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DESCRIPTIONAlzheimer's disease (AD) 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 4 genes have been associated with Alzheimer's disease (AD), while mutations in chromosomes 1, 14, and 21 have been associated with early onset familial AD.
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. The APOE gene has 3 alleles—epsilon 2, 3, and 4—with the epsilon 3 allele being the most common. Every person carries 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 allele. It should be noted that the epsilon 4 allele represents a risk factor for AD rather than a disease-causing mutation.
Susceptibility Testing at the Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Gene
Recent studies identified rs75932628-T, a rare functional substitution for R47H of 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.
Patients with early onset AD (i.e., before age 65 but as early as 30 years) are a small subset of patients. The families of these patients may show an autosomal dominant pattern of inheritance. Three genes have been identified by linkage analysis of affected families: amyloid-beta precursor protein gene (APP), presenilin 1 (PS1) gene, and presenilin 2 (PS2) gene. These genes have nearly 100% penetrance absent death from other causes; however, rare cases of lack of penetrance in elderly individuals have been reported. A variety of mutations within these genes have 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, overall, identifiable genetic mutations are rare causes of AD.
Genetic testing for the APOE 4 allele in patients with late-onset AD and testing for APP, PSEN1, or PSEN2 mutations in the rare patient with early-onset AD have been investigated as an aid in diagnosis in patients presenting with symptoms suggestive of AD, or a technique for risk assessment in asymptomatic patients with a family history of AD. Mutations in PSEN1 and PSEN2 are specific for AD; the only other disease in which APP mutations are found is cerebral hemorrhagic amyloidosis of the Dutch type, a disease in which dementia and brain amyloid plaques are uncommon.
Currently, the clinical diagnosis of AD is established by the presence of a consistent history, and excluding treatable causes of dementia In 1984, the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer’s and Related Disorders Association (ADRDA) developed clinical criteria for the diagnosis of AD. Three categories were defined: possible, probable, and definite AD. The diagnosis of definite AD requires a brain biopsy confirming the presence of characteristic neurofibrillary tangles. While definite AD is almost always diagnosed by autopsy, in approximately 85% of those with a diagnosis of probable AD, pathological findings are found to be consistent. The diagnostic categories are defined as follows:
Possible Alzheimer's Disease
Probable Alzheimer's Disease
The criteria for the clinical diagnosis of probable AD include:
The diagnosis of probable AD is supported by:
Other clinical features consistent with the diagnosis of probable AD, after exclusion of causes of dementia other than AD, include
Features that make the diagnosis of probable AD uncertain or unlikely include:
Definite Alzheimer's Disease
Other diagnostic tests for AD include cerebrospinal (CSF) fluid levels of Tau protein or beta-amyloid precursor protein. These CSF tests are considered separately in Biochemical Markers of Alzheimer's Disease medical policy.
POLICYGenetic testing for the diagnosis or risk assessment of Alzheimer's disease is considered investigational. Genetic testing includes, but is not limited to, testing for the apolipoprotein E epsilon 4 allele, presenilin genes, amyloid precursor gene, or TREM2.
Investigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.
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.
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.