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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.

Genetic Mutations

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

1. May be made on the basis of the dementia syndrome in the absence of other neurological, psychiatric, or systemic disorders sufficient to cause dementia, and in the presence of variations in the onset, in the presentation, or in the clinical course
2. May be made in the presence of a second systemic or brain disorder sufficient to produce dementia, which is not considered to be the cause of the dementia
3. Should be used in research studies when a single gradually progressive severe cognitive deficit is identified in the absence of other identifiable cause.

Probable Alzheimer's Disease

The criteria for the clinical diagnosis of probable AD include:

1. Dementia, established by clinical examination and documented by the Mini-Mental State Examination, the Blessed Dementia Scale, or some similar examination and confirmed by neuropsychological tests
2. Deficits in 2 or more areas of cognition
3. Progressive worsening of memory and other cognitive functions
4. No disturbance of consciousness
5. Onset between ages 40 and 90, most often after the age of 65
6. Absence of systemic disorders or other brain diseases that in and of themselves could account for the progressive deficits in memory and cognition.

The diagnosis of probable AD is supported by:

1. Progressive deterioration of specific cognitive functions such as language (aphasia), motor skills (apraxia), and perception (agnosia) Impaired activities of daily living and altered patterns of behavior
   Family history of similar disorders, particularly if confirmed neuropathologically
   Laboratory results: normal lumbar puncture as evaluated by standard techniques, normal pattern or nonspecific changes in the EEG, and evidence of cerebral atrophy on CT scanning with progression documented by serial observation.

Other clinical features consistent with the diagnosis of probable AD, after exclusion of causes of dementia other than AD, include

1. Plateaus in the course of progression of the illness;
2. Associated symptoms of depression, insomnia, incontinence, delusions, illusions, hallucinations, sexual disorders, weight loss, and catastrophic verbal, emotional, or physical outbursts;
3. Other neurologic abnormalities in some patients, especially with more advanced disease and including motor signs such as increased muscle tone, myoclonus, or gait disorder;
4. Seizures in advanced disease CT normal for age

Features that make the diagnosis of probable AD uncertain or unlikely include:

1. Sudden apoplectic onset
   Focal neurological findings such as hemiparesis, sensory loss, visual field deficits, and incoordination early in the course of the illness
   Seizures or gait disturbances at the onset or very early in the course of the illness

Definite Alzheimer's Disease

1. Clinical criteria for probable Alzheimer's disease AND
2. Histopathologic evidence obtained from a biopsy or autopsy

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.

None

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.

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.

All codes billed for this procedure are considered investigational and not eligible for coverage.

Non-Covered Codes

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