Genetic Testing for Alzheimer Disease

POLICY NUMBER

A.2.04.13

DESCRIPTION

Alzheimer disease (AD) is the most common cause of dementia in elderly patients. For late-onset AD, there is a component of risk that runs in families, suggesting the contribution of genetic factors. Early-onset AD is much less common but can occur in non-elderly individuals. Early-onset AD has a stronger component of family risk, with clustering in families, thus suggesting an inherited genetic disease-causing variant.

Alzheimer Disease

Alzheimer disease (AD) is commonly associated with a family history; 40% of patients with AD have at least one other afflicted first-degree relative. Numerous genes have been associated with late-onset AD, while variants in chromosomes 1, 14, and 21 have been associated with early-onset familial AD. 

Genetic Variants

Individuals with early-onset familial AD (i.e., before age 65 years but as early as 30 years) form a small subset of AD patients. Alzheimer disease within families of these patients may show an autosomal dominant pattern of inheritance. Pathogenic variants in three genes have been identified in affected families: the amyloid-beta precursor protein (APP) gene, presenilin 1 (PSEN1) gene, and presenilin 2 (PSEN2) gene. APP and PSEN1 variants have 100% penetrance absent death from other causes, while PSEN2 has 95% penetrance. Variants within these genes have been associated with AD; variants in PSEN1 appear to be the most common. While only 3% to 5% of all patients with AD have early-onset disease, pathogenic variants have been identified in 70% or more of these patients. Identifiable genetic variants are, therefore, rare causes of AD.

Testing for the apolipoprotein E epsilon 4 (APOE ε4) allele among patients with late-onset AD and for APP, PSEN1, or PSEN2 pathogenic variants in the rare patient with early-onset AD has been investigated as an aid in diagnosis of patients presenting with symptoms suggestive of AD, or as a technique for risk assessment in asymptomatic patients with a family history of AD. Pathogenic variants in PSEN1 and PSEN2 are specific for AD; APP variants are also found in cerebral hemorrhagic amyloidosis of the Dutch type, a disease in which dementia and brain amyloid plaques are uncommon.

The APOE lipoprotein is a carrier of cholesterol produced in the liver and brain glial cells. The APOE gene has 3 alleles—ε2, 3, and 4—with the ε3 allele being the most common. Individuals carry two APOE alleles. The presence of at least one ε4 allele is associated with a 1.2- to 3-fold increased risk of AD, depending on the ethnic group. Among those homozygous for ε4 (approximately 2% of the population), the risk of AD is higher than for those heterozygous for ε4. The mean age of onset of AD is about age 68 years for ε4 homozygotes, about 77 years for heterozygotes, and about 85 years for those with no ε4 alleles. About half of patients with sporadic AD carry an ε4 allele. However, not all patients with the allele develop AD. The ε4 allele represents a risk factor for AD rather than a disease-associated variant. In the absence of APOE testing, first-degree relatives of an individual with sporadic or familial AD are estimated to have a 2- to 4-fold greater risk of developing AD than the general population. There is evidence of possible interactions between ε4 alleles, other risk factors for AD (eg, risk factors for cerebrovascular disease such as smoking, hypertension, hypercholesterolemia, diabetes), and a higher risk of developing AD. However, it is not clear that all risk factors have been taken into account in such studies, including the presence of variants in other genes that may increase the risk of AD.

Studies have also identified rs75932628-T, a rare functional substitution for R47H on the triggering receptor expressed on myeloid cells 2 (TREM2), as a heterozygous risk variant for late-onset AD. On chromosome 6p21.1, at position 47 (R47H), the T allele of rs75932628 encodes a histidine substitute for arginine in the gene that encodes TREM2.

TREM2 is highly expressed in the brain and is known to have a role in regulating inflammation and phagocytosis. TREM2 may serve a protective role in the brain by suppressing inflammation and clearing it of cell debris, amyloids, and toxic products. A decrease in the function of TREM2 would allow inflammation in the brain to increase and may be a factor in the development of AD. The effect size of the TREM2 variant confers a risk of AD that is similar to the APOEε4 allele, although it occurs less frequently.

Diagnosis

The diagnosis of AD is divided into three categories: possible, probable, and definite AD. A diagnosis of definite AD requirespostmortem confirmation of AD pathology, documenting the presence of extracellular amyloid-beta plaques and intraneuronal neurofibrillary tangles in the cerebral cortex. As a result, a diagnosis of definite AD cannot be made during life, and the diagnosis of probable or possible AD is made on clinical grounds. Probable AD dementia is diagnosed clinically when the patient meets core clinical criteria for dementia and has a typical clinical course for AD. Criteria for diagnosis of probable AD have been developed by the National Institute on Aging and the Alzheimer’s Association. These criteria require evidence of a specific pattern of cognitive impairment, a typical clinical course, and exclusion of other potential etiologies, as follows:

• Cognitive impairment

  • Cognitive impairment established by history from the patient and a knowledgeable informant, plus objective assessment by bedside mental status examination or neuropsychological testing.

  • Cognitive impairment involving a minimum of 2 of the following domains:

    • Impaired ability to acquire and remember new information;

    • Impaired reasoning and handling of complex tasks, poor judgment;

    • Impaired visuospatial abilities;

    • Impaired language functions;

    • Changes in personality, behavior, or comportment.

  • Initial and most prominent cognitive deficits are one of the following:

    • Amnestic presentation;

    • Nonamnestic presentations, either a language presentation with prominent word-finding deficits; a visuospatial presentation with visual cognitive defects; or a dysexecutive presentation with prominent impairment of reasoning, judgment, and/or problem solving.

  • Clinical course

    • Insidious onset;

    • Clear-cut history of worsening over time;

    • Interference with the ability to function at work or usual activities;

    • Decline from previous level of functioning and performing.

  • Exclusion of other disorders:

    • Cognitive decline not explained by delirium or major psychiatric disorder;

    • No evidence of other active neurologic diseases, including substantial cerebrovascular disease or dementia with Lewy bodies;

    • Lack of prominent features of variant frontotemporal dementia or primary progressive aphasia;

    • No medication use with substantial effects on cognition.

A diagnosis of possible AD dementia is made when the patient meets most of the AD criteria, but has an atypical course or an etiologically mixed presentation. This may consist of an atypical onset (eg, sudden onset) or atypical progression. A diagnosis of possible AD is also made when there is another potentially causative systemic or neurologic disorder that is not thought to be the primary etiology of dementia.

Mild cognitive impairment is a precursor of AD in many instances. Mild cognitive impairment may be diagnosed when there is a change in cognition, but insufficient impairment for the diagnosis of dementia. Features of mild cognitive impairment are evidence of impairment in one or more cognitive domains and preservation of independence in functional abilities. In some patients, mild cognitive impairment may be a predementia phase of AD. Patients with mild cognitive impairment may undergo ancillary testing (eg, neuroimaging, laboratory studies, neuropsychological assessment) to rule out vascular, traumatic, and medical causes of cognitive decline and to evaluate genetic factors.

Biomarker evidence has been integrated into the diagnostic criteria for probable and possible AD for use in research settings. Other diagnostic tests for AD include cerebrospinal fluid levels of tau protein or amyloid precursor protein, as well as positron emission tomography amyloid imaging. The cerebrospinal fluid tests are considered separately in the Evaluation of Biomarkers for Alzheimer Disease  medical policy. Positron emission tomography amyloid imaging is considered in the Selected Positron Emission Tomography Technologies for Evaluation of Alzheimer Disease  medical policy.

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 licensed by the CLIA for high-complexity testing.

In November 2017, the 23andMe Personal Genome Service (PGS) Test with Genetic Health Risk Report for Late-onset Alzheimer Disease was granted a de novo classification by the U.S. Food and Drug Administration (class II with general and special controls, FDA product code: PTA). This is a direct-to-consumer test that has been evaluated by the FDA for accuracy, reliability, and consumer comprehension. This test reports whether an individual has variants associated with late-onset AD by detecting the presence of the APOE ε4 (rs429353) gene variant.

In January 2023, lecanemab (Leqembi; Eisai) was approved by the FDA for the treatment of AD under accelerated approval based on the reduction in amyloid beta plaques observed in patients treated with lecanemab. On July 6, 2023, the FDA converted the accelerated approval of Leqembi to traditional approval for the treatment of AD in patients with mild cognitive impairment or mild dementia stage of disease. The label includes a boxed warning for amyloid related imaging abnormalities (ARIA), in general, and emphasizing that APOE ε4 homozygotes have a higher incidence of ARIA.

In July 2024, donanemab (Kisunla, Eli Lilly) was approved by the FDA via a traditional approval for the treatment of AD in patients with mild cognitive impairment or mild dementia stage of disease. The label includes a boxed warning for amyloid related imaging abnormalities (ARIA), in general, and emphasizing that APOE ε4 homozygotes have a higher incidence of ARIA.

POLICY

Targeted genetic testing for a known familial variant in the presenilin (PSEN) genes or amyloid-beta precursor protein (APP) gene associated with autosomal dominant early-onset Alzheimer disease may be considered medically necessary in an asymptomatic individual to determine future risk of disease when the following criteria are met:

• The individual has a close relative (ie, first- or second-degree relative) with a known familial variant associated with autosomal dominant early-onset Alzheimer disease (see Policy Guidelines) AND

• Results of testing will inform reproductive decision making.

Genetic testing for variants in presenilin (PSEN) genes or amyloid-beta precursor protein (APP) gene associated with autosomal dominant early-onset Alzheimer disease may be considered medically necessary in an asymptomatic individual to determine future risk of disease when the following criteria are met:

• The individual has a family history of dementia consistent with autosomal dominant Alzheimer disease for whom the genetic status of the affected family members is unavailable AND

• Results of testing will inform reproductive decision making.

Genetic testing for the apolipoprotein E (APOE) gene to guide initiation or management of a U.S. Food and Drug Administration-approved amyloid-beta targeting therapy is considered medically necessary in individuals with mild cognitive impairment or mild dementia associated with Alzheimer disease.

Genetic testing for the risk assessment of Alzheimer disease in asymptomatic individuals is considered investigational in all other situations. Genetic testing includes, but is not limited to, testing for the apolipoprotein E epsilon (APOE ε4) allele or triggering receptor expressed on myeloid cells 2 (TREM2).

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.

Genetic testing for Alzheimer disease (AD) may be offered along with analysis of cerebral spinal fluid levels of the tau protein and amyloid-beta peptide 1-42 (see the Evaluation of Biomarkers for Alzheimer Disease medical policy). This group of tests may be collectively referred to as the ADmark™ Profile, offered by Athena Diagnostics.

Testing Strategy for Asymptomatic Individuals

The 2011 guidelines from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors recommended that genetic testing for early-onset, autosomal dominant AD should only occur in the context of genetic counseling with support by someone expert in the area. In asymptomatic patients, a testing protocol based on the 1994 International Huntington Association and World Federation of Neurology Research Group on Huntington’s Chorea guidelines has been recommended.

A family history of autosomal dominant AD is suggested by 3 affected members in two generations. Testing for genes associated with early-onset autosomal dominant AD is appropriate for symptomatic individuals with early-onset Alzheimer disease in the setting of a family history of dementia, the setting of an unknown family history (eg, adoption), or for guiding testing of unaffected family members making reproductive decisions. In individuals at risk of early-onset, autosomal dominant AD, ideally, an affected family member should be tested first to identify the familial variant. Additionally, targeted testing of the parents of a proband with early-onset autosomal dominant AD and a confirmed genetic variant to identify mode of transmission (germline versus de novo) may be considered appropriate in some families, such as families with unaffected parents and no affected closely related family members. If no affected family member is available for testing and an asymptomatic individual remains interested in testing to inform reproductive decision making, then in-depth sequencing of the 3 genes (APP, PSEN1, PSEN2) associated with autosomal dominant AD may be indicated.

Treatment with Amyloid-beta Plaque Targeting Therapy

The lecanemab (LEQEMBI®) and donanemab (KISUNLA™) product labels include a boxed warning regarding the risk of amyloid-related imaging abnormalities (ARIA). The warning states that providers should discuss the potential risk of serious adverse events associated with ARIA with individuals considering treatment. The warning also states that patients who are APOE ε4 homozygotes have a higher incidence of ARIA and testing for APOE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA.

Genetics Nomenclature Update

The Human Genome Variation Society nomenclature is used to report information on variants found in deoxyribonucleic acid (DNA) and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table 1). The Society'snomenclature is recommended by the Human Variome Project, the HUman Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.

Table 1. Nomenclature to Report on Variants Found in DNA

Table 2. ACMG-AMP Standards and Guidelines for Variant Classification

Genetic Counseling

Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and understanding risk factors can be difficult for some patients; genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

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

11/2003: Approved by Medical Policy Advisory Committee (MPAC).

2/16/2004: Code Reference section completed.

3/8/2006: Policy reviewed, no changes.

3/27/2006: Coding updated. CPT4 2006 revisions added to policy.

12/28/2006: Code Reference section updated per the 2007 CPT/HCPCS revisions.

12/19/2007: Coding updated per the 2008 CPT/HCPCS revisions.

1/10/2008: Policy reviewed, no changes.

12/29/2008: Code reference section updated per the 2009 CPT/HCPCS revisions.

1/5/2009: Policy reviewed. No changes.

04/22/2010: Policy description updated regarding new findings in diagnosing Alzheimer’s disease. Policy statement unchanged. Deleted outdated reference from the Sources section.

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

01/14/2013: Added the following new 2013 CPT code to the Code Reference section: 81479.

12/13/2013: Policy description updated regarding the Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Gene. Policy statement revised to state that testing for TREM2 is considered investigational.

10/27/2014: Policy reviewed; description updated regarding susceptibility polymorphism at the APOE gene and diagnosis of AD. Policy statement unchanged. Removed deleted CPT codes 83891, 83892, 83894, 83898, 83900, 83902, 83904, 83907, 83908, 83909, 83912, and 83914 from the Code Reference section.

07/30/2015: Code Reference section updated for ICD-10.

02/24/2016: Policy title changed from "Genetic Testing for Familial Alzheimer's Disease" to "Genetic Testing for Alzheimer Disease." Policy description updated regarding late- and early-onset of AD. Policy statement revised to replace "diagnosis" with "in asymptomatic individuals." It previously stated: Genetic testing for the diagnosis or risk assessment of Alzheimer's disease is considered investigational. Policy statement also revised to change "amyloid precursor gene" to "amyloid-beta precursor protein." Policy guidelines updated regarding genetic counseling. Investigative definition updated. Removed deleted HCPCS code S3855 from the Code Reference section.

06/06/2016: Policy number A.2.04.13 added.

09/14/2017: Policy description updated to change "mutations" to "variants." Added policy statements that genetic testing for variants in the presenilin genes (PSEN) or amyloid-beta precursor protein (APP) gene associated with autosomal dominant early-onset Alzheimer disease may be considered medically necessary to determine future risk of disease when certain criteria are met. Investigational policy statement revised to remove PSEN and APP and to state that genetic testing for the risk assessment of Alzheimer disease in asymptomatic individuals is considered investigational in all other situations. Policy Guidelines updated regarding testing strategies and standard terminology for variant classification. Added medically necessary definition. Code Reference section updated to add medically necessary codes table. Added CPT codes 81405 and 81406.

12/22/2017: Code Reference section updated to revise descriptions for CPT codes 81405 and 81406 effective 01/01/2018.

05/01/2018: Second medically necessary statement updated to add "early-onset." Policy Guidelines updated regarding genetic counseling.

05/07/2019: Policy reviewed; no changes.

05/15/2020: Policy reviewed; no changes.

06/14/2021: Policy description updated regarding tests. Policy statements unchanged. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

08/02/2022: Policy description updated regarding the FDA approval of aducanumab. Added policy statement that genetic testing to guide initiation or management of a U.S. Food and Drug Administration-approved amyloid-beta targeting therapy (eg, aducanumab) is considered investigational. Genetic testing includes but is not limited to, testing for the APOE epsilon 4 allele. Policy Guidelines updated regarding tests and testing strategy. Added CPT code 81401 as investigational.

12/07/2022: Policy reviewed; no changes.

06/15/2025: Policy description updated regarding treatments for patients with Alzheimer Disease. Policy statement regarding genetic testing to guide initiation or management of an FDA-approved amyloid-beta targeting therapy changed from investigational to medically necessary for APOE testing in individuals with mild cognitive impairment or mild dementia associated with Alzheimer disease. It previously stated: Genetic testing to guide initiation or management of a U.S. Food and Drug Administration-approved amyloid-beta targeting therapy (eg, aducanumab) is considered investigational. Genetic testing includes but is not limited to, testing for the APOE epsilon 4 allele. Policy Guidelines updated regarding testing strategy for asymptomatic individuals and treatment with amyloid-beta plaque targeting therapy. Code Reference section updated to move CPT code 81401 from the Investigational Codes table to the Medically Necessary Codes table. Added ICD-10 diagnosis codes G30.0 - G30.9.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.13

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

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