APOE Alzheimer's Risk

CPT: 81401
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Test Details

Use

This test is to detect the presence of the APOE4 variant, which is associated with increased risk of late-onset (age >60-65) Alzheimer's disease (AD). Testing may be considered for patients with dementia to supplement information from clinical and other evaluations. This test is not appropriate for children. APOE genotype results are E2/E2, E2/E3, E2/E4, E3/E3, E3,E4, or E4/E4. APOE genotyping supplies supplementary information for the clinical diagnosis of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia in the elderly and currently affects more that 5 million Americans. It is a progressive neurodegenerative disorder with brain findings of amyloid plaques containing β-amyloid and neurofibrillary tangles. AD is a complex and heterogeneous disease, influenced by many genetic and environmental factors.

An early-onset variety in 1% to 5% of AD cases is autosomal-dominant and caused by rare mutations in known genes, including PSEN1, PSEN2, and APP. The predominant form of AD is late-onset (age >60-65), which can be familial (15% to 20%) or sporadic. The APOE4 (E4) variant of apolipoprotein E is strongly associated with risk of late-onset AD.

Apolipoprotein E (apoE) has multiple roles, including lipid transport in the blood and the brain. The APOE4 variant increases the risk for late-onset Alzheimer's disease and may contribute to the pathology of the disease through influence on β-amyloid, inflammation, or other processes.

The risk for development of late-onset AD is increased approximately two- to threefold for individuals with one copy of the APOE4 variant and by approximately 10- to 15-fold for individuals with two copies of the variant (E4/E4 genotype). The APOE2 variant has some protective effect against development of late-onset AD. The lifetime risk for late-onset Alzheimer's disease is approximately 10% to 12% in the general population, though it is higher in women than men and doubles when there is a first-degree relative with this disorder. The lifetime risk is approximately 9% for individuals negative for APOE4, and for individuals with E4/E4 may be as high as 25% for males and 45% for females. Among patients with late-onset AD, the presence of APOE4 may lead to earlier development of symptoms.

However, APOE4 is neither necessary nor sufficient for the development of Alzheimer's disease. Approximately 30% to 50% of patients with late-onset Alzheimer's disease do not have an APOE4 allele.

APOE4 is common, with 25% of the general population having one copy and 1% having two copies of this variant. Among patients with late-onset AD, 50% to 70% are positive for APOE4.

The development of late-onset Alzheimer's disease is influenced by many factors other than APOE4, including age, gender, family history, level of education, and history of head trauma. Midlife cardiovascular risk factors in individuals with APOE4 also increase risk for cognitive decline. A number of genetic influences on Alzheimer's development in addition to APOE4 have also been reported and are under investigation. APOE4 is also associated with poor outcome to brain trauma, and it can influence therapeutic response to drugs for AD.

Limitations

This is not a diagnostic test. APOE4 increases risk of late-onset Alzheimer's disease, but many patients with APOE4 do not develop AD and—of patients with late-onset AD—30% to 50% are negative for APOE4.

This test was developed, and its performance characteristics determined, by LabCorp. It has not been cleared or approved by the US Food and Drug Administration (FDA).

Methodology

Polymerase chain reaction (PCR) with restriction enzyme digestion and polyacrylamide gel electrophoresis

Specimen Requirements

Specimen

Whole blood

Volume

5 mL whole blood or 4 buccal swabs

Minimum Volume

0.5 mL or two buccal swabs (Note: This volume does not allow for repeat testing.)

Container

Lavender-top (EDTA) tube (preferred), yellow-top (ACD) tube, or buccal swab kit provided by LabCorp.

Storage Instructions

Maintain specimen refrigerated or at room temperature. Stable at room temperature or refrigerated for seven days. Specimen is unstable frozen.

Causes for Rejection

Frozen whole blood samples; quantity not sufficient for analysis; improper container; one buccal swab

Clinical Information

References

Altmann A, Tian L, Henderson VW, Greicius MD; Alzheimer's Disease Neuroimaging Initiative Investigators. Sex modifies the APOE-related risk of developing Alzheimer disease. Ann Neurol. 2014 Apr; 75(4):563-573. 24623176
Bangen KJ, Beiser A, Delano-Wood L, et al. APOE genotype modifies the relationship between midlife vascular risk factors and later cognitive decline. J Stroke Cerebrovasc Dis. 2013 Nov; 22(8):1361-1369. 23601373
Bird TD. Alzheimer disease overview. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews. Seattle, Wash: University of Washington; 2014. 20301340
Goldman JS, Hahn SE, Catania JW, et al. 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. Erratum: 2011 Aug;13(8):749. 21577118
Schipper HM. Apolipoprotein E: Implications for AD neurobiology, epidemiology and risk assessment. Neurobiol Aging. 2011 May; 32(5):778-790. 19482376

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