence in their definitions of AD:

Decreased Aβ1-42 together with increased T-tau or P-tau in CSF

Increased tracer retention on amyloid PET

AD autosomal dominant mutation present (in PSEN1, PSEN2, or APP)

Situations where CSF analysis can be considered (guideline summaries)

Guideline-based conditional recommendations where CSF testing may be appropriate:

CSF analysis not recommended routinely but can be considered in dementia patients with diagnostic uncertainty and onset at an early age (<65)

CCCDTD 2020

CSF analysis can be considered in dementia patients with diagnostic uncertainty and predominance of language, visuospatial, dysexecutive, or behavioral features to rule out AD pathophysiology

CCCDTD 2020

CSF abeta1-42/tau/p-tau assessment helps to differentiate AD; routine CSF analysis may help rule in/out certain infectious causes

EFNS Level B; EFNS Good Practice Point

Assessment of CSF total tau and 14-3-3 protein is recommended in rapidly progressive dementia when sCJD is suspected

EFNS Good Practice Point

Provider Actions & Requirements

Documentation Required

Benefit verification required

Application of coverage criteria is dependent upon an individual's benefit coverage at the time of the request; providers must verify member benefits and applicable Medicare/Medicaid specifications (referenced in Section VII).

Verify member benefits and any Medicare or state Medicaid specifications referenced in Section VII before submitting requests.

Documentation Required

Follow applicable government/local coverage

If there is a conflict between this policy and any relevant government policy (e.g., Local Coverage Determinations or National Coverage Determinations for Medicare, or state Medicaid coverage), the government policy governs determinations. Providers should reference CMS and state Medicaid coverage databases for the most up-to-date rules.

Check LCD/NCD and applicable state Medicaid coverage databases for any conflicts or differing coverage rules.

Documentation Required

Laboratory-developed tests (LDTs) regulatory status

Many laboratories develop specific tests that they validate and perform in-house as laboratory-developed tests (LDTs). LDTs are regulated by CMS under CLIA '88 as high-complexity tests and are not approved or cleared by the U.S. Food and Drug Administration for clinical use; labs must validate these in-house tests per CLIA requirements.

Note that LDTs are regulated under CLIA '88 as high-complexity tests and are not FDA approved/cleared for clinical use.

Background and Evidence Summary

Alzheimer disease (AD) is a common neurodegenerative dementia with progressive cognitive decline and substantial public health burden. Biomarker research has focused on earlier detection and staging because pathological processes often precede symptoms; commonly studied markers include CSF Aβ42 (and the Aβ42/40 ratio), total and phosphorylated tau, and other CSF proteins that may reflect neuronal injury or disease progression.

Research extends beyond CSF to less invasive specimens: plasma/serum assays (Aβ42, Aβ42/40, P‑tau217/P‑tau181, total tau, NfL), urine biomarkers such as AD7c‑NTP and urinary extracellular vesicle proteomes, and exploratory media including saliva and exosomes. Meta-analyses and cohort studies report variable diagnostic performance (for example, higher concordance of CSF Aβ42/40 with amyloid PET than Aβ42 alone, and reported sensitivities/specificities for some blood and urine markers), indicating promising but heterogeneous results.

Limitations include substantial between-laboratory assay variability, lack of standardized techniques and uniform cutoff thresholds, and incomplete evidence that biomarker testing improves clinical outcomes—particularly given the current paucity of widely available disease‑modifying treatments. Guidelines therefore do not recommend routine biomarker testing for general clinical use and emphasize that biomarkers are currently of limited clinical utility outside specific research or select clinical scenarios.

Label	Value
CSF Aβ42/40 vs Aβ42 concordance with amyloid PET	Aβ42/40 ratio showed higher concordance with PET (89.4%) than Aβ42 alone (74.9%); AUC 0.936 vs 0.814
Urinary AD7c-NTP meta-analysis diagnostic performance	Sensitivity 0.87; Specificity 0.89; Positive LR 8.13; Negative LR 0.15
Plasma biomarkers diagnostic performance (meta-analyses)	Various meta-analyses report plasma Aβ42, Aβ42/40, P-tau217, T-tau, NfL show diagnostic accuracy; reported sensitivities/specificities vary across studies
USPSTF 2020 statement	Current evidence insufficient to assess benefits/harms of screening for cognitive impairment in older adults
IWG in-vivo evidence	Decreased CSF Aβ1-42 with increased T-tau or P-tau; amyloid PET positivity; or autosomal dominant AD mutation

Definitions

CSFCerebrospinal fluid

Aβ42/40Ratio of Amyloid Beta 42 to Amyloid Beta 40

AD7c-NTPAlzheimer-associated neuronal thread protein (urinary neuronal thread protein)

LDTLaboratory-developed test validated and performed in-house; regulated by CMS under CLIA '88; not FDA-approved/cleared for clinical use.

OpenPayer

Biochemical Markers of Alzheimer Disease and Dementia

Coverage Summary

Medical Necessity and Diagnostic Criteria

Provider Actions & Requirements

Coding

Background and Evidence Summary

Revision History