Latest Review Date: October 2024

Category: Laboratory

DRAFT

POLICY:

For dates of service on and after December 16, 2024:

Measurement of cerebrospinal fluid biomarkers of Alzheimer disease, including, but not limited to, amyloid beta peptides, tau protein, or neural thread proteins, is considered investigational for including, but not limited to, the following situations:

• as an adjunct to clinical diagnosis in individuals with mild cognitive impairment;
• as an adjunct to clinical diagnosis in individuals with mild dementia due to Alzheimer disease;
• 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;
• as part of an evaluation for the continuation of amyloid beta targeting therapy in individuals with mild cognitive impairment or mild dementia due to Alzheimer disease

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.

Cerebrospinal fluid biomarker testing of neural thread proteins 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 investigational.

Measurement of urinary and blood biomarkers as an adjunct to clinical diagnosis in individuals with mild cognitive impairment or mild dementia due to Alzheimer Disease, is considered investigational.

For dates of service prior to December 16, 2024:

Measurement of cerebrospinal fluid biomarkers of Alzheimer disease, including, but not limited to, amyloid beta peptides, tau protein, or neural thread proteins, is considered investigational for including, but not limited to, the following situations:

• as an adjunct to clinical diagnosis in individuals with mild cognitive impairment;
• as an adjunct to clinical diagnosis in individuals with mild dementia due to Alzheimer disease;
• 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;
• as part of an evaluation for the continuation of amyloid beta targeting therapy in individuals with mild cognitive impairment or mild dementia due to Alzheimer disease

Measurement of urinary and blood biomarkers as an adjunct to clinical diagnosis in individuals with mild cognitive impairment or mild dementia due to Alzheimer Disease, is considered investigational.

DESCRIPTION OF PROCEDURE OR SERVICE:

Biochemical changes associated with the pathophysiology of Alzheimer disease (AD) are being evaluated to aid in the diagnosis of the disease. This includes the potential use of biomarkers, such as amyloid beta peptide 1-42 and total or phosphorylated tau protein, in cerebrospinal fluid (CSF), urine, and blood. Additionally, the potential correlation between CSF biomarkers and positron emission tomography (PET) amyloid scans has been proposed as useful in selecting appropriate patients for the initiation or discontinuation of amyloid beta plaque targeted therapy.

Alzheimer Disease

Alzheimer Disease (AD) is a fatal neurodegenerative disease that causes progressive loss in memory, language, and thinking, with the eventual loss of ability to perform social and functional activities in daily life. Survival after a diagnosis of dementia due to AD generally ranges between four and eight years; however, life expectancy can be influenced by other factors, such as comorbid medical conditions. It is estimated that 6.2 million Americans aged 65 and older are currently living with AD dementia, and the number is projected to reach over 12 million by 2050. Per the 2018 American Academy of Neurology practice guideline update on mild cognitive impairment (MCI), the prevalence of MCI was 6.7% for ages 60 to 64, 8.4% for ages 65 to 69, 10.1% for ages 70 to 74, 14.8% for ages 75 to 79, and 25.2% for ages 80 to 84. The cumulative dementia incidence was 14.9% in individuals with MCI >65 years of age followed for two years.

Data from the National Institute on Aging have shown that Black Americans are approximately 1.5 to 2 times more likely to develop AD and related dementias as compared to Whites. Additionally, Black participants in AD research studies were 35% less likely to be diagnosed with AD and related dementias and were found to have more risk factors for the disease as well as greater cognitive impairment and symptom severity than White participants. Findings from 2 national surveys conducted by the Alzheimer's Association also found that people of color face discrimination when seeking health care for AD and related dementias with the highest level of discrimination in dementia health care reported by Black Americans (50%) followed by Native (42%), Asian (34%), and Hispanic (33%)Americans. Non-Hispanic White Americans reported a discrimination rate of 9%.

Pathophysiology

The pathologic hallmarks of AD are extracellular deposits of amyloid beta, referred to as amyloid plaques, and intracellular aggregates of hyperphosphorylated tau in the form of neurofibrillary tangles. There are different forms of amyloid such as plaques, oligomers, and monomers, and the roles of these different forms and their contributions to the pathophysiology of AD is not well understood. Generally referred to as the “amyloid hypothesis”, it is believed that aggregation of amyloid beta oligomers in the brain leads to amyloid plaques. Amyloid aggregation in addition to accumulation of tau pathology and neurodegeneration are thought to be the main drivers of the disease process. These changes in the brain result in widespread neurodegeneration and cell death, and ultimately cause the clinical signs and symptoms of dementia.

The pathophysiological changes and clinical manifestations of AD are progressive and occur along a continuum, and accumulation of amyloid beta may begin 20 years or more before symptoms arise. The National Institute on Aging-Alzheimer’s Association (NIA-AA) has created a “numeric clinical staging scheme” (see table below) that avoids traditional syndromal labels and is applicable for only those in the Alzheimer continuum. This staging scheme is primarily used in the research setting and reflects the sequential evolution of AD from an initial stage characterized by the appearance of abnormal AD biomarkers in asymptomatic individuals. As biomarker abnormalities progress, the earliest subtle symptoms become detectable. Further progression of biomarker abnormalities is accompanied by progressive worsening of cognitive symptoms, culminating in dementia.

Table 1. National Institute on Aging-Alzheimer’s Association Numerical Clinical Staging for Individuals in the Alzheimer Continuuma

Stage	Stage 1	Stage 2	Stage 3	Stage 4	Stage 5	Stage 6
Severity	Pre-clinical	Pre-clinical	MCI due to Alzheimer disease	Mild Dementia	Moderate Dementia	Severe Dementia
Clinical Features	Performance within expected range on objective cognitive tests.   No evidence of recent cognitive decline or new neurobehavioral symptoms.	Normal performance within expected range on objective cognitive tests.   Transitional cognitive decline (change from individual baseline within past 1 to 3 years, and persistent for at least 6 months).   Mild neurobehavioral changes may coexist or may be the primary complaint rather than cognitive.   No functional impact on daily life activities.	Performance in the impaired/abnormal range on objective cognitive tests.   Evidence of decline from baseline.   Performs daily life activities independently, but cognitive difficulty may result in detectable but mild functional impact on the more complex activities of daily life.	Substantial progressive cognitive impairment affecting several domains, and/or neurobehavioral disturbance.   Clearly evident functional impact on daily life, affecting mainly instrumental activities.   No longer fully independent/requires occasional assistance with daily life activities.	Progressive cognitive impairment or neurobehavioral changes.   Extensive functional impact on daily life with impairment in basic activities.   No longer independent and requires frequent assistance with daily life activities.	Progressive cognitive impairment or neurobehavioral changes.   Clinical interview may not be possible.   Complete dependency due to severe functional impact on daily life with impairment in basic activities, including basic self-care.

Adapted from Jack et al (2018)

aApplicable only to individuals in the Alzheimer continuum that fall into 1 of the 4 biomarker groups: 1) A+T+N+ 2) A+T-N- 3) A+T+N- 4) A+T-N+ where A: Aggregated Aβ or associated pathologic state (CSF Aβ42, or Aβ42/Aβ40 ratio or Amyloid PET), T: Aggregated tau (neurofibrillary tangles) or associated pathologic state (CSF phosphorylated tau or Tau PET) and N: Neurodegeneration or neuronal injury (anatomic MRI, FDG PET or CSF total tau)

For stages 1 to 6: Cognitive test performance may be compared to normative data of the investigators choice, with or without adjustment (choice of the investigators) for age, sex, education, etc.

For stages 2 to 6: Although cognition is the core feature, neurobehavioral changes—for example, changes in mood, anxiety, or motivation—may coexist.

For stages 3 to 6: Cognitive impairment may be characterized by presentations that are not primarily amnestic.

CSF: cerebrospinal fluid; FDG: fluorodeoxyglucose; MCI: mild cognitive impairment; MRI: magnetic resonance imaging; PET: positron emission tomography.

Biomarkers

Several potential biomarkers of AD are associated with AD pathophysiology (e.g., amyloid beta plaques, neurofibrillary tangles). Altered cerebrospinal fluid (CSF) levels of specific proteins have been found in patients with AD. These include tau protein, phosphorylated at AD-specific epitopes such as phosphorylated threonine 181 or total tau protein, an amyloid beta peptide such as 1-42 (Aβ42), and the synaptic protein, neurogranin. Other potential CSF, urinary, and blood peptide markers have been explored. Tau protein is a microtubule-associated molecule found in neurofibrillary tangles that are typical of AD. Tau protein is thought to be related to degenerating and dying neurons and high levels of tau protein in the CSF have been associated with AD. Amyloid beta-42 is a subtype of amyloid beta peptide produced from the metabolism of the amyloid precursor protein. Amyloid beta-42 is the key peptide deposited in amyloid plaques characteristic of AD. Low levels of amyloid beta-42 in the CSF have been associated with AD, perhaps because amyloid beta-42 is deposited in amyloid plaques instead of remaining in the fluid. Investigators have suggested the tau/amyloid beta-42 ratio may be a more accurate diagnostic marker than either alone. Neurogranin is a dendritic protein and CSF measurement may serve as a biomarker for dendritic instability and synaptic degeneration. Elevated CSF neurogranin may predict prodromal AD in MCI and has been confirmed in AD dementia and prodromal AD in several studies.

A variety of kits are commercially available to measure amyloid beta-42 and tau proteins. Between-laboratory variability in CSF biomarker measurement is large. Neural thread protein is associated with neurofibrillary tangles of AD. Both CSF and urine levels of this protein have been investigated as a potential marker of AD. Urine and CSF tests for neural thread protein may be referred to as the AD7C test.

More recently, research has focused on blood as a new matrix for AD biomarkers that have already been validated in the CSF. As blood is more accessible than CSF, blood sampling would be preferable to CSF when taking samples to measure AD biomarkers, both for clinical diagnosis or screening. However, developing blood AD biomarkers has proven complex. While the CSF is continuous with the brain extracellular fluid, with a free exchange of molecules from the brain to the CSF, only a fraction of brain proteins enter the bloodstream. Examples of blood biomarkers that are currently under examination for use in AD include amyloid beta, tau protein, and neurofilament light. Results from initial studies show that these blood biomarkers may potentially assist in early and more precise diagnosis, prognosis, or monitoring of disease progression and treatment in AD. In 2019, the Geneva AD Biomarker Roadmap Initiative expert panel concluded that of the currently assessed blood biomarkers plasma pTau has shown analytical validity and initial evidence of clinical validity, whereas the maturity level for amyloid beta remains to be partially achieved.

KEY POINTS:

The most recent literature review was updated through May 15, 2024.

Summary of Evidence

For individuals who have mild cognitive impairment (MCI) or dementia who receive cerebrospinal fluid (CSF) biomarker testing for Alzheimer disease (AD), the evidence includes systematic reviews. These studies assess using CSF biomarkers for diagnosis of AD or for the prognosis of progression of MCI to AD. Relevant outcomes include test validity, correct treatment, avoiding unnecessary subsequent testing, harms of invasive testing, and quality of life (QOL). Most clinical validity studies have been derived from select patient samples and defined optimal test cutoffs without validation; thus, the generalizability of results is uncertain. For predicting conversion from MCI to AD, limited evidence has suggested that testing may define increased risk. Whether an earlier diagnosis leads to improved health outcomes through a delay of AD onset due to medical therapy or other interventions or improved QOL is unknown. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have MCI or dementia who receive urinary biomarker testing for AD, the evidence includes a systematic review. Relevant outcomes include test validity, correct treatment, avoiding unnecessary subsequent testing, harms of invasive testing, and QOL. Clinical validity studies have included normal healthy controls and defined optimal test cutoffs without validation; thus, clinical validity is uncertain. Whether an earlier diagnosis leads to improved health outcomes through a delay of AD onset or improved QOL is unknown. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have MCI or dementia who receive blood biomarker testing for AD, the evidence includes a systematic review and cohort studies. Relevant outcomes include test validity, correct treatment, avoiding unnecessary subsequent testing, harms of invasive testing, and QOL. Clinical validity studies have primarily focused on the biomarker, plasma pTau, and have shown that this biomarker may be beneficial in screening for and diagnosing AD. Whether an earlier diagnosis leads to improved health outcomes through a delay of AD onset or improved QOL is unknown. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have MCI or mild dementia due to AD who are being considered for initial treatment with an approved amyloid beta plaque targeting therapy, the evidence includes randomized controlled trials, multisite longitudinal studies, and an analysis of a mixed cohort. These studies assess both the correlation between CSF biomarkers and positron emission tomography (PET) amyloid scans and the clinical utility of amyloid PET or CSF biomarkers in cognitively impaired patients who are being evaluated for treatment with anti-amyloid therapies. Relevant outcomes include test validity, symptoms, change in disease status, functional outcomes, health status measures, and QOL. Overall, the diagnostic accuracy of CSF biomarkers versus amyloid PET scans to identify MCI-AD was found to be similar. CSF biomarkers have been used as an alternative to PET amyloid scans to establish eligibility regarding the presence of amyloid beta pathology in randomized controlled trials that showed the efficacy of anti-amyloid therapies, which in turn demonstrates that the CSF biomarkers can identify patients who may benefit from therapy. The FDA-approved labels for lecanemab and donanemab state that the presence of amyloid beta pathology should be confirmed prior to initiating treatment. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have MCI or mild dementia due to AD, who are being treated with an amyloid beta plaque targeting therapy and are being evaluated for therapy continuation, the evidence includes multisite longitudinal studies and an analysis of a mixed cohort. Two of these studies assess the correlation between CSF biomarkers and PET amyloid scans and another assesses the clinical utility of amyloid PET in cognitively impaired patients who met appropriate use criteria for clinical amyloid PET. Relevant outcomes include test validity, symptoms, change in disease status, functional outcomes, health status measures, and QOL. The diagnostic accuracy of CSF biomarkers versus amyloid beta PET scans to identify MCI-AD was found to be similar. Further research is required to determine whether the use of CSF biomarkers alone in conjunction with amyloid beta PET scans is useful for determining whether or not amyloid beta targeting therapy should be continued. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Practice Guidelines and Position Statements

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

National Institute of Aging

2011 Revised Diagnostic Criteria

In 2011, probable Alzheimer disease (AD) was defined by the National Institute on Aging and the Alzheimer’s Association workgroup using the following diagnostic criteria:

“Meets criteria for dementia described ... and in addition, have the following characteristics:

• Insidious onset. Symptoms have a gradual onset over months to years, not sudden over hours or days;
• Clear-cut history of worsening of cognition by report or observation; and
• The initial and most prominent cognitive deficits are evident on history and examination in one of the following categories:
  • Amnestic presentation: It is the most common syndromic presentation of AD dementia. The deficits should include impairment in learning and recall of recently learned information. There should also be evidence of cognitive dysfunction in at least one other cognitive domain, as defined earlier in the text.
  • Nonamnestic presentations: Language presentation: The most prominent deficits are in word-finding, but deficits in other cognitive domains should be present. Visuospatial presentation: The most prominent deficits are in spatial cognition, including object agnosia, impaired face recognition, simultanagnosia, and alexia. Deficits in other cognitive domains should be present. Executive dysfunction: The most prominent deficits are impaired reasoning, judgment, and problem solving. Deficits in other cognitive domains should be present.
• The diagnosis of probable AD dementia should not be applied when there is evidence of:
  • substantial concomitant cerebrovascular disease, defined by a history of a stroke temporally related to the onset or worsening of cognitive impairment; or the presence of multiple or extensive infarcts or severe white matter hyperintensity burden; or
  • core features of dementia with Lewy bodies other than dementia itself; or
  • prominent features of behavioral variant frontotemporal dementia; or
  • prominent features of semantic variant primary progressive aphasia or nonfluent/agrammatic variant primary progressive aphasia; or
  • evidence for another concurrent, active neurological disease, or a non-neurological medical comorbidity or use of medication that could have a substantial effect on cognition.”

The diagnosis for possible AD dementia should meet the following criteria:

• Core criteria for the nature of cognitive deficits for AD dementia but is marked by sudden onset of cognitive impairment or insufficient history or documentation describing progressive decline; or
• All core clinical criteria for AD dementia but presents with concomitant cerebrovascular disease, features of dementia with Lewy bodies, or evidence of another neurological disease or any condition that could affect cognition.

Additionally, a category "Probable AD dementia with evidence of the AD pathophysiological process" has been added. Evidence of the AD pathophysiologic process is supported by detection of low cerebrospinal fluid (CSF) amyloid beta peptide 1-42 (Aβ42), positive positron emission tomography amyloid imaging, or elevated CSF tau, and decreased fluorine 18 fluorodeoxyglucose uptake on positron emission tomography in the temporoparietal cortex with accompanying atrophy by magnetic resonance imaging in relevant structures. Detection of the "pathophysiological process" is further divided by when in the disease natural history markers are expected to be detectable. Biomarker evidence in cases of probable AD may increase the certainty that the dementia is due to AD pathophysiological process.

Note on the 2011 Revised AD Criteria and Biomarkers

Some of the biomarkers considered in this evidence review are in a category among the 2011 revisions to AD diagnostic criteria, "probable AD dementia with evidence of the AD pathophysiological process." However, the diagnostic criteria workgroup noted the following:

 “[We] do not advocate the use of AD biomarker tests for routine diagnostic purposes at the present time. There are several reasons for this limitation: 1) the core clinical criteria provide very good diagnostic accuracy and utility in most patients; 2) more research needs to be done to ensure that criteria that include the use of biomarkers have been appropriately designed, 3) there is limited standardization of biomarkers from one locale to another, and 4) access to biomarkers is limited to varying degrees in community settings. Presently, the use of biomarkers to enhance certainty of AD pathophysiological process may be useful in three circumstances: investigational studies, clinical trials, and as optional clinical tools for use where available and when deemed appropriate by the clinician.”

Alzheimer’s Association

In 2009, the Alzheimer’s Association initiated a quality control program for CSF markers, noting that “Measurements of CSF AD biomarkers show large between laboratory variability, likely caused by factors related to analytical procedures and the analytical kits. Standardization of laboratory procedures and efforts by kit vendors to increase kit performance might lower variability, and will likely increase the usefulness of CSF AD biomarkers.” In 2012, the Alzheimer's Biomarkers Standardization Initiative published consensus recommendations for standardization of preanalytical aspects (e.g., fasting, tube types, centrifugation, storage time, temperature) of CSF biomarker testing.

In 2013, the Alzheimer’s Association published recommendations for operationalizing the detection of cognitive impairment during the Medicare annual wellness visit in primary care settings. The recommended algorithm for cognitive assessment was based on “current validated tools and commonly used rule-out assessments.” Guideline authors noted that use of biomarkers (e.g., CSF tau and β-amyloid proteins) “was not considered as these measures are not currently approved or widely available for clinical use.”

In 2018, the Alzheimer’s Association published appropriate use criteria for lumbar puncture and CSF testing for AD. Table 4 summarizes the indications for these practices. In 2021, the Alzheimer's Association also published international guidelines for the appropriate handling of CSF for routine clinical measurements of amyloid beta and tau.

Table 4. Indications for Appropriate Use of Lumbar Puncture and CSF Testing in Diagnosing AD

Appropriate Indications

Patients with SCD who are considered at increased risk for AD

MCI that is persistent, progressing, and unexplained

Patients with symptoms that suggest possible AD

MCI or dementia with an onset at an early age (<65 y)

Meeting core clinical criteria for probable AD with typical age of onset

Patients whose dominant symptom is a change in behavior where AD diagnosis is being considered

Inappropriate Indications

Cognitively unimpaired and within normal range functioning for age as established by objective testing; no conditions suggesting high risk and no SCD or expressed concern about developing AD

Cognitively unimpaired patient based on objective testing, but considered by patient, family informant and/or clinician to be at risk for AD based on family history.

Patients with SCD who are not considered to be at increased risk for AD

Individuals who are apolipoprotein E (APOE) Ɛ4 carriers with no cognitive impairment

Use of lumbar puncture in lieu of genotyping for suspected ADAD mutation carriers

ADAD mutation carriers, with or without symptoms

AD: Alzheimer disease; ADAD: autosomal-dominant Alzheimer disease; CSF: cerebrospinal fluid; MCI: mild cognitive impairment; SCD: subjective cognitive decline.

In 2022, the Alzheimer's Association Global Workgroup released appropriate use recommendations for blood biomarkers in AD. The Workgroup recommended "use of blood-based markers as (pre-)screeners to identify individuals likely to have AD pathological changes for inclusion in trials evaluating disease-modifying therapies, provided the AD status is confirmed with PET or CSF testing. “The Workgroup also encouraged "studying longitudinal blood-based marker changes in ongoing as well as future interventional trials “but cautioned that these markers "should not yet be used as primary endpoints in pivotal trials." Further, the Workgroup also recommended cautiously starting to use blood-based biomarkers "in specialized memory clinics as part of the diagnostic work-up of patients with cognitive symptoms" with the results confirmed with CSF or PET whenever possible. Additional data are needed before use of blood-based biomarkers as stand-alone diagnostic AD markers, or before considering use in primary care.

National Institute for Health and Care Excellence

In 2018, the National Institute for Health and Care Excellence (NICE) released a guideline on assessment, management, and support for people living with dementia and their care-givers. The guideline states that in cases of uncertain diagnosis, but highly suspicious for AD, providers can consider examining CSF for total tau or total tau and phosphorylated-tau 181 and either beta amyloid 42 or beta amyloid 42 and beta amyloid 40. People who are older are more likely to receive a false positive with a CSF analysis.

U.S. Preventive Services Task Force Recommendations

In 2020, the U.S. Preventive Services Task Force released recommendations for screening cognitive impairment in older adults, concluding that the current evidence is insufficient to determine benefits versus harms of screening for cognitive impairment in older adults. The statement discusses that screening tests are not intended to diagnose mild cognitive impairment or dementia, but a positive screening test result should prompt additional testing consisting of blood tests, radiology examinations, and/or medical and neuropsychologic evaluation.

KEY WORDS:

Biochemical marker, amyloid beta peptides, AB-42 Protein, Alzheimer’s Disease, ADmark ProfileAD7C, Alzheimer’s Disease, Beta-amyloid Protein, Neural thread Protein, Tau Protein, Alzheimer, Innotest, AlzheimAlert, MCI, mild cognitive impairment, AD, Alzheimer Disease, PrecivityAD, SYNTap® biomarker test, Elecsys® Phospho-Tau (181P) CSF, Elecsys® Total Tau CSF(tTau), β-Amyloid (1-42) CSF II (Abeta 42), pTau181, Neurocode, Simoa® ALZpath, p-Tau 217, PrecivityAD2, C2N Diagnostics, Lumipulse G Amyloid Ratio (1-42/1-40), Elecsys B-Amyloid (1-42) CSF II, Elecsys Phospho-Tau (181P) CSF, Elecsys ß-Amyloid (1-42) CSF II, Elecsys Total-Tau CSF

APPROVED BY GOVERNING BODIES:

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer laboratory-developed tests (LDTs) must be certified by CLIA for high-complexity testing. To date, the FDA has chosen not to require any regulatory review of these tests. Several AD biomarker tests are available as LDTs.

The FDA has cleared AD biomarker tests for marketing via the De Novo and 510(k) pathways with product code QSE, see Table 3.

Table 3. FDA Cleared Biomarker Tests for Alzheimer Disease

Test	Manufacturer	Location	Date Cleared	De Novo or 510(k) Number	Indication(s)
Lumipulse G Amyloid Ratio (1-42/1-40)	Fujirebio Diagnostics, Inc	Malvern, PA	May 2022	DEN200072	CSF test Intended to be used in adult patients, aged 55 years and older, presenting with cognitive impairment who are being evaluated for AD and other causes of cognitive decline. A test result ≥0.073 is a negative result which is consistent with a negative amyloid PET scan result. A negative result reduces the likelihood that a patient's cognitive impairment is due to AD. A test result ≤0.058 is a positive result which is consistent with a positive amyloid PET scan result. A positive result does not establish a diagnosis of AD or other cognitive disorder. A test result between 0.059 and 0.072 is considered as a likely positive result as it is more likely consistent with a positive amyloid PET scan result. A likely positive result does not establish a diagnosis of AD or other cognitive disorders and has increased uncertainty in regard to amyloid PET positivity. The Lumipulse G P-Amyloid Ratio ( 1-42/ 1-40) results must be interpreted in conjunction with other patient clinical information. This test is not intended as a screening or stand-alone diagnostic test.
Elecsys B-Amyloid (1-42) CSF II, Elecsys Phospho-Tau (181P) CSF	Roche Diagnostics	Indianapolis, IN	December 2022	K221842	CSF test Intended to be used in adult patients, aged 55 years and older, being evaluated for AD and other causes of cognitive impairment to generate a pTau181/Abeta42 ratio value. The adjusted ratio cutoff is 0.023. A negative result, defined as pTau181/Abeta42 ratio value below cutoff or an Abeta42 value above the measuring range, is consistent with a negative amyloid PET scan result. A negative result reduces the likelihood that a patient’s cognitive impairment is due to AD. A positive result, defined as pTau181/Abeta42 ratio value above cutoff, is consistent with a positive amyloid PET scan result. A positive result does not establish a diagnosis of AD or other cognitive disorder. The pTau181/Abeta42 ratio result is used as an adjunct to other clinical diagnostic evaluations. The performance of the pTau181/Abeta42 ratio has not been established for predicting development of dementia or other neurologic conditions or monitoring responses to therapies
Elecsys ß-Amyloid (1-42) CSF II, Elecsys Total-Tau CSF	Roche Diagnostics	Indianapolis, IN	June 2023	K231348	CSF test Intended to be used in adult patients, aged 55 years and older, being evaluated for AD and other causes of cognitive impairment to generate a tTau/Abeta42 ratio value. The numerical ratio must be compared to the cutoff of 0.28. A negative result, defined as tTau/Abeta42 ratio value below cutoff or an Abeta42 value above the measuring range, is consistent with a negative amyloid PET scan result. A negative result reduces the likelihood that a patient's cognitive impairment is due to AD. A positive result, defined as tTau/Abeta42 ratio value above cutoff, is consistent with a positive amyloid PET scan result. A positive result does not establish a diagnosis of AD or other cognitive disorder. The tTau/Abeta42 ratio result is used as an adjunct to other clinical diagnostic evaluations. The performance of the tTau/Abeta42 ratio has not been established for predicting development of dementia or other neurologic conditions or monitoring responses to therapies.

AD: Alzheimer disease; CSF: cerebral spinal fluid; FDA: Food and Drug Administration; PET: positron emission tomography.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group-specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP contracts: Special benefit consideration may apply. Refer to member’s benefit plan.

CURRENT CODING: 

CPT Codes:

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	imaging of  quantitative 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 (List separately in addition to code for primary procedure) (Use 0207U in conjunction with 0206U) (DISCERN™)
0358U	Neurology (mild cognitive impairment), analysis of β-amyloid 1-42 and 1-40, chemiluminescence enzyme immunoassay, cerebral spinal fluid, reported as positive, likely positive, or negative (Lumipulse test, FujiReBio) (Effective 1/1/2023)
0361U	Neurofilament light chain, digital immunoassay, plasma, quantitative (Mayo NFL) (Effective 1/1/2023)
0393U	Neurology (eg, Parkinson disease, dementia with Lewy bodies), cerebrospinal fluid (CSF), detection of misfolded α-synuclein protein by seed amplification assay, qualitative (Effective 7/1/2023)
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 (Effective 10/1/2023)
0443U	Neurofilament light chain (NfL), ultra-sensitive immunoassay , serum or cerebrospinal fluid (Effective 04/01/2024)
0445U	βamyloid (Abeta42) and Phospho Tau (181P) (pTau181), electrochemiluminescence immunoassay (ECLIA), cerebral spinal fluid, ratio reported as positive or negative for amyloid pathology (Effective 04/01/2024)
0459U	β-amyloid (Abeta42) and total tau (tTau), electrochemiluminescent immunoassay (ECLIA), cerebral spinal fluid, ratio reported as positive or negative for amyloid pathology (Effective 07/01/2024)
0479U	Tau, phosphorylated, pTau217 (Effective 10/01/24)
0503U	Neurology (Alzheimer disease), beta amyloid (Aβ40, Aβ42, Aβ42/40 ratio) and tau-protein (ptau217, np-tau217, ptau217/nptau217 ratio), blood, immunoprecipitation with quantitation by liquid chromatography with tandem mass spectrometry (LC-MS/MS), algorithm score reported as likelihood of positive or negative for amyloid plaques (Effective 10/01/24)
81099	Unlisted urinalysis procedure
82233	Beta-amyloid; 1-40 (Effective 01/01/25)
82234	Beta-amyloid; 1-42 (Effective 01/01/25)
83520	Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative; not otherwise specified
83884	Neurofilament light chain (Effective 01/01/25)
84393	Tau, phosphorylated (eg, pTau 181, pTau 217), each (Effective 01/01/25)
84394	Tau, total (Effective 01/01/25)
86849	Unlisted immunology procedure

REFERENCES:

1. 2021 Alzheimer's disease facts and figures. Alzheimers Dement. Mar 2021; 17(3): 327-406.
2. Albert MS, DeKosky ST, Dickson D et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011; 7(3):270-9.
3. Alzheimer's Association. 2022 Alzheimer's disease facts and figures. www.alz.org/media/documents/alzheimers-facts-and-figures.pdf.
4. Ashton NJ, Leuzy A, Karikari TK, et al. The validation status of blood biomarkers of amyloid and phospho-tau assessed with the5-phase development framework for AD biomarkers. Eur J Nucl Med Mol Imaging. Jul 2021; 48(7): 2140-2156.
5. Blennow K, Zetterberg H. Biomarkers for Alzheimer's disease: current status and prospects for the future. J Intern Med. Dec 2018; 284(6): 643-663.
6. Bloudek LM, Spackman DE, Blankenburg M et al. Review and meta-analysis of biomarkers and diagnostic imaging in Alzheimer's disease. J Alzheimers Dis 2011; 26(4):627-45.
7. Budd Haeberlein S, Aisen PS, Barkhof F, et al. Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer's Disease. J Prev Alzheimers Dis. 2022; 9(2): 197-210. 
8. Centers for Disease Control and Prevention. Barriers to equity in Alzheimer's and dementia care. June 2, 2021. www.cdc.gov/aging/publications/features/barriers-to-equity-in-alzheimers-dementia-care/index.html.
9. Chetelat G, Arbizu J, Barthel H, et al. Amyloid-PET and 18 F-FDG-PET in the diagnostic investigation of Alzheimer's disease and other dementias. Lancet Neurol. Nov 2020; 19(11): 951-962. 
10. Cognitive impairment in older adults: screening. U.S. Preventative Task Force. Published February 25, 2020.uspreventiveservicestaskforce.org/uspstf/recommendation/cognitive-impairment-in-older-adults-screening.
11. Cordell CB, Borson S, Boustani M, et al. Alzheimer's Association recommendations for operationalizing the detection of cognitive impairment during the Medicare Annual Wellness Visit in a primary care setting. Alzheimers Dement. Mar 2013; 9(2):141-150.
12. Cure S, Abrams K, Belger M, et al. Systematic literature review and meta-analysis of diagnostic test accuracy in Alzheimer's disease and other dementia using autopsy as standard of truth. J Alzheimers Dis. May 19 2014; 42(1):169-182.
13. Dementia: assessment, management and support for people living with dementia and their carers. National Institute for Health and Care Excellence. Published June 20, 2018. www.nice.org.uk/guidance/ng97.
14. Dumurgier J, Vercruysse O, Paquet C, et al. Intersite variability of CSF Alzheimer's disease biomarkers in clinical setting. Alzheimers Dement. Jul 2013; 9(4):406-413.
15. Feldman HH, Ferris S, Winblad B et al. Effect of rivastigmine on delay to diagnosis of Alzheimer's disease from mild cognitive impairment: the InDDEx study. Lancet Neurol 2007; 6(6):501-12.
16. Ferreira D, Perestelo-Perez L, Westman E, et al. Meta-review of CSF core biomarkers in Alzheimer's disease: the state-of-the-art after the new revised diagnostic criteria. Front Aging Neurosci. 2014; 6:47.
17. Fink HA, Linskens EJ, Silverman PC, et al. Accuracy of Biomarker Testing for Neuropathologically Defined Alzheimer Disease in Older Adults With Dementia. Ann Intern Med. May 19 2020; 172(10): 669-677.
18. Formichi P, Battisti C, Radi E and Federico A.  Cerebrospinal fluid tau, A beta, and phosphorylated tau protein for the diagnosis of Alzheimer’s disease.  J Cell Physiol, July 2006; 208(1): 39-46.
19. Galasko D, Clark C, Chang L, et al. Assessment of CSF levels of tau protein in mildly demented patients with Alzheimer’s disease. Neurology. Mar 1997; 48(3): 632-5.
20. Hansson O, Batrla R, Brix B, et al. The Alzheimer's Association international guidelines for handling of cerebrospinal fluid for routine clinical measurements of amyloid and tau. Alzheimers Dement. Mar 31 2021. 
21. Hansson O, Edelmayer RM, Boxer AL, et al. The Alzheimer's Association appropriate use recommendations for blood biomarkers in Alzheimer's disease. Alzheimers Dement. Jul 31 2022.
22. Hansson O, Lehmann S, Otto M, et al. Advantages and disadvantages of the use of the CSF Amyloid (A) 42/40 ratio in the diagnosis of Alzheimer's Disease. Alzheimers Res Ther. Apr 22 2019; 11(1): 34.
23. Hazan, J., Wing, M., Liu, K. Y., Reeves, S., & Howard, R. (2023). Clinical utility of cerebrospinal fluid biomarkers in the evaluation of cognitive impairment: a systematic review and meta-analysis. Journal of neurology, neurosurgery, and psychiatry, 94(2), 113–120.
24. IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press.
25. Izzo, N. J., Yuede, C. M., LaBarbera, K. M., Limegrover, C. S., Rehak, C., Yurko, R., Waybright, L., Look, G., Rishton, G., Safferstein, H., Hamby, M. E., Williams, C., Sadlek, K., Edwards, H. M., Davis, C. S., Grundman, M., Schneider, L. S., DeKosky, S. T., Chelsky, D., Pike, I., … Catalano, S. M. (2021). Preclinical and clinical biomarker studies of CT1812: A novel approach to Alzheimer's disease modification. Alzheimer's & dementia : the journal of the Alzheimer's Association, 17(8), 1365–1382.
26. Jack CR, Albert MS, Knopman DS, et al. Introduction to the recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. May 2011; 7(3): 257-62.
27. Jack CR, Bennett DA, Blennow K, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. Apr 2018; 14(4): 535-562.
28. Janelidze S, Mattsson N, Palmqvist S, et al. Plasma P-tau181 in Alzheimer's disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer's dementia. Nat Med. Mar 2020; 26(3): 379-386.
29. Janelidze S, Pannee J, Mikulskis A, et al. Concordance Between Different Amyloid Immunoassays and Visual Amyloid Positron Emission Tomographic Assessment. JAMA Neurol. Dec 01 2017; 74(12): 1492-1501.
30. Kaduszkiewicz H, Zimmermann T, Beck-Bornholdt HP, et al. Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials. BMJ. Aug 06 2005; 331(7512): 321-7.
31. Krishna G, Thangaraju Sivakumar P, Dahale AB, et al. Potential Utility of Plasma Biomarker Panels in Differential Diagnosis of Alzheimer's Disease. J Alzheimers Dis Rep. 2024; 8(1): 1-7. 
32. Lewczuk P, Matzen A, Blennow K, et al. Cerebrospinal Fluid A42/40 Corresponds Better than A42 to Amyloid PET in Alzheimer's Disease. J Alzheimers Dis. 2017; 55(2): 813-822.
33. Maddalena A, Papassotiropoulos A, Muller-Tillmanns B, et al. Biochemical diagnosis of Alzheimer disease by measuring the cerebrospinal fluid ratio of phosphorylated tau protein to beta-amyloid peptide42. Arch Neurol. Sep 2003; 60(9): 1202-6.
34. Mattsson N, Andreasson U, Persson S et al. The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers. Alzheimers Dement 2011; 7(4):386-95 e6.
35. McKhann GM, Knopman DS, Chertkow H et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging and the Alzheimer's Association workgroup. Alzheimers Dement 2011; 7(3):263-9.
36. McShane R, Areosa Sastre A and Minakaran N.  Memantine for dementia.  Cochrane Database Syst Rev, April 2006; (2): CD003154.
37. Motter R, Vigo-Pelfrey C, Kholodenko D, et al. Reduction of beta-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer’s disease. Ann Neurol. Oct 1995; 38(4): 643-8.
38. National Institutes on Aging. Data shows racial disparities in Alzheimer's disease diagnosis between Black and white research study participants. December 16, 2021. www.nia.nih.gov/news/data-shows-racial-disparities-alzheimers-disease-diagnosis-between-black-and-white-research.
39. Nisenbaum L, Martone R, Chen T, et al. CSF biomarker concordance with amyloid PET in Phase 3 studies of aducanumab. Alzheimers Dement. Aug 2023; 19(8): 3379-3388. 
40. Olsson B, Lautner R, Andreasson U, et al. CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis. Lancet Neurol. Jun 2016; 15(7):673-684.
41. Palmqvist S, Janelidze S, Quiroz YT, et al. Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders. JAMA. Aug 25 2020; 324(8): 772-781.
42. Palmqvist S, Zetterberg H, Mattsson N, et al. Detailed comparison of amyloid PET and CSF biomarkers for identifying early Alzheimer disease. Neurology. Oct 06 2015; 85(14): 1240-9. 
43. Petersen RC, Lopez O, Armstrong MJ, et al. Practice guideline update summary: Mild cognitive impairment: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. Jan 16 2018; 90(3): 126-135. 
44. Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N EnglJ Med. Jun 09 2005; 352(23): 2379-88.
45. Prescribing Label for LEQEMBI (lecanemab-irmb) injection, for intravenous use. Available at www.leqembi.com/-/media/Files/Leqembi/Prescribing-Information.pdf?hash=3d7bf1a2-5db2-4990-8388-81086f415676.
46. Rabinovici GD, Gatsonis C, Apgar C, et al. Association of Amyloid Positron Emission Tomography With Subsequent Change in Clinical Management Among Medicare Beneficiaries With Mild Cognitive Impairment or Dementia. JAMA. Apr 02 2019; 321(13): 1286-1294.
47. Raina P, Santaguida P, Ismaila A, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med. Mar 4 2008; 148(5):379-397.
48. Ritchie C, Smailagic N, Noel-Storr AH, et al. CSF tau and the CSF tau/ABeta ratio for the diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev. Mar 22 2017; 3:CD010803.
49. Ritchie C, Smailagic N, Noel-Storr AH, et al. Plasma and cerebrospinal fluid amyloid beta for the diagnosis of Alzheimer’s disease dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev. Jun 102014; (6): CD008782.
50. Roberts RO, Aakre JA, Kremers WK, et al. Prevalence and Outcomes of Amyloid Positivity Among Persons Without Dementia in a Longitudinal, Population-Based Setting. JAMA Neurol. Aug 01 2018; 75(8): 970-979.
51. Rosa MI, Perucchi J, Medeiros LR, et al. Accuracy of cerebrospinal fluid Abeta(1-42) for Alzheimer's disease diagnosis: a systematic review and meta-analysis. J Alzheimers Dis. 2014; 40(2):443-454.
52. Schneider LS, Mangialasche F, Andreasen N, et al. Clinical trials and late-stage drug development for Alzheimer's disease: an appraisal from 1984 to 2014. J Intern Med. Mar 2014; 275(3):251-283.
53. Schraen-Maschke S, Duhamel A, Vidal JS, et al. The free plasma amyloid Aβ 1 - 42 /Aβ 1 - 40 ratio predicts conversion to dementia for subjects with mild cognitive impairment with performance equivalent to that of the total plasma Aβ 1 - 42 /Aβ 1 - 40 ratio. The BALTAZAR study. Neurobiol Dis. Apr 2024; 193: 106459. 
54. Shaw LM, Arias J, Blennow K, et al. Appropriate use criteria for lumbar puncture and cerebrospinal fluid testing in the diagnosis of Alzheimer's disease. Alzheimers Dement, 2018 Oct 15; 14(11).
55. Summary Review for Leqembi (lecanemab) Application Number: 761269Orig1s000. Center for Drug Evaluation and Research. Available at www.accessdata.fda.gov/drugsatfda_docs/summary_review/2023/761269Orig1s000SumR.pdf. 
56. Teunissen CE, Verberk IMW, Thijssen EH, et al. Blood-based biomarkers for Alzheimer's disease: towards clinical implementation. Lancet Neurol. Jan 2022; 21(1): 66-77.
57. Thijssen EH, La Joie R, Strom A, et al. Plasma phosphorylated tau 217 and phosphorylated tau 181 as biomarkers in Alzheimer's disease and frontotemporal lobar degeneration: a retrospective diagnostic performance study. Lancet Neurol. Sep 2021; 20(9): 739-752.
58. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in Early Alzheimer's Disease. N Engl J Med. Jan 05 2023; 388(1): 9-21.
59. Vanderstichele H, Bibl M, Engelborghs S, et al. Standardization of preanalytical aspects of cerebrospinal fluid biomarker testing for Alzheimer's disease diagnosis: a consensus paper from the Alzheimer's Biomarkers Standardization Initiative. Alzheimers Dement. Jan 2012; 8(1):65-73.
60. Vermunt L, Sikkes SAM, van den Hout A, et al. Duration of preclinical, prodromal, and dementia stages of Alzheimer's disease in relation to age, sex, and APOE genotype. Alzheimers Dement. Jul 2019; 15(7): 888-898.
61. Winblad B, Gauthier S, Scinto L et al. Safety and efficacy of galantamine in subjects with mild cognitive impairment. Neurology 2008; 70(22):2024-35.
62. Zhang J, Zhang CH, Li RJ, et al. Accuracy of urinary AD7c-NTP for diagnosing Alzheimer's disease: a systematic review and meta-analysis. J Alzheimers Dis. 2014; 40(1):153-159.

POLICY HISTORY:

Medical Policy Group, August 2004 (4)

Medical Policy Administration Committee, August 2004

Available for comment August 24-October 7, 2004

Medical Policy Group, August 2006 (1)

Medical Policy Group, August 2008 (1)

Medical Policy Group, August 2010 (1): 2010 Description and Key Points Updated, No change in policy coverage

Medical Policy Group, May 2011 (1): 2011 Update to Description, Key Points and References

Medical Policy Panel, September 2012

Medical Policy Group, September 2012 (1): 2012 Update to Key Points and References; no change to policy statement

Medical Policy Group, December 2012 (3): 2013 Code Updates – Deleted 83912

Medical Policy Panel, August 2013

Medical Policy Group, September 2013 (1): 2013 Update to Key Points and References; removed codes 83912 and G0452, unlisted codes 81099 and 86849 added to policy; no change to policy statement

Medical Policy Panel, August 2014

Medical Policy Group, August 2014 (1): 2014 Update to Key Points, Key Words, Governing Bodies and References; no change to policy statement

Medical Policy Panel, August 2015

Medical Policy Group, August 2015 (3):  2015 Update to Description & Key Points; no change in policy statement

Medical Policy Panel, December 2016

Medical Policy Group, December 2016 (3): 2016 Updates to Title, Key Points, Approved by Governing Bodies & References; no change to policy statement.

Medical Policy Panel, December 2017

Medical Policy Group, December 2017 (3): 2017 Updates to Description, Key Points, Practice Guidelines and References; no change to policy statement.

Medical Policy Panel, December 2018

Medical Policy Group, January 2019 (3): Updates to Key Points and References. No change in policy statement.

Medical Policy Panel, December 2019

Medical Policy Group, December 2019 (9): 2019 Updates to Description, Key Points, References. Added key words: MCI, mild cognitive impairment, AD, Alzheimer Disease. No change to policy statement.

Medical Policy Group, September 2020 (9): Added CPT codes 0206U and 0207U due to 10/1/2020 Coding Update.

Medical Policy Panel, December 2020

Medical Policy Group, December 2020 (9): 2020 Updates to Key Points, Description, References. Title changed to "Evaluation of Biomarkers for Alzheimer Disease" to accommodate two new PLA codes 0206U and 0207U that were added effective 10/1/2020. No change to policy statement.

Medical Policy Panel, October 2021

Medical Policy Group, October 2021 (9): 2021 Updates to Key Points, Description, References. Policy statement updated to remove “not medically necessary”;  additional investigational statements added for use of CSF biomarkers in the management of MCI or mild dementia due to AD who are being evaluated for the initiation or continuation of amyloid beta targeting therapy; no change to policy intent.

Medical Policy Panel, October 2022

Medical Policy Group, October 2022 (9): 2022 Updates to Key Points, Description, References. Policy statement revised to clarify that the use of blood biomarker testing in patient with mild cognitive impairment or dementia due to Alzheimer disease is considered investigational. No change to policy intent.

Medical Policy Group, May 2023 (5): 2023 Quarterly Coding Update: Added CPT code 0393U to Current Coding section.

Medical Policy Group, August 2023 (5): 2023 Quarterly Coding Update. Added CPT code 0412U to Current Coding section. Key Words section updated to include: PrecivityAD. No change to Policy Section.

Medical Policy Group, November 2023 (5): Updates to Key Points, Benefit Application, and References. No change to Policy Statement.

Medical Policy Group, February 2024 (5): Quarterly Coding Update: Added CPT codes 0443U and 0445U to Current Coding section.

Medical Policy Group, May 2024 (5): Quarterly Coding Update: Added CPT code 0459U to Current Coding Section. Key Words updated to include: SYNTap® biomarker test, Elecsys® Phospho-Tau (181P) CSF, Elecsys® Total Tau CSF(tTau), β-Amyloid (1-42) CSF II (Abeta 42), pTau181. No change to Policy Statement.

Medical Policy Group, September 2024 (5): Quarterly Coding Update: Added CPT codes 0479U and 0503U to Current Coding section. Update to Key Words to include: Neurocode, Simoa® ALZpath, p-Tau 217, PrecivityAD2, C2N Diagnostics. No change to Policy Statement.

Medical Policy Panel, October 2024

Medical Policy Group, October 2024 (5): Updates to Key Points, Key Words: Lumipulse G Amyloid Ratio (1-42/1-40), Elecsys B-Amyloid (1-42) CSF II, Elecsys Phospho-Tau (181P) CSF, Elecsys ß-Amyloid (1-42) CSF II, Elecsys Total-Tau CSF; Approved by Governing Bodies, and References. Policy Statement updated to include 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 as medically necessary. Cerebrospinal fluid biomarker testing of neural thread proteins 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 investigational.

Medical Policy Administration Committee, November 2024

Available for Comment November 1, 2024, through December 15, 2024

Medical Policy Group, November 2024 (5): 2025 Annual coding update. Added the following CPT codes to the Current Coding section: 82233, 82234, 83884, 84393, 84394. No change to Policy statement.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.