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

Investigational and 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 and 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 individuals with or without a family history of Alzheimer's disease is considered investigational and not medically necessary.

Diagnosis of Alzheimer's disease (AD) by exclusion is frustrating for both physicians and individuals, 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 AD in individuals with probable disease provide a sensitivity of 85% compared to autopsy confirmed cases (definitive AD). Therefore, additional diagnostic techniques should have a diagnostic performance exceeding that of clinical diagnosis.

Genetic Testing
Alzheimer's disease is commonly associated with a family history: 40% of individuals 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 individuals 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
Early onset AD occurs before age 65 but as early as 30 years.  Some families 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 those with AD have early onset AD, and genetic mutations have only been identified in 30%-50%. 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 individuals 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 individuals, biochemical markers have only been investigated in those who are symptomatic.

Symptomatic Individuals
There is inadequate data to suggest that the addition of either genetic testing or biochemical markers improves the clinical diagnosis of AD. The majority of available studies focus on those with probable AD, for which the clinical diagnosis has a sensitivity of 85%. There is inadequate data regarding the use of these tests in individuals 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 clinical management in terms of either altering the diagnostic work up or therapy. There are currently no published data suggesting that either biochemical or genetic testing of individuals with possible or probable Alzheimer's disease affects the conventional diagnostic work up, let alone clinical outcome.

Asymptomatic Individuals
There is inadequate data regarding the role of genetic testing in asymptomatic individuals and no data regarding how test results may alter their medical management or clinical outcome.

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 65 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 Disease 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.

Alzheimer's Disease: A progressive neurological condition that primarily affects memory.

The following codes for treatments and procedures applicable to this document 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 and Not Medically Necessary:
For the following procedure and diagnosis codes, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

When services are also Investigational and Not Medically Necessary:

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

Peer Reviewed Publications:

1. Andersson C, Blennow K, Almkvist O, et al. Increasing CSF phospho-tau levels during cognitive decline and progression to dementia. Neurobiol Aging. 2008; 29(10):1466-1473.
2. Andreasen N, Blennow K. CSF biomarkers for mild cognitive impairment and early Alzheimer's disease. Clinical Neurol Neurosurg. 2005; 107:165-173.
3. Beecham GW, Martin ER, Li YJ, et al. Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease. Am J Hum Genet. 2009; 84(1):35-43.
4. Bian H, Van Swieten JC, Leight S, et al. CSF biomarkers in frontotemporal lobar degeneration with known pathology. Neurology. 2008; 70(19 Pt 2):1827-1835.
5. 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.
6. Du Y, Dodel R, Hampel H, et al. Reduced levels of amyloid beta-peptide antibody in Alzheimer disease. Neurol. 2001; 57(5):801-805.
7. Farlow MR . Alzheimer's disease: clinical implications of the apolipoprotein E genotype. Neurology. 1997; 48(5 Suppl 6):S30-S34.
8. 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.
9. Growdon JH. To tap or not to tap: cerebrospinal fluid biomarkers of Alzheimer's disease. Ann Neurol. 1998; 44(1):6-7.
10. 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.
11. 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.
12. Josephs KA, Whitwell JL, Knopman DS, et al. Abnormal TDP-43 immunoreactivity in AD modifies clinicopathologic and radiologic phenotype. Neurology. 2008; 70(19 Pt 2):1850-1857.
13. 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.
14. Lane R, Feldman HH, Meyer J, He Y, et al. Synergistic effect of apolipoprotein E epsilon4 and butyrylcholinesterase K-variant on progression from mild cognitive impairment to Alzheimer's disease. Pharmacogenet Genomics. 2008; 18(4):289-298.
15. Lannfelt L, Blennow K, Zetterberg H, et al.; PBT2-201-EURO study group. Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2008; 7(9):779-786.
16. Mattsson N, Zetterberg H, Hansson O, et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA. 2009 22; 302(4):385-393.
17. 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.
18. Sinha S. The role of beta-amyloid in Alzheimer's disease. Med Clin North Am. 2002; 86(3): 629-639.
19. 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.
2. 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.

1. Human Genome Project Information. Gene Testing.  Available at: http://www.ornl.gov/sci/techresources/Human_Genome/medicine/genetest.shtml.  Accessed on February 2, 2011.
2. National Institute on Aging. Alzheimer's Disease Fact Sheet. Available at: http://www.nia.nih.gov/Alzheimers/Publications/adfact.htm. Accessed on February 2, 2011.

AB-42, Alzheimer's Disease
ADmark^® Alzheimer's Evaluation 
Alzheimer's Disease, Genetic and Biochemical Testing for
ApoE Epsilon 4 Allele
Apolipoprotein E Epsilon 4 Allele
Genetic Testing for Alzheimer's Disease
Neural Thread Protein, Alzheimer's Disease
Tau Protein, Alzheimer's Disease

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