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Alzheimer disease (AD) is the most common cause of dementia in elderly patients. For late-onset AD, there is a component of risk that runs in families, suggesting the contribution of genetic factors. Early-onset AD is much less common but can occur in nonelderly individuals. Early-onset AD has a stronger component of family risk, with clustering in families, thus suggesting an inherited genetic mutation.
Alzheimer disease (AD) is commonly associated with a family history; 40% of patients with AD have at least one other afflicted first-degree relative. Numerous genes have been associated with late-onset Alzheimer disease (AD), while mutations in chromosomes 1, 14, and 21 have been associated with early onset familial AD.
Susceptibility Polymorphism at the Apolipoprotein E Gene
The APOE lipoprotein is a carrier of cholesterol produced in the liver and brain glial cells. The APOE gene has 3 alleles—epsilon 2, 3, and 4—with the epsilon 3 allele being the most common. Individuals carry two APOE alleles. The presence of at least 1 epsilon 4 allele is associated with an increased risk of AD in the range of 1.2- to 3-fold, depending on the ethnic group. For those homozygous for epsilon 4 (about 2% of the population), the risk of AD is higher than for those heterozygous for epsilon 4. The mean age of onset of AD is about 68 years for epsilon 4 homozygotes, about 77 years for heterozygotes, and about 85 years for those with no epsilon 4 alleles. About half of patients with sporadic AD carry an epsilon 4 allele. However, not all patients with the allele develop AD. The epsilon 4 allele represents a risk factor for AD rather than a disease-causing mutation. In the absence of APOE testing, first-degree relatives of an individual with sporadic or familial AD are estimated to have a 2- to 4-fold greater risk of developing AD than the general population. There is evidence of possible interactions between epsilon 4 alleles, other risk factors for AD (eg, risk factors for cerebrovascular disease such as smoking, hypertension, hypercholesterolemia, diabetes), and a higher risk of developing AD. However, it is not clear that all risk factors have been taken into account in such studies, including the presence of polymorphisms in other genes that may increase the risk of AD.
Individuals with early-onset AD (i.e., before age 65 but as early as 30 years) are a small subset of AD patients. AD within families of these patients may show an autosomal dominant pattern of inheritance. Pathogenic mutations in three genes have been identified in affected families: amyloid-beta precursor protein gene (APP), presenilin 1 (PSEN1) gene, and presenilin 2 (PSEN2) gene. APP and PSEN1 mutations have 100% penetrance absent death from other causes, while PSEN2 has 95% penetrance. A variety of mutations within these genes has been associated with AD; mutations in PSEN1 appear to be the most common. While only 3%–5% of all patients with AD have early-onset disease, pathogenic mutations have been identified in up to 70% or more of these patients. Therefore, identifiable genetic mutations are rare causes of AD.
Testing for the APOE 4 allele in patients with late-onset AD and for APP, PSEN1, or PSEN2 mutations in the rare patient with early-onset AD have been investigated as an aid in diagnosis of patients presenting with symptoms suggestive of AD, or as a technique for risk assessment in asymptomatic patients with a family history of AD. Mutations in PSEN1 and PSEN2 are specific for AD; APP mutations are also found in cerebral hemorrhagic amyloidosis of the Dutch type, a disease in which dementia and brain amyloid plaques are uncommon.
Susceptibility Testing at the Triggering Receptor Expressed on Myeloid Cells 2 Gene
Recent studies identified rs75932628-T, a rare functional substitution for R47H of triggering receptor expressed on myeloid cells 2 (TREM2), as a heterozygous risk variant for late-onset AD. On chromosome 6p21.1, at position 47 (R47H), the T allele of rs75932628 encodes a histidine substitute for arginine in the gene that encodes TREM2.
TREM2 is highly expressed in the brain and is known to have a role in regulating inflammation and phagocytosis. TREM2 may serve a protective role in the brain by suppressing inflammation and clearing it of cell debris, amyloids and toxic products. A decrease in the function of TREM2 would allow inflammation in the brain to increase and may be a factor in the development of AD. The effect size of the TREM2 variant confers a risk of AD that is similar to the APOE epsilon 4 allele, although it occurs less frequently.
Diagnosis of AD
The diagnosis of AD is divided into three categories: possible, probable, and definite AD. A diagnosis of definite AD requires postmortem confirmation of AD pathology, documenting the presence of extracellular beta amyloid plaques and intraneuronal neurofibrillary tangles in the cerebral cortex. As a result, a diagnosis of definite AD cannot be made during life, and the diagnosis of probable or possible AD is made on clinical grounds. Probable AD dementia is diagnosed clinically when the patient meets core clinical criteria for dementia and has a typical clinical course for AD. Criteria for diagnosis of probable AD have been developed by the National Institute on Aging and the Alzheimer’s Association. These criteria require evidence of a specific pattern of cognitive impairment, a typical clinical course, and exclusion of other potential etiologies, as follows:
A diagnosis of possible AD dementia is made when the patient meets most of the AD criteria, but has an atypical course or an etiologically mixed presentation. This may consist of an atypical onset (eg, sudden onset) or atypical progression. A diagnosis of possible AD is also made when there is another potentially causative systemic or neurologic disorder that is not thought to be the primary etiology of dementia.
Mild cognitive impairment (MCI) is a precursor of AD in many instances. MCI may be diagnosed when there is a change in cognition, but not sufficient impairment for the diagnosis of dementia. Features of MCI are evidence of impairment in one or more cognitive domains and preservation of independence in functional abilities. In some patients, MCI may be a predementia phase of AD. Patients with MCI may undergo ancillary testing (eg, neuroimaging, laboratory studies, neuropsychological assessment) to rule out vascular, traumatic, and medical causes of cognitive decline and to evaluate genetic factors.
Biomarker evidence has been integrated into the diagnostic criteria for probable and possible AD for use in research settings. Other diagnostic tests for AD include CSF levels of tau protein or beta amyloid precursor protein, as well as PET amyloid imaging. The CSF tests are considered separately in Biochemical Markers of Alzheimer's Disease medical policy. PET amyloid imaging is considered in Beta Amyloid Imaging with Positron Emission Tomography (PET) for Alzheimer’s Disease medical policy.
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.
POLICYGenetic testing for the risk assessment of Alzheimer disease in asymptomatic individuals is considered investigational. Genetic testing includes, but is not limited to, testing for the apolipoprotein E epsilon 4 allele, presenilin genes, amyloid-beta precursor protein, or TREM2.
Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY11/2003: Approved by Medical Policy Advisory Committee (MPAC)
2/16/2004: Code Reference section completed
3/8/2006: Policy reviewed, no changes
3/27/2006: Coding updated. CPT4 2006 revisions added to policy.
12/28/2006: Code Reference section updated per the 2007 CPT/HCPCS revisions
12/19/2007: Coding updated per the 2008 CPT/HCPCS revisions
1/10/2008: Policy reviewed, no changes
12/29/2008: Code reference section updated per the 2009 CPT/HCPCS revisions
1/5/2009: Policy reviewed. No changes.
04/22/2010: Policy description updated regarding new findings in diagnosing Alzheimer’s disease. Policy statement unchanged. Deleted outdated reference from the Sources section.
11/28/2012: Policy reviewed; no changes.
01/14/2013: Added the following new 2013 CPT code to the Code Reference section: 81479.
12/13/2013: Policy description updated regarding the Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Gene. Policy statement revised to state that testing for TREM2 is considered investigational.
10/27/2014: Policy reviewed; description updated regarding susceptibility polymorphism at the APOE gene and diagnosis of AD. Policy statement unchanged. Removed deleted CPT codes 83891, 83892, 83894, 83898, 83900, 83902, 83904, 83907, 83908, 83909, 83912, and 83914 from the Code Reference section.
07/30/2015: Code Reference section updated for ICD-10.
02/24/2016: Policy title changed from "Genetic Testing for Familial Alzheimer's Disease" to "Genetic Testing for Alzheimer Disease." Policy description updated regarding late- and early-onset of AD. Policy statement revised to replace "diagnosis" with "in asymptomatic individuals." It previously stated: Genetic testing for the diagnosis or risk assessment of Alzheimer's disease is considered investigational. Policy statement also revised to change "amyloid precursor gene" to "amyloid-beta precursor protein." Policy guidelines updated regarding genetic counseling. Investigative definition updated. Removed deleted HCPCS code S3855 from the Code Reference section.
06/06/2016: Policy number added.
SOURCE(S)Blue Cross Blue Shield Association policy # 2.04.13
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.