Evaluation of Biomarkers for Alzheimer Disease

POLICY NUMBER

A.2.04.14

DESCRIPTION

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 4 and 8 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 2 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 the 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 Continuum^a

Adapted from Table 6, 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 (eg, 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 that 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.

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

Clinical laboratories located in New York State, and laboratories conducting testing on specimens originating in New York State, must hold a New York State Department of Health clinical laboratory permit pursuant to Title V, Section 574 of the New York State Public Health Law. The Clinical Laboratory Evaluation Program (CLEP) regulates clinical laboratories that accept clinical specimens collected in New York State. Laboratories holding a New York State clinical laboratory permit must participate in regular proficiency testing to demonstrate analytical validity. For additional details, see https://www.wadsworth.org/regulatory/clep .

Laboratory-developed tests approved by the New York State Department of Health may be identified through an online search tool at: https://www.wadsworth.org/regulatory/clep/approved-ldt . Laboratories may administer FDA-cleared (510k), approved (PMA/De Novo), exempted, or Emergency Use Authorization (EUA) applicable assays that have not been modified to change the procedure or the intended use without further action if the laboratory holds a permit in the test appropriate category. A listing of approved clinical laboratories is available at: https://wadsworth.org/regulatory/clep/approved-labs.

Several AD biomarker tests are available as LDTs. Not all laboratories choose to seek a New York State clinical laboratory permit. Several blood-based tests have received Breakthrough Device Designation from the FDA, including Roche and Eli Lilly's Elecsys p-Tau217 plasma assay, and Beckman Coulter Diagnostics p-Tau217/β-Amyloid 1-42 plasma ratio. No blood-based tests have received FDA clearance or approval at the time of review.

The FDA has cleared CSF AD biomarker tests for marketing via the De Novo and 510(k) pathways with product code QSE, see Table 2.

Table 2. FDA Cleared Biomarker Tests for Alzheimer Disease

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

Related medical policies - 

• Genetic Testing for Alzheimer Disease

• Selected Positron Emission Tomography Technologies for Evaluation of Alzheimer Disease

POLICY

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 (see Policy Guidelines).

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.

Cerebrospinal fluid biomarker testing, including but not limited to amyloid beta peptides, tau protein, or neural thread proteins, as an adjunct to clinical diagnosis in individuals with mild cognitive impairment is considered investigational.

Cerebrospinal fluid biomarker testing, including but not limited to amyloid beta peptides, tau protein, or neural thread proteins, as an adjunct to clinical diagnosis in individuals with mild dementia due to Alzheimer disease is considered investigational.

Cerebrospinal fluid biomarker testing, including but not limited to amyloid beta peptides, tau protein, or neural thread proteins, 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 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.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

The labels for FDA-approved, amyloid beta targeting therapies, LEQEMBI® (lecanemab) and Kisunla™ (donanemab) state that the presence of amyloid beta pathology should be confirmed prior to initiating treatment. In the pivotal randomized controlled trial for lecanemab (Clarity AD), the protocol states that the eligibility criteria related to amyloid beta pathology required "confirmed amyloid pathology indicated by either 1) positive amyloid load confirmed by amyloid PET assessment, or 2) CSF assessment of t-tau / Aβ[1-42].'" In the pivotal randomized controlled trial for donanemab (TRAILBLAZER-ALZ 2), eligibility was based on flortaucipir F18 and florbetapir F18 PET assessment only. Per the protocol, p-tau 181 was removed as a screening and eligibility criterion in February 2021.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B. appropriate with regard to standards of good medical practice; and

C. not solely for the convenience of the Member, his or her Provider; and

D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting. 

POLICY HISTORY

7/2003: Approved by Medical Policy Advisory Committee (MPAC)

9/2/2003: Code Reference section completed

12/17/2008: Policy reviewed, no changes

05/13/2010: Policy description updated with new research findings; policy statement unchanged. Added CPT codes 83520 and 83912, which are used to identify the steps in testing for tau protein and amyloid beta peptides. There are no specific codes used for testing for neural thread protein.

07/29/2011: Policy reviewed; no changes.

11/28/2012: Policy reviewed; no changes.

05/06/2013: Removed ICD-9 diagnosis code 331.0 from the Code Reference section.

11/15/2013: Policy reviewed; no changes.

07/08/2015: Policy reviewed; policy statements unchanged. Code Reference section updated for ICD-10. Removed deleted CPT code 83912.

11/02/2015: Policy description revised. Policy statements unchanged. Investigative definition updated in policy guidelines section.

06/06/2016: Policy number A.2.04.14 added.

01/16/2017: Policy title changed from "Biochemical Markers for Alzheimer's Disease" to "Cerebrospinal Fluid and Urinary Biomarkers of Alzheimer Disease." Policy description updated. Policy statements unchanged.

01/15/2018: Policy description updated. Policy statements unchanged.

01/14/2019: Policy reviewed; no changes.

01/20/2020: Policy description updated to remove information regarding Alzheimer disease and mild cognitive impairment. Policy statements unchanged.

02/01/2021: Policy title changed from "Cerebrospinal Fluid and Urinary Biomarkers of Alzheimer Disease" to "Evaluation of Biomarkers for Alzheimer Disease." Second policy statement re-worded; intent unchanged.

07/26/2022: Policy description updated regarding Alzheimer disease, pathophysiology, and biomarkers. Added investigational policy statements for the use of cerebrospinal fluid biomarker testing: 1) as an adjunct to clinical diagnosis in individuals with mild cognitive impairment or mild dementia due to Alzheimer disease. 2) as part of an evaluation for the initiation or continuation of amyloid beta targeting therapy in individuals with mild cognitive impairment or mild dementia due to Alzheimer disease. Code Reference section updated to add CPT codes 81099 and 86849.

03/03/2023: Policy description updated regarding blood biomarker testing in patients with mild cognitive impairment or dementia due to Alzheimer disease. Policy statement revised to state that 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.

09/25/2023: Code Reference section updated to add new CPT code 0412U, effective 10/01/2023.

03/27/2024: Code Reference section updated to add new CPT code 0445U, effective 04/01/2024.

10/01/2024: Code Reference section updated to add new CPT code 0503U.

12/19/2024: Code Reference section updated to add new CPT codes 82233, 82234, 84393, and 84394 effective 01/01/2025.

04/01/2025: Code Reference section updated to add new CPT codes 0547U, 0548U, and 0551U, effective 04/01/2025.

06/15/2025: Policy description updated regarding Alzheimer Disease and FDA cleared biomarker tests for Alzheimer Disease. Policy statement changed from investigational to medically necessary for 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. Policy Guidelines updated regarding FDA-approved labels for LEQEMBI® (lecanemab) and Kisunla™ (donanemab). Added medically necessary definition. Code Reference section updated to move the following CPT codes from investigational to medically necessary: 82233, 82234, 84393, and 84394. Added ICD-10 diagnosis codes G30.0 - G30.9. Added the following CPT codes 0358U, 0361U, 0443U, 0445U, and 0459U as investigational.

07/18/2025: Code Reference section updated to add new CPT code 0568U. Effective 07/01/2025.

08/11/2025: Policy description updated regarding laboratory-developed tests. Policy statements unchanged. Policy Guidelines updated regarding the randomized controlled trial for donanemab.

10/01/2025: Code Reference section updated to add new CPT code 0596U.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.14

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Medically Necessary Codes

Investigational Codes

CPT copyright American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.