Jurisprudencia Vinculante Del Tribunal Constitucional

• Alzheimer disease (AD) is characterized by adult-onset, progressive dementia with cerebral cortical atrophy and beta amyloid plaque formation.1 Common findings include memory loss, confusion, speech issues, hallucinations, and personality and behavioral changes such as poor judgment, agitation, and withdrawal.2,3 Symptoms of Alzheimer disease usually start after 60-65 years old.2

• The general population lifetime risk of Alzheimer disease is about 10%. First- degree relatives (siblings, offspring) of a single person in the family with Alzheimer disease have a 20-25% lifetime risk.2

• Of all people with Alzheimer disease, about 25% have at least two affected people in the family (called "familial Alzheimer disease").2

o Most people (95%) with familial Alzheimer disease develop symptoms after 65.2 This is called "late-onset familial Alzheimer disease." Late-onset familial Alzheimer disease is believed to have complex inheritance with multiple susceptibility genes and environmental factors playing a role.2 o In about 5% of familial cases, symptoms consistently start before

65.2 This is called "early onset familial Alzheimer disease" (EOFAD). EOFAD is an autosomal dominant inherited disorder caused by different genes than those that may predispose to late-onset Alzheimer disease.1 • There are three common versions of the APOE gene — e2, e3, and e4. The

e4 variant is significantly associated with Alzheimer disease.2

o People with Alzheimer disease, and especially late-onset familial

Alzheimer disease, are more likely to have one or two copies of APOE e4. For example, less than 1% of unaffected people have two copies of e4 (e4/e4), but nearly 19% of people with familial Alzheimer disease have two copies of e4.2

o However, e4 is not necessary to develop Alzheimer disease and having no copies of e4 does not rule out the disease.2,4

o APOE e4 appears to cause susceptibility to Alzheimer disease, but the reason is unclear.2,5

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Test Information

• Clinical testing is available to determine which two APOE gene versions a person has inherited.

• Many laboratories in the U.S. directly test for these three variants (e2, e3, e4) to assist diagnosis or predict risk of Alzheimer disease.

Guidelines and Evidence

• Diagnostic:

o No current U.S. evidence-based guidelines have been identified. o A clinical diagnosis relies on symptoms and neuroimaging, which is

correct about 80-90% of the time. When two copies of e4 are identified in someone with a clinical diagnosis, the accuracy of that diagnosis

increases to 97%.2 The diagnosis can only be confirmed by

neuropathology at autopsy. Because finding APOE e4 neither confirms nor rules out Alzheimer disease on its own, its clinical utility is unclear.4 • European Federation of Neurological Societies (2010): "The ApoE e4 allele is

the only genetic factor consistently implicated in late-onset 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."4

• Consensus-based guidelines include:

o American College of Medical Genetics and The National Society of Genetic Counselors (2011): "Genetic testing for susceptibility loci (e.g., APOE is not clinically recommended due to limited clinical utility and poor predictive value."5

o National Institute of Aging/Alzheimer's Association Working (1997):6  "Insofar as patients with AD are more likely to have an APOE-e4

allele than are patients with other forms of dementia or individuals without dementia, physicians may choose to use APOE genotyping as an adjunct to other diagnostic tests for AD."6

 "Since genotyping cannot provide certainty about the presence or absence of AD, it should not be used as the sole diagnostic test." 6 o Predictive:

 APOE results have been used to predict a person’s lifetime risk for Alzheimer disease. For example, a person with two copies of APOE e4 has an estimated 30% lifetime risk to develop the disease.2 Predicted risks vary based on gender and number of e4 variants. While these risk estimates may be of personal interest, they do not currently have significant clinical utility.2,5

o National Institute of Aging/Alzheimer's Association Working (1997):6  "The use of APOE genotyping to predict future risk of AD in

symptom-free individuals is not recommended at this time." 6

Lab Management Guidelines V1.0.2016

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Criteria

• This test is considered investigational and/or experimental.

o Investigational and experimental (I&E) molecular and genomic (MolGen) tests refer to assays involving chromosomes, DNA, RNA, or gene

products that have insufficient data to determine the net health impact, which typically means there is insufficient data to support that a test accurately assesses the outcome of interest (analytical and clinical validity), significantly improves health outcomes (clinical utility), and/or performs better than an existing standard of care medical management option. Such tests are also not generally accepted as standard of care in the evaluation or management of a particular condition.

o In the case of MolGen testing, FDA clearance is not a reliable standard given the number of laboratory developed tests that currently fall outside of FDA oversight and FDA clearance often does not assess clinical utility.

References

1. Bird T. (Updated October 2012). Early-Onset Familial Alzheimer Disease. In GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. Available at

http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=alzheimer-early.

2. Bird T. (Updated April 2014). Alzheimer Disease Overview. In GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of

Washington, Seattle. Available

at:http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=alzheimer.

3. Genetics Home Reference. Alzheimer disease. Published September 19, 2010. Available at http://ghr.nlm.nih.gov/condition/alzheimer-disease.

4. Hort J, O'Brien JT, Gainotti G, et al. EFNS guidelines for the diagnosis and management of Alzheimer's disease.Eur J Neurol. 2010 Oct;17(10):1236-48.

5. Goldman JS, Hahn SE, Catania JW, LaRusse-Eckert S, Butson MB, Rumbaugh M, Strecker MN, Roberts JS, Burke W, Mayeux R, Bird T, American College of Medical Genetics and the National Society of Genetic Counselors. 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. 2011 Jun;13(6):597-605.

6. National Institute on Aging-Alzheimer's Association Working Group; Apolipoprotein E genotyping in Alzheimer's disease. National Institute on Aging/Alzheimer’s Association Working Group. Lancet. 1996;347:1091-5.

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