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Biochemical changes associated with the pathophysiology of Alzheimer disease (AD) are being evaluated to aid in the diagnosis of AD. Some of the most commonly studied biomarkers are amyloid-β peptide-1-42 (AB-42) and total or phosphorylated tau protein (T-tau or P-tau) in cerebrospinal fluid (CSF).
The diagnosis of Alzheimer disease (AD) is divided into three categories: possible, probable, and definite AD. A diagnosis of definite AD requires postmortem confirmation of AD pathology, including the presence of extracellular beta amyloid plaques and intraneuronal neurofibrillary tangles in the cerebral cortex. Probable AD dementia is diagnosed clinically when the patient meets core clinical criteria for dementia and has a typical clinical course for AD. A typical clinical course is defined as an insidious onset, with the initial and most prominent cognitive deficits being either amnestic or nonamnestic (eg, language, visuospatial, or executive function deficits), and a progressively worsening cognition over time. A diagnosis of possible AD dementia is made when the patient meets core clinical criteria for AD dementia but has an atypical course or an etiologically mixed presentation.
Mild cognitive impairment (MCI) may be diagnosed when there is a change in cognition but insufficient impairment for the diagnosis of dementia. MCI is characterized by impairment in one or more cognitive domains but preserved functional independence. In some patients, MCI may be a predementia phase of AD. Patients with MCI or suspected AD may undergo ancillary testing (eg, neuroimaging, laboratory tests, neuropsychological assessment) to rule out vascular, traumatic, and medical causes of cognitive decline and to evaluate genetic factors. Because clinical diagnosis can be difficult, particularly early in the course of disease, there has been considerable interest in developing an accurate laboratory test for AD. Several potential biomarkers of AD are associated with AD pathophysiology (ie, β-amyloid plaques and neurofibrillary tangles).
Elevated cerebrospinal fluid (CSF) levels of specific proteins have been found in patients with AD. These include tau protein, phosphorylated at AD-specific epitopes such as threonine 181 (P-tau) or total tau protein (T-tau), or an amyloid-β peptide such as AB-42. Other potential CSF and serum peptide markers also have been explored. Tau protein is a microtubule-associated molecule found in neurofibrillary tangles that are typical of AD. Tau protein is thought to be related to degenerating and dying neurons, and high levels of tau protein in the CSF have been associated with AD. AB-42 is a subtype of amyloid-β peptide that is produced from metabolism of amyloid precursor protein. AB-42 is the key peptide deposited in amyloid plaques characteristic of AD. Low levels of AB-42 in the CSF have been associated with AD, perhaps because AB-42 is deposited in amyloid plaques instead of remaining in fluid. Investigators have suggested that the tau/AB-42 ratio may be a more accurate diagnostic marker than either alone. A variety of kits are commercially available to measure AB-42 and tau proteins. Between laboratory variability in CSF biomarker measurement is large.
Neural thread protein is associated with neurofibrillary tangles of AD. Both CSF and urine levels of this protein have been investigated as a potential marker of AD. Urine and CSF tests for neural thread protein may be referred to as the AD7C test.
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). AlzheimAlert™ and AdMark® CSF analysis are available under the auspices of 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 these tests.
Genetic testing for Alzheimer's disease has also been investigated and is considered separately in the Genetic Testing for Familial Alzheimer's Disease medical policy.
POLICYMeasurement of cerebrospinal fluid biomarkers of Alzheimer's disease, including but not limited to tau protein, amyloid beta peptides, or neural thread proteins, is considered investigational.
Measurement of urinary biomarkers of Alzheimer's disease is considered investigational, including but not limited to neural thread proteins.
POLICY GUIDELINESInvestigative 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 HISTORY7/2003: Approved by Medical Policy Advisory Committee (MPAC)
9/2/2003: Code Reference section completed
12/17/2008: Policy reviewed, no changes
05/13/2010: Policy description updated with new research findings; policy statement unchanged. Added CPT codes 83520 and 83912, which are used to identify the steps in testing for tau protein and amyloid beta peptides. There are no specific codes used for testing for neural thread protein.
07/29/2011: Policy reviewed; no changes.
11/28/2012: Policy reviewed; no changes.
05/06/2013: Removed ICD-9 diagnosis code 331.0 from the Code Reference section.
11/15/2013: Policy reviewed; no changes.
07/08/2015: Policy reviewed; policy statements unchanged. Code Reference section updated for ICD-10. Removed deleted CPT code 83912.
11/02/2015: Policy description revised. Policy statements unchanged. Investigative definition updated in policy guidelines section.
SOURCE(S)Blue Cross Blue Shield Association policy # 2.04.14
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.