This policy addresses the use of testing for genetic mutations, polymorphisms, or biochemical markers for either the diagnosis or screening of Alzheimer’s disease.

Investigational/Not Medically Necessary:

Genetic testing (including both genetic polymorphisms and genetic mutations) or measurements of biochemical markers (including but not limited to tau protein, AB-42, neural thread protein) is considered investigational/not medically necessary as a diagnostic technique for individuals with symptoms suggestive of Alzheimer’s disease.

Genetic testing or measurements of biochemical markers as a screening technique in asymptomatic patients with a family history of Alzheimer’s disease is considered investigational/not medically necessary.

Rationale

Diagnosis by exclusion is frustrating for both physicians and patients, and there has been considerable research interest in identifying an inclusive laboratory test to bolster the clinical diagnosis. However, the currently used clinical criteria for Alzheimer’s disease (AD) in patients with probable disease provide a sensitivity of 85% compared to autopsy confirmed cases (definitive AD). Therefore, additional diagnostic technique should have a diagnostic performance exceeding that of clinical diagnosis.

Genetic Testing
Alzheimer’s disease is commonly associated with a family history: 40% of patients with AD have at least one other afflicted first-degree relative. At present, the following four genes have been associated with AD and have been investigated as a possible diagnostic test: (1) Apolipoprotein E, (2) Amyloid AB precursor gene, (3) Presenilin 1 gene, and (4) Presenilin 2 gene. Genetic testing has been investigated both in patients with probable AD and in asymptomatic family members.

Susceptibility Polymorphism at the Apolipoprotein E (ApoE) Gene
The ApoE lipoprotein is a carrier of cholesterol and is produced in the liver and brain glial cells. Epsilon 2, 3, and 4 are the three principal types of apolipoprotein in humans. Every person carries two ApoE alleles. The presence of at least one epsilon 4 allele is associated with an increased risk of AD in the range of 1.2 to 3 fold, depending on ethnic group. For those homozygous for epsilon 4, the risk of AD is higher. It should be noted that the epsilon 4 allele represents a susceptibility polymorphism and not a genetic mutation, discussed below.

Genetic Mutations
Patients with early onset AD (before age 65 but as early as 30 years) are a small subset of patients. The families of these individuals may show an autosomal dominant pattern of inheritance. Three genes have been identified by linkage analysis of affected families: amyloid AB precursor gene (APP), presenilin 1 gene, and presenilin 2 gene. A variety of mutations within these genes have been associated with AD; mutations in presenilin-1 appear to be the most common. However, only 2%-10% of all patients with AD have early onset AD, and genetic mutations have only been identified in 30%-50% of these patients. Therefore, overall, identifiable genetic mutations are rare causes of AD.

Biochemical Markers
Abnormal levels of the tau and amyloid beta proteins in the cerebrospinal fluid have been seen in patients with known AD and thus these two proteins have been investigated for their diagnostic utility. Neural thread protein is a protein that is associated with neurofibrillary tangles. Both CSF and urine levels of this protein have been investigated as a biochemical marker of AD. While genetic testing for Alzheimer’s disease has been investigated in both symptomatic and asymptomatic at risk patients, biochemical markers have only been investigated in symptomatic patients.

Symptomatic Patients
There is inadequate data to suggest that the addition of either genetic testing or biochemical markers improve the clinical diagnosis of AD. The majority of available studies focus on patients with probable AD in which the clinical diagnosis has a sensitivity of 85%. There is inadequate data regarding the use of these tests in patients with possible Alzheimer’s disease in which the diagnosis is more uncertain. Additionally, there is no data to suggest that the use of the above tests would change the management of the patient, either in terms of altering the diagnostic work up, or altering therapy. There are currently no published data suggesting that the diagnostic performance of either biochemical markers or genetic testing of patients with possible or probable Alzheimer’s disease would change the conventional diagnostic work up.

Asymptomatic Patients
There is inadequate data regarding the role of genetic testing in asymptomatic patients and no data regarding how test results may alter the medical management of the patient.

Background/Overview

Alzheimer’s disease (AD) is a progressive and ultimately fatal dementia that can be familial or idiopathic (no family history). The majority of AD is late-onset, but there is also a less common early-onset form of AD, which appears before the age of 60 and is associated with a rapid decline and severe neurochemical and neuropathological changes.

Currently the diagnosis of Alzheimer’s disease is a clinical diagnosis, focusing on the exclusion of other causes of senile dementia. In 1988 the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer’s and Related Disorders Association (ADRDA) published clinical criteria for the diagnosis of Alzheimer’s disease. These organizations defined three categories: possible, probable and definite Alzheimer’s disease. The only difference between probable and definite Alzheimer’s disease is that the definite category requires a brain biopsy confirming the presence of characteristic neurofibrillary tangles.

Definitions

Alzheimer’s Disease: a progressive neurological condition that primarily affects memory

Coding

The following codes for treatments and procedures applicable to this policy are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational/Not Medically Necessary:

For the following procedure and diagnosis codes, or when the code describes a procedure indicated in the Policy section as investigational/not medically necessary.

CPT

CPT Genetic Testing Code Modifier

ICD-9 Diagnosis

When services are also Investigational/Not Medically Necessary:

HCPCS

ICD-9 Diagnosis

References

Peer Reviewed Publications:

1. Andreasen N, Blennow K. CSF biomarkers for mild cognitive impairment and early Alzheimer’s disease. Clinical Neurol Neurosurg. 2005; 107:165-173.
2. Colciaghi F, Marcello E, Borroni B, et al. Platelet APP, ADAM 10 and BACE alterations in the early stages of Alzheimer disease. Neurology. 2004; 62(3):498-501. 
3. Du Y, Dodel R, Hampel H, et al. Reduced levels of amyloid beta-peptide antibody in Alzheimer disease. Neurol. 2001; 57(5):801-805. 
4. Farlow MR . Alzheimer's disease: clinical implications of the apolipoprotein E genotype. Neurology. 1997; 48(5 Suppl 6):S30-S34.
5. Galasko D, Clark C, Chang L, et al. Assessment of CSF levels of tau protein in mildly demented patients with Alzheimer’s disease. Neurology. 1997; 48(3):632-635.
6. Growdon JH. To tap or not to tap: cerebrospinal fluid biomarkers of Alzheimer’s disease. Ann Neurol. 1998; 44(1):6-7.
7. Hsuing GR, Sadovnick AD, Feldman H. Apolipoptrotein E 4 genotype as a risk factor for cognitive decline and dementia. Data from the Canadian Study of Health and Aging. CMAJ. 2004; 171:863-867.
8. Jia JP, Meng R, Sun YX, et al. Cerebrospinal fluid tau, AB(1-42) and inflammatory cytokines in patients with Alzheimer’s disease and vascular dementia. Neuroscience Letters. 2005; 383:12-16. 
9. Kapaki E, Liappas I. Paraskevas GP, et al. The diagnostic value of tau protein, beta-amyloid (1-42) and their ration for the discrimination of alcohol-related cognitive  disorders from Alzheimer’s disease in the early stages. Internat J Geriatric Psych. 2005; 20:722-729.
10. 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. 1995; 38(4):643-648. 
11. Sinha S. The role of beta-amyloid in Alzheimer's disease. Med Clin North Am. 2002; 86(3): 629-639.
12. Teunissen CE, de Vente J, Steinbusch HW, De Bruijn C. Biochemical markers related to Alzheimer's dementia in serum and cerebrospinal fluid. Neurobiol Aging. 2002; 23(4):485-508.

Government Agency, Medical Society, and Other Authoritative Publications:

1. American College of Medical Genetics/American Society of Human Genetics. Statement on use of apolipoprotein E testing for Alzheimer disease. American College of Medical Genetics/American Society of Human Genetics Working Group on ApoE and Alzheimer disease. JAMA 1995; 274(20):1627-1629. Available at: http://www.acmg.net/resources/policies/pol-001.asp. Accessed on February 26, 2007. 
2. Alzheimer’s Disease. 2000. Available at: http://www.americangeriatrics.org/products/positionpapers/gen_test.shtm. Accessed on February 26, 2007.
3. National Institute on Aging/Alzheimer's Association. Apolipoprotein E genotyping in Alzheimer's disease. National Institute on Aging/Alzheimer's Association Working Group. Lancet 1996; 347(9008):1091-1095. 
4. Hayes, Inc. Hayes Medical Technology Directory. Biochemical Testing for Alzheimer's Disease. Lansdale, PA: Hayes, Inc.; May 2003. Search updated February 26, 2006. Search updated February 25, 2006.
5. Hayes, Inc. Hayes Medical Technology Directory. Genetic Testing for Susceptibility to Alzheimer’s Disease. Lansdale, PA: Hayes, Inc.; May 2003. Search updated February 26, 2006. Search updated February 25, 2006.

1. National Institute on Aging. Alzheimer’s Disease Fact Sheet. Available at: http://www.nia.nih.gov/Alzheimers/Publications/adfact.htm. Accessed on February 26, 2007.

Policy History

Federal and State law, as well as contract language, including definitions and specific contract provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The member's contract benefits in effect on the date that services are rendered must be used. Medical Policy, which addresses medical efficacy, should be considered before utilizing medical opinion in adjudication. Medical technology is constantly evolving, and we reserve the right to review and update Medical Policy periodically. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by an means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan.

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