Genetic Testing for Familial Alzheimer’s Disease AHS – M2038

Description of Procedure or Service

Alzheimer’s disease (AD) is a neurodegenerative disease defined by a gradual decline in memory, cognitive functions, gross atrophy of the brain, and accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles (Karch, Cruchaga, & Goate, 2014). Familial Alzheimer’s disease (FAD) is a rare, inherited form of Alzheimer’s disease. FAD has a much earlier onset than other type of Alzheimer’s, with symptoms developing in individuals in their thirties or forties.

***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician.

Policy

Example of medically necessary statement: BCBSNC will provide coverage for [Name of Procedure] when it is determined to be medically necessary because the medical criteria and guidelines shown below are met.

Example of Investigational Statement: [Name of Procedure] is considered investigational for [all applications}. BCBSNC does not provide coverage for investigational services or procedures.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy.

When Genetic Testing for Familial Alzheimer’s Disease is covered

Genetic counseling for familial Alzheimer’s disease genetic testing is considered medically necessary.

Genetic testing for APP, PSEN1 and PSEN2 genes associated with familial Alzheimer’s disease (i.e., autosomal-dominant, early-onset dementia not attributable to other factors) is considered medically necessary

• when the results of the testing will inform reproductive decision making AND 
• the individual is in one of the following situations 
  • Individuals with a family history of autosomal dominant dementia with one or more instances of early-onset AD, OR
  • Individuals with a first degree biological relative with a known mutation in the PSEN1, PSEN2, or APP genes, OR 
  • Symptomatic individuals with suspected early-onset AD when there is an unknown family history (adoption)

When Genetic Testing for Familial Alzheimer’s Disease is not covered

Genetic testing for Alzheimer’s disease is considered investigational in the following situations:

• Testing to confirm a diagnosis of Alzheimer’s disease (any type) 
• Testing for familial Alzheimer’s disease in children 
• Testing for late-onset Alzheimer’s disease (age >65 years) 
• Testing for other purposes than reproductive decision making 
• Testing of APOE gene and/or any other genes not listed above 
• Testing for purposes of Alzheimer’s disease risk assessment 
• Screening asymptomatic individuals 
• Testing in all other situations not described above

Policy Guidelines

Alzheimer disease (AD) is a devastating neurodegenerative disease with a strong genetic component, and the predominant form of dementia (50–75%) (M. Prince et al., 2013). In 2015, over 46 million people live with dementia worldwide, and this number is estimated to increase to 131.5 million by 2050 (Martin Prince, 2016). The average lifetime risk of developing Alzheimer disease is 10–12%. This risk at least doubles with the presence of a first-degree relative with the disorder (Goldman et al., 2011). The genetic predisposition of AD, even for late-onset AD patients, is estimated to be 60–80% (Gatz et al., 2006).

Most patients develop clinical symptoms at after the age of 65 (spontaneous or late-onset AD), however 2–10% of patients have an earlier onset of disease (early-onset AD) (Shea et al., 2016). AD is characterized by severe neuronal loss, aggregation of extracellular amyloid β plaques, and intraneuronal tau protein tangles resulting in progressive deterioration of memory and cognitive functions and ultimately requiring full-time medical care (Frigerio & Strooper, 2016). There is an enormous burden on public health due to the high costs associated with care and treatment. Aside from drugs that temporarily relieve symptoms, no treatment exists for AD (Van Cauwenberghe, Van Broeckhoven, & Sleegers, 2016).

Autosomal dominant AD is very rare (<1%), but the discovery of fully penetrant pathogenic mutations of Amyloid precursor protein (APP) (Goate et al., 1991; St George-Hyslop et al., 1987), Presenilin 1 (PSEN1) (Sherrington et al., 1995; Van Broeckhoven et al., 1992), and Presenilin 2 (PSEN2) (Sherrington et al., 1996) in autosomal dominant AD families has identified molecular mechanisms and pathways involved in AD pathogenesis and valuable targets currently used in diagnosis and drug development (Schneider et al., 2014; Van Cauwenberghe et al., 2016).

APP is proteolytically processed in the constitutive pathway by α- and γ-secretases resulting in nonpathogenic fragments. However, in the amyloidogenic pathway, subsequent proteolysis of APP by β-secretase and γ-secretase gives rise to a mixture of Aβ peptides with different lengths, of which Aβ1–42 are more aggregation-prone and are predominantly present in amyloid plaques in brains of AD patients. 39 APP mutations have been described, all of which affect proteolysis of APP in favor of Aβ1–42 (Cruts, Theuns, & Van Broeckhoven, 2012).

PSEN1 and PSEN2 are highly homologous genes. Both proteins are essential components of the γsecretase complex, which catalyzes the cleavage of membrane proteins, including APP. Mutations in PSEN1 and PSEN2 impair the γ-secretase mediated cleavage of APP resulting in an increased proportion of of Aβ1–42 (Cruts & Van Broeckhoven, 1998).

Late-onset AD is considered to be multifactorial, with a strong but complex genetic predisposition (Gatz et al., 2006) involving gene mutations and polymorphisms that may interact with each other or with environmental factors. The ɛ4 allele of APOE was the only major gene known to increase disease risk for both early-onset and late-onset AD, more recently genome-wide association studies (GWAS) and massive parallel resequencing (MPS) efforts have identified of at least 21 additional genetic risk loci. These loci, shown in the table below from Van Cauwenberghe et al, 2016, are estimated to explain about 28% of the heritability of liability, 30% of familial risk, and over 50% of sibling recurrence risk of developing Alzheimer's disease (Van Cauwenberghe et al., 2016).

Recently, Chung et al (Chung et al., 2018) conducted genome-wide pleiotropy analyses using association summary statistics. Significant findings were further examined by expression quantitative trait locus and differentially expressed gene analyses in AD vs. control brains using gene expression data. They found that pleiotropy analysis is a useful approach to identifying novel genetic associations with complex diseases and their endophenotypes. Functional studies are needed to determine whether ECRG4 or HDAC9 is plausible as a therapeutic target.

Clinical Validity and Utility

Patients concerned over their risk increasingly request testing. The utility and advisability of testing differs for early-onset versus late-onset disease, and genetics consultation should be recommended for families who express an interest in testing (Sherva & Kowall, 2018).

Early Onset AD

Comprehensive genetic counseling protocols are available for AD diagnostic and predictive testing to provide a framework for clinicians and geneticists to evaluate which patients may benefit from genetic testing. Available genetic diagnostic and predictive screening for causal mutations of early onset AD in APP, PSEN1, and PSEN2 are only responsible for a small portion of AD patients’ risk. They account for approximately two-thirds of familial autosomal dominant AD (Campion et al., 1999), but less than 10 percent of early-onset AD, less than one percent of AD overall (Sherva & Kowall, 2018). For a significant number of patients for whom genetic diagnostic screening is requested, the tests will be negative without excluding a genetic cause of disease (Van Cauwenberghe et al., 2016), Furthermore, the identification of a mutation is not a certain predictor of disease or onset age, given that these mutations can vary in terms of penetrance and gene expression. Nevertheless, the ability to identify an explanation for the clustering of AD in a family and the ability to use this toward predictive testing in subsequent generations provide an important step toward autonomy of patients and at-risk individuals (Van Cauwenberghe et al., 2016), thus testing for these highly penetrant mutations often carries significant personal and familial utility which the ACMG has recently supported as important clinical utilities (ACMG, 2015). 

Jannssen et al(2003) aimed to determine the proportion of patients with early onset AD with a positive family history accounted for by mutations in these genes by mutational analysis of the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes was performed in 31 probands with probable or definite AD from UK families with an age at onset (AAO) <61 years. They found that “The majority of patients (23 of 31; 74%) fulfilled recognized criteria for autosomal dominant inheritance. In 17 (55%) probands the authors identified eight novel PSEN1 sequence variants and eight recognized pathogenic mutations. In 4 (13%) probands the authors identified one novel APP sequence variant (H677R) and two recognized mutations. Thus in this series 21 of 31 (68%) probands were associated with a sequence variant in APP or PSEN1. Nine of the 11 (82%) probands with neuropathologically confirmed AD who additionally fulfilled recognized criteria for autosomal dominant inheritance were associated with a sequence variant in APP or PSEN1. The 10 patients in whom the authors were unable to identify a mutation in APP, PSEN1, or PSEN2 were older than the probands with sequence variants (55.4 vs 44.7 years: p = 0.001).” Sequence variants in APP and PSEN1 accounted for the majority of neuropathologically confirmed autosomal dominant early onset AD.

Late Onset AD

The role of genetics in diagnosis and risk prediction in late-onset AD is much less straightforward. Despite the established evidence of APOE ɛ4 as a risk factor for AD, its value in disease prediction in a clinical setting is limited, and the relevance of clinical testing for common genetic variations identified in GWAS is even more limited. Combining multiple susceptibility loci into a global genetic risk score (GRS) might improve the prediction of individuals at risk. However, the most comprehensive risk prediction model developed to date only achieved a sensitivity of 55% and a specificity of 78%, impeding use in clinical practice (de Calignon et al., 2012; Van Cauwenberghe et al., 2016).

Neu et al (Neu et al., 2017) performed a global meta-analysis of observational studies in more than 57,000 adults has found that the differential effect in women may be age-dependent and limited to ages 55 to 70 years for the development of mild cognitive impairment (MCI) and ages 65 to 75 years for the development of AD (Sherva & Kowall, 2018).

Cohn-Hokke et al (Cohn-Hokke et al., 2017) examined the social and personal effects of testing for hereditary neurodegenerative diseases and found that “the result of predictive testing on adult-onset neurodegenerative diseases does not have a large negative effect on social and personal life, although these observations should be interpreted with caution because of the small number of participants and low response rate.”

Applicable Federal Regulations

On April 6, 2017 the FDA approved the 23andMe PGS Genetic Health Risk Report for Late-onset Alzheimer’s Disease, indicated for reporting of the ε4 variant in the APOE gene. The report describes if a person's genetic result is associated with an increased risk of developing Late-onset Alzheimer’s Disease, but it does not describe a person's overall risk of developing Alzheimer’s Disease. The ε4 variant included in this report is found and has been studied in many ethnicities. Detailed risk estimates have been studied the most in people of European descent.

Other tests for Alzheimer’s genes are considered laboratory developed tests (LDT); developed, validated and performed by individual laboratories. LDTs are regulated by the Centers for Medicare and Medicaid (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA’88). As an LDT, the U. S. Food and Drug Administration has not approved or cleared these tests; however, FDA clearance or approval is not currently required for clinical use.

Policy Statement(s)

Guidelines and Recommendations

American College of Medical Genetics and Genomics (ACMG) and National Society of Genetic Counselors (NSGC)

The American College of Medical Genetics and Genomics (ACMG) and the National Society of Genetic Counselors (NSGC) issued joint practice guidelines related to the genetic assessment of AD. These guidelines include the following recommendations (Goldman et al, 2011):

• “Pediatric testing for AD should not occur.” 
• “Prenatal testing for AD is not advised if the patient intends to continue a pregnancy with a mutation.” 
• “Genetic testing for AD should only occur in the context of genetic counseling (in-person or through videoconference) and support by someone with expertise in this area. Symptomatic patients: Genetic counseling for symptomatic patients should be performed in the presence of the individual’s legal guardian or family member.” 
• “DTC (direct to consumer) APOE testing is not advised.” 
• “A risk assessment should be performed by pedigree analysis to determine whether the family history is consistent with EOAD [early-onset AD] or LOAD (late-onset AD) and with autosomal dominant (with or without complete penetrance), familial or sporadic inheritance.” 

For families in which an autosomal dominant AD gene mutation is a possibility:

• “Testing for genes associated with early-onset autosomal dominant AD should be offered in the following situations[MO1]: 
  • “A symptomatic individual with EOAD in the setting of a family history of dementia or in the setting of an unknown family history (e.g., adoption). 
  • “Autosomal dominant family history of dementia with one or more cases of EOAD. ◦ 
  • “A relative with a mutation consistent with EOAD (currently PSEN1/2 or APP).” 
• “Ideally, an affected family member should be tested first. If no affected family member is available for testing and an asymptomatic individual remains interested in testing despite counseling about the low likelihood of an informative result (a positive result for a pathogenic mutation), he/she should be counseled according to the recommended protocol. If the affected relative, or their next of kin, is uninterested in pursuing tested, the option of DNA banking should be discussed.” 

For families in which an autosomal dominant AD is unlikely:

• “Discuss that both sporadic and familial cases can be due to a genetic susceptibility. Risk estimates are only available for first-degree relatives of an affected individual in sporadic or familial cases.” 
• “Genetic testing for susceptibility loci (e.g., APOE) is not clinically recommended due to limited clinical utility and poor predictive value. If a patient wishes to pursue testing despite genetic counseling and recommendations to the contrary, testing may be considered at the clinician’s discretion.”

American College of Medical Genetics and Genomics (ACMG)

In the Choosing Wisely Initiative, the ACMG recommended “Don’t order APOE genetic testing as a predictive test for Alzheimer's disease.” The rationale for the recommended is that “APOE is a susceptibility gene for later-onset Alzheimer disease (AD), the most common cause of dementia. The presence of an ε4 allele is neither necessary nor sufficient to cause AD. The relative risk conferred by the ε4 allele is confounded by the presence of other risk alleles, gender, environment and possibly ethnicity. APOE genotyping for AD risk prediction has limited clinical utility and poor predictive value.”

American Association of Neurology (AAN)

In 2001 (reaffirmed in 2004), AAN made the following recommendation on the use of genetic testing for Alzheimer’s disease (Knopman et al, 2001):

• Routine use of APOE genotyping in patients with suspected AD is not recommended at this time (Guideline). 
• There are no other genetic markers recommended for routine use in the diagnosis of AD (Guideline). 

European Federation of Neurological Sciences (EFNS)

In 2010, EFNS published revised recommendations on the diagnosis and management of Alzheimer disease. It stated that “the ApoE 4 allele is the only genetic factor consistently implicated in lateonset AD, but it is neither necessary nor sufficient for development of the disease. Hence, there is no evidence to suggest ApoE testing is useful in a diagnostic setting” (Hort et al, 2010). The EFNS recommended that “screening for known pathogenic mutations can be undertaken in patients with appropriate phenotype or a family history of an autosomal dominant dementia. Routine Apo E genotyping is not recommended.”

National Institute on Aging (NIH)

In 2011, Alzheimer’s Disease diagnostic guidelines were revised including latest research results and better scientific understanding of the disease. The development of the new guidelines was led by the National Institute of Health and the Alzheimer’s Association. Diagnostic criteria for Alzheimer’s disease were re-defined. In respect to genetic testing, NIH issued following guidance and recommendations: “A rare type of familial Alzheimer’s disease, called Early-Onset Alzheimer’s Disease (EOAD), is caused by mutations in the amyloid precursor protein, presenilin 1, or presenilin 2 genes. A person who inherits any of these mutations from a parent will almost surely develop Alzheimer’s dementia before age 65. Genetic testing for the disease is common in families with a history of EOAD”; “The major genetic risk factor for the more common, sporadic form of the disease, or Late-Onset Alzheimer’s disease (LOAD), is the ε4 allele of the APOE gene. But carrying this allele by itself does not mean a person has or will develop Alzheimer’s dementia, so genetic testing for APOE ε4 is not recommended outside of a research setting”.

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

Scientific Background and Reference Sources

ACMG. (2015). Clinical utility of genetic and genomic services: a position statement of the American College of Medical Genetics and Genomics. Genet Med, 17(6), 505-507. doi:10.1038/gim.2015.41

Campion, D., Dumanchin, C., Hannequin, D., Dubois, B., Belliard, S., Puel, M., . . . Frebourg, T. (1999). Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet, 65(3), 664-670. doi:10.1086/302553

Chung, J., Zhang, X., Allen, M., Wang, X., Ma, Y., Beecham, G., . . . Farrer, L. A. (2018). Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer’s disease. Alzheimers Res Ther, 10. doi:10.1186/s13195-018-0349-z

Cohn-Hokke, P. E., van Swieten, J. C., Pijnenburg, Y. A. L., Tibben, A., Meijers-Heijboer, H., & Kievit, A. (2017). The Effect of Predictive Testing in Adult-Onset Neurodegenerative Diseases on Social and Personal Life. J Genet Couns. doi:10.1007/s10897-017-0195-3

Cruts, M., Theuns, J., & Van Broeckhoven, C. (2012). Locus-specific mutation databases for neurodegenerative brain diseases. Hum Mutat, 33(9), 1340-1344. doi:10.1002/humu.22117

Cruts, M., & Van Broeckhoven, C. (1998). Presenilin mutations in Alzheimer's disease. Hum Mutat, 11(3), 183-190. doi:10.1002/(sici)1098-1004(1998)11:3<183::aid-humu1>3.0.co;2-j

de Calignon, A., Polydoro, M., Suarez-Calvet, M., William, C., Adamowicz, D. H., Kopeikina, K. J., . . . Hyman, B. T. (2012). Propagation of tau pathology in a model of early Alzheimer's disease. Neuron, 73(4), 685-697. doi:10.1016/j.neuron.2011.11.033

FDA. (2017). Decision Summary for 23andMe PGS Genetic Health Risk Report. U.S. Food and Drug Administration

Frigerio, C. S., & Strooper, B. D. (2016). Alzheimer's Disease Mechanisms and Emerging Roads to Novel Therapeutics. doi:10.1146/annurev-neuro-070815-014015

Gatz, M., Reynolds, C. A., Fratiglioni, L., Johansson, B., Mortimer, J. A., Berg, S., . . . Pedersen, N. L. (2006). Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry, 63(2), 168-174. doi:10.1001/archpsyc.63.2.168

Goate, A., Chartier-Harlin, M. C., Mullan, M., Brown, J., Crawford, F., Fidani, L., . . . et al. (1991). Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature, 349(6311), 704-706. doi:10.1038/349704a0

Goldman, J. S., Hahn, S. E., Catania, J. W., LaRusse-Eckert, S., Butson, M. B., Rumbaugh, M., . . . Bird, T. (2011). Genetic counseling and testing for Alzheimer disease: Joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genet Med, 13(6), 597-605. doi:10.1097/GIM.0b013e31821d69b8

Janssen, J. C., Beck, J. A., Campbell, T. A., Dickinson, A., Fox, N. C., Harvey, R. J., . . . Collinge, J. (2003). Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology, 60(2), 235-239.

Karch, C. M., Cruchaga, C., & Goate, A. M. (2014). Alzheimer's disease genetics: from the bench to the clinic. Neuron, 83(1), 11-26. doi:10.1016/j.neuron.2014.05.041

Neu, S. C., Pa, J., Kukull, W., Beekly, D., Kuzma, A., Gangadharan, P., . . . Toga, A. W. (2017). Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-analysis. JAMA Neurol, 74(10), 1178-1189. doi:10.1001/jamaneurol.2017.2188

Prince, M. (2016). World Alzheimer Report 2015.

Prince, M., Bryce, R., Albanese, E., Wimo, A., Ribeiro, W., & Ferri, C. P. (2013). The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement, 9(1), 63- 75.e62. doi:10.1016/j.jalz.2012.11.007

Schneider, L. S., Mangialasche, F., Andreasen, N., Feldman, H., Giacobini, E., Jones, R., . . . Kivipelto, M. (2014). Clinical trials and late-stage drug development for Alzheimer's disease: an appraisal from 1984 to 2014. J Intern Med, 275(3), 251-283. doi:10.1111/joim.12191

Shea, Y. F., Chu, L. W., Chan, A. O., Ha, J., Li, Y., & Song, Y. Q. (2016). A systematic review of familial Alzheimer's disease: Differences in presentation of clinical features among three mutated genes and potential ethnic differences. J Formos Med Assoc, 115(2), 67-75. doi:10.1016/j.jfma.2015.08.004

Sherrington, R., Froelich, S., Sorbi, S., Campion, D., Chi, H., Rogaeva, E. A., . . . St GeorgeHyslop, P. H. (1996). Alzheimer's disease associated with mutations in presenilin 2 is rare and variably penetrant. Hum Mol Genet, 5(7), 985-988.

Sherrington, R., Rogaev, E. I., Liang, Y., Rogaeva, E. A., Levesque, G., Ikeda, M., . . . St GeorgeHyslop, P. H. (1995). Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature, 375(6534), 754-760. doi:10.1038/375754a0

Sherva, R., & Kowall, N. (2018). Genetics of Alzheimer disease - UpToDate. In J. Wilterdink (Ed.), UpToDate. 

St George-Hyslop, P. H., Tanzi, R. E., Polinsky, R. J., Haines, J. L., Nee, L., Watkins, P. C., . . . et al. (1987). The genetic defect causing familial Alzheimer's disease maps on chromosome 21. Science, 235(4791), 885-890.

Van Broeckhoven, C., Backhovens, H., Cruts, M., De Winter, G., Bruyland, M., Cras, P., & Martin, J. J. (1992). Mapping of a gene predisposing to early-onset Alzheimer's disease to chromosome 14q24.3. Nat Genet, 2(4), 335-339. doi:10.1038/ng1292-335

Van Cauwenberghe, C., Van Broeckhoven, C., & Sleegers, K. (2016). The genetic landscape of Alzheimer disease: clinical implications and perspectives. Genet Med, 18(5), 421-430. doi:10.1038/gim.2015.117

Policy Implementation/Update Information

1/1/19 New policy developed. BCBSNC will provide coverage for genetic testing for familial alzheimer’s disease when it is determined to be medically necessary because the medical criteria and guidelines are met. Medical Director review 1/1/2019. Policy noticed 1/1/2019 for effective date 4/1/2019. (sk)