Medical Policy


Subject: Genetic Testing and Biochemical Markers for the Diagnosis of Alzheimer's Disease
Document #: GENE.00003 Publish Date:    04/25/2018
Status: Reviewed Last Review Date:    03/22/2018


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

Position Statement

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 challenging for both physicians and individuals. There has been considerable research interest in identifying an accurate and conclusive laboratory test to bolster the clinical diagnosis.

Genetic Testing
AD 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 gene, (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 can occur as early as age 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 (PSEN1), and presenilin 2 (PSEN2) genes. 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% of those individuals. Overall, identifiable genetic mutations are rare causes of AD.

Chen and colleagues (2012) conducted a meta-analysis to evaluate the association of PSEN2 polymorphisms, rs8383 and 5'indel, with the risk of sporadic AD. Overall, the meta-analysis included six case-control studies for each polymorphism with 2186 confirmed AD cases and 2507 healthy controls in total. The analysis suggested a significant association between SNP rs8383 polymorphism and AD risk with no evidence of between-study heterogeneity or publication bias. In contrast, the authors did not find any evidence supporting the association between the 5'indel polymorphism and the risk of AD. The stratified analyses of apolipoprotein ε4 status or ethnicity also failed to reveal a statistically significant association between the 5'indel polymorphism of PSEN2 and AD risk. The authors concluded that PSEN2 rs8383 polymorphism is associated with an increased risk of sporadic AD. The authors also acknowledged that larger scale studies are needed to confirm these findings and to define potential gene-gene interactions. 

Biochemical Markers
Abnormal levels of the tau and amyloid beta proteins in the cerebrospinal fluid have been seen in individuals with known AD and 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 potential 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.

The revised diagnostic guidelines for AD from the National Institute on Aging and the Alzheimer’s Association do not advocate for the routine diagnostic use of biomarkers for AD at the present time. The authors indicate that while the core clinical criteria may provide diagnostic accuracy and utility in most subjects, more research needs to be done to ensure that criteria which include the use of biomarkers have been appropriately designed and standardized. The authors also state that “the use of biomarkers to enhance certainty of AD pathophysiological process may be useful in three circumstances: investigational studies, clinical trials and as optional clinical tools for use where available and when deemed appropriate by the clinician” (McKahn, 2011).

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 whom the clinical diagnosis has a sensitivity of 85%. There is inadequate data regarding the use of these tests in individuals with possible AD where the diagnosis is less certain. 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 AD affects the conventional diagnostic work up, treatment or clinical outcomes.

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


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, cognitive and behavioral changes, and severe neurochemical and neuropathological changes.

Currently the diagnosis of AD 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, including dementia, which 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.




Molecular pathology procedure, Level 2 (eg, 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat)  [when specified as the following]:

  • APOE (apolipoprotein E) (eg, hyperlipoproteinemia type III, cardiovascular disease, Alzheimer disease), common variants (eg, *2, *3, *4) 


Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis)  [when specified as the following]:

  • PSEN1 (presenilin 1) (eg, Alzheimer disease), full gene sequence


Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia)  [when specified as the following]:

  • APP (amyloid beta [A4] precursor protein) (eg, Alzheimer disease), full gene sequence
  • PSEN2 (presenilin 2 [Alzheimer disease 4]) (eg, Alzheimer disease), full gene sequence


Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified [when specified as tau protein, amyloid beta peptide testing]


Unlisted chemistry procedure [when specified as tau protein, amyloid beta peptide or neural thread protein biochemical testing]



ICD-10 Diagnosis



Unspecified dementia


Alzheimer's disease


Senile degeneration of brain, not elsewhere classified


Disorientation, unspecified


Other amnesia (memory loss NOS)


Age-related cognitive decline

When services are also Investigational and Not Medically Necessary:




DNA analysis for APOE epsilon 4 allele for susceptibility to Alzheimer's disease



ICD-10 Diagnosis



All diagnoses


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. Chen C, Zhou Z, Li M, et al. Presenilin-2 polymorphisms and risk of sporadic AD: evidence from a meta-analysis. Gene. 2012; 503(2):194-199.
  6. 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.
  7. Du Y, Dodel R, Hampel H, et al. Reduced levels of amyloid beta-peptide antibody in Alzheimer disease. Neurol. 2001; 57(5):801-805.
  8. Farlow MR. Alzheimer's disease: clinical implications of the apolipoprotein E genotype. Neurology. 1997; 48(5 Suppl 6):S30-S34.
  9. 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.
  10. Growdon JH. To tap or not to tap: cerebrospinal fluid biomarkers of Alzheimer’s disease. Ann Neurol. 1998; 44(1):6-7.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. Sinha S. The role of beta-amyloid in Alzheimer's disease. Med Clin North Am. 2002; 86(3): 629-639.
  20. 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. Herukka SK, Simonsen AH, Andreasen N, et al. Recommendations for cerebrospinal fluid Alzheimer's disease biomarkers in the diagnostic evaluation of mild cognitive impairment. Alzheimers Dement 2017; 13(3):285-295.
  3. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011; 7(3):263-269.
  4. 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.

ADmark® Alzheimer’s Evaluation 
Alzheimer’s Disease
Apolipoprotein E
Epsilon 4 Allele
Neural Thread Protein
Tau Protein

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History






Medical Policy & Technology Assessment Committee (MPTAC) review. The document header wording updated from “Current Effective Date” to “Publish Date.” Updates the References and History section. Deleted the Websites for Additional Information section.



MPTAC review. Updated Background/Overview and History sections.



MPTAC review. Updated Rationale and Reference sections. Removed ICD-9 codes from Coding section.



MPTAC review. Updated References and History sections.



Updated Coding section with 01/01/2015 HCPCS changes; removed S3855 deleted 12/31/2014.



MPTAC review. Updated Rationale, References, Index and History sections.



Updated Coding section with 01/01/2014 CPT descriptor changes.



MPTAC review. Updated the Rationale and References sections.



Updated Coding section with 01/01/2013 CPT changes; removed 83890-83914, 88384-88386 deleted 12/31/2012; removed 81228, 81229, 88245-88249, 88261-88264, 88271-88275, 88280-88291 (not applicable).



MPTAC review. Updated Review Date, Rationale, References and History sections.



Updated Coding section with 01/01/2012 CPT changes.



MPTAC review. Updated Review Date, References and History sections.



MPTAC review. Updated review date, References and History sections.



MPTAC review. No change to position statement.  Updated References section.



MPTAC review. Revised second investigational and not medically necessary position statement to add the following italicized text: “with or without a family history”. Updated references.



The phrase "investigational/not medically necessary" was clarified to read "investigational and not medically necessary." This change was approved at the November 29, 2007 MPTAC meeting.



MPTAC review.  No changes to position statement.



Updated Coding section with 01/01/2007 CPT/HCPCS changes.



MPTAC review.  No changes to position statement; minor wording revisions; updated references.



Updated Coding section with 01/01/2006 CPT/HCPCS changes



MPTAC review.  Revision based on Pre-merger Anthem and Pre-merger WellPoint Harmonization.

Pre-Merger Organizations

Last Review Date

Document Number


Anthem, Inc.




Genetic Molecular Testing for Inherited Disorders

WellPoint Health Networks, Inc.



Genetic Testing and Biochemical Markers for the Diagnosis of Alzheimer's Disease