MEDICAL POLICY
POLICY TITLE
DIAGNOSTIC TESTING AND RISK ASSESSMENT FOR ALZHEIMER'S
DISEASE (BIOCHEMICAL AND GENETIC)
POLICY NUMBER
MP- 2.050
Original Issue Date (Created):
7/1/2002
Most Recent Review Date (Revised): 5/31/2016
Effective Date:
POLICY
RATIONALE
DISCLAIMER
POLICY HISTORY
11/15/2016
PRODUCT VARIATIONS
DEFINITIONS
CODING INFORMATION
DESCRIPTION/BACKGROUND
BENEFIT VARIATIONS
REFERENCES
I. POLICY
Biochemical Markers for Diagnosis of Alzheimer’s Disease
Measurement 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.
Genetic Testing for Diagnosis of Alzheimer’s Disease
Genetic 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.
There is insufficient evidence to support a conclusion concerning the health outcomes or
benefits associated with the above procedures.
Policy Guidelines
Genetic testing for Alzheimer’s disease may be offered along with cerebral spinal fluid
(CSF) levels of the Tau protein and AB-42 peptide. This group of tests may be collectively
referred to as the ADmark™ Profile, offered by Athena Diagnostics (Worcester, Mass.).
Cross-references: None
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DIAGNOSTIC TESTING AND RISK ASSESSMENT FOR ALZHEIMER'S
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POLICY NUMBER
MP- 2.050
II. PRODUCT VARIATIONS
TOP
This policy is applicable to all programs and products administered by Capital BlueCross unless
otherwise indicated below.
FEP PPO*
* Refer to FEP Medical Policy Manual MP-2.04.13 Genetic Testing for Familial Alzheimer’s
Disease and MP- 2.01.14 Biochemical Markers for Alzheimer’s Disease. FEP Medical Policy
Manual can be found at: www.fepblue.org
III. DESCRIPTION/BACKGROUND
TOP
Genetic Testing for Alzheimer Disease
Alzheimer disease (AD) is commonly associated with a family history; 40% of patients with AD
have a least 1 other afflicted first-degree relative. Numerous genes have been associated with
late-onset AD, while mutations in chromosomes 1, 14, and 21 have been associated with early
onset familial AD.1
Susceptibility Polymorphism at the Apolipoprotein E Gene
The apolipoprotein E (APOE) lipoprotein is a carrier of cholesterol produced in the liver and
brain glial cells. The APOE gene has 3 alleles—ε2, 3, and 4—with the epsilon 3 allele being the
most common. Individuals carry 2 APOE alleles. The presence of at least 1 ε4 allele is associated
with a 1.2- to 3-fold increased risk of AD, depending on the ethnic group. Among those
homozygous for epsilon 4 (2% of the population), the risk of AD is higher than for those
heterozygous for ε4. Mean age of onset of AD is at about age 68 years for ε4 homozygotes,
about 77 years for heterozygotes, and about 85 years for those with no ε4 alleles. About half of
patients with sporadic AD carry an ε4 allele. However, not all patients with the allele develop
AD. The ε4 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.2
There is evidence of possible interactions between ε4 alleles, other risk factors for AD (eg, risk
factors for cerebrovascular disease such as smoking, hypertension, hypercholesterolemia,
diabetes3), 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.
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MEDICAL POLICY
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DIAGNOSTIC TESTING AND RISK ASSESSMENT FOR ALZHEIMER'S
DISEASE (BIOCHEMICAL AND GENETIC)
POLICY NUMBER
MP- 2.050
Genetic Mutations
Individuals with early-onset familial AD (ie, before age 65 years but as early as 30 years) form a
small subset of AD patients. AD within families of these patients may show an autosomal
dominant pattern of inheritance. Pathogenic mutations in 3 genes have been identified in affected
families: amyloid-beta precursor protein (APP) gene, 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% to 5%
of all patients with AD have early-onset disease, pathogenic mutations have been identified in up
to 70% or more of these patients. Identifiable genetic mutations are, therefore, rare causes of AD.
Testing for the APOE 4 allele among 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.4,5 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 ε4
allele, although it occurs less frequently.
Diagnosis of AD
The diagnosis of AD is divided into 3 categories: possible, probable, and definite AD.6 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.7 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.6 These criteria require evidence of
a specific pattern of cognitive impairment, a typical clinical course, and exclusion of other
potential etiologies, as follows:

Cognitive impairment
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POLICY NUMBER
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

o Cognitive impairment established by history from patient and a knowledgeable
informant, plus objective assessment by bedside mental status examination or
neuropsychological testing
o Cognitive impairment involving a minimum of 2 of the following domains:
 Impaired ability to acquire and remember new information
 Impaired reasoning and handling of complex tasks, poor judgment
 Impaired visuospatial abilities
 Impaired language functions
 Changes in personality, behavior, or comportment
o Initial and most prominent cognitive deficits are one of the following:
 Amnestic presentation
 Nonamnestic presentations, either a language presentation with prominent
word-finding deficits; a visuospatial presentation with visual cognitive
defects; or a dysexecutive presentation with prominent impairment of
reasoning, judgment, and/or problem solving.
Clinical course
o Insidious onset
o Clear-cut history of worsening over time
o Interference with ability to function at work or usual activities
o Decline from previous level of functioning and performing
Exclusion of other disorders
o Cognitive decline not explained by delirium or major psychiatric disorder
o No evidence of other active neurologic disease, including substantial
cerebrovascular disease or dementia with Lewy bodies.
o Lack of prominent features of variant frontotemporal dementia or primary
progressive aphasia.
o No medication use with substantial effects on cognition.
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.6 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.8 Features of MCI are evidence of impairment in 1 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.
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DIAGNOSTIC TESTING AND RISK ASSESSMENT FOR ALZHEIMER'S
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POLICY NUMBER
MP- 2.050
Biomarker evidence has been integrated into the diagnostic criteria for probable and possible
AD for use in research settings.6 Other diagnostic tests for AD include CSF levels of tau protein
or beta amyloid precursor protein, as well as positron emission tomography amyloid imaging.
The CSF tests are considered separately in evidence review 2.04.14. PET amyloid imaging is
considered in evidence review 6.01.55 (Beta Amyloid Imaging With Positron Emission
Tomography for Alzheimer Disease).
REGULATORY STATUS
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.
Biochemical Markers for Diagnosis of Alzheimer’s Disease
The diagnosis of AD is divided into 3 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.1 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.
MCI may be diagnosed when there is a change in cognition but insufficient impairment for the
diagnosis of dementia.2 MCI is characterized by impairment in 1 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, - -amyloid plaques and neurofibrillary tangles).
Elevated 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- _ peptide such as AB -42. Other potential CSF3,4 and serum5 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
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POLICY NUMBER
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and dying neurons, and high levels of tau protein in the CSF have been associated with AD. AB42 is a subtype of amyloid- I 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.6 A variety of kits are
commercially available to measure AB-42 and tau proteins. Between-laboratory variability in
CSF biomarker measurement is large.7,8
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.
Regulatory Status
No biochemical marker tests for AD are currently approved by the U.S. Food and Drug
Administration (FDA). Commercially available tests include:
 AlzheimAlert™ (Nymox Pharmaceutical Corp., Hasbrouck Heights, NJ)
 Innotest® assays for T-tau, P-tau, and AB-42 (Fujirebio [previously Innogenetics],
Malvern, PA)
 AdMark® CSF analysis
These are laboratory-developed tests (LDTs). Clinical laboratories may develop and validate
tests in-house and market them as a laboratory service; 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, FDA has chosen not to require any
regulatory review of these tests.
Nymox Pharmaceutical Corp. previously offered AD7C testing as an LDT but no longer lists
the test on its website.
IV. RATIONALE
TOP
Genetic Testing for Alzheimer’s Disease
The most recent update was performed through September 4, 2015. This review addresses
BCBSA genetic testing category 3 on testing an asymptomatic individual to determine future risk
of disease (see Appendix Table 1 for BCBSA genetic testing categories).
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POLICY NUMBER
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Genetic Testing for Late-Onset Alzheimer Disease
Analytic Validity
There is a lack of published evidence on the analytic validity of genetic testing for late-onset
familial Alzheimer disease (AD). Analytic validity is expected to be high when current methods
of sequencing are performed, ie, Sanger sequencing and/or next-generation sequencing.
Clinical Validity
Subsequent to the TEC Assessment, advances in genetic understanding of AD have been
considerable,10 with associations between late-onset AD and more than 20 non-APOE genes
suggested.
In 2014, Naj et al published a genome-wide association study of multiple genetic loci in lateonset AD.11 Genetic data from 9162 white race participants with AD from the Alzheimer Disease
Genetics Consortium were assessed for polymorphisms at 10 loci significantly associated with
risk of late-onset AD. Analysis confirmed the association of APOE with an earlier age of onset
and found significant associations for CR1, BIN1, and PICALM. APOE contributed 3.7% of the
variation in age of onset and the other 9 loci combined contributed 2.2% of the variation. Each
additional copy of the APOE ε4 allele reduced age of onset by 2.45 years.
Susceptibility Testing at the Apolipoprotein E Gene
The association of the APOE ε4 allele with AD is significant; however, APOE genotyping does
not have high specificity or sensitivity, and is of little value in the predictive testing of
asymptomatic individuals.12
The American College of Medical Genetics and Genomics has concluded that APOE genotyping
for AD risk prediction has limited clinical utility and poor predictive value.13
The association of APOE genotype with response to AD therapy has been examined. The USA-1
Study group found APOE genotype did not predict therapeutic response.14 Rigaud et al followed
117 individuals with AD over 36 weeks in an open-label trial of donepezil; 80 (68%) completed
the trial.15 They found no statistically significant effect of APOE genotype on change in
cognition (assessed by Cognitive subscale of the Alzheimer's Disease Assessment Scale).
However, the study was not designed to examine predictive therapeutic response, and there were
baseline cognitive differences according to APOE genotype. There is currently insufficient
information to make treatment decisions based on APOE subtype.
Susceptibility Testing at the Triggering Receptor Expressed on Myeloid Cells 2 Gene
Jonsson et al evaluated 3550 subjects with AD and found a genome-wide association with only 1
marker, the T allele of rs75932628 (excluding the APOE locus and the A673T variant in
APP11).4 The frequency of rs75932628 (triggering receptor expressed on myeloid cells 2
[TREM2]) was then tested in a general population of 110,050 Icelanders of all ages and was
found to confer a risk of AD of 0.63% (odds ratio [OR], 2.26; 95% confidence interval [CI], 1.71
to 2.98; p=1.1310−8). In the control population of 8888 patients 85 years of age or older without
a diagnosis of AD, TREM2 frequency was 0.46% (OR=2.92; 95% CI, 2.09 to 4.09;
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p=3.4210−10). In 1236 cognitively intact controls age 85 or older, the frequency of TREM2
decreased even further to 0.31% (OR=4.66; 95% CI, 2.38 to 9.14; p=7.3910−6). The decrease in
TREM2 frequency in elderly patients who are cognitively intact supports the findings associating
TREM2 with increasing risk of AD.
Guerriero et al also found a strong association of the R47H TREM2 variant with AD (p=0.001).5
Using 3 imputed data sets of genome-wide association AD studies, a meta-analysis found a
significant association with the variant and disease (p=0.002). The authors further reported direct
genotyping of R47H in 1994 AD patients and 4062 controls, and found a highly significant
association with AD (OR=5.05; 95% CI, 2.77 to 9.16; p=9.010−9).
Clinical Utility
The REVEAL study was designed to examine consequences of AD risk assessment by APOE
genotyping.16 Of 289 eligible participants, 162 were randomized (mean age, 52.8 years; 73%
female; average education, 16.7 years) to either risk assessment based on APOE testing and
family history (n=111) or family history alone (n=51). During a 1-year follow-up, those
undergoing APOE testing with a high-risk genotype were more likely than low-risk or untested
individuals to take more vitamins (40% vs 24% and 30%, respectively), change diet (20% vs
11% and 7%, respectively), or change exercise behaviors (8% vs 4% and 5%, respectively).
While in this well-educated sample of women there were some behavior changes, none can be
considered a meaningful surrogate end point.
No studies were identified that addressed how the use of the TREM2 rs75932628-T variant might
be incorporated into clinical practice.
There is a lack of interventions that can delay or mitigate late-onset AD. There is no evidence
that early intervention for asymptomatic mutation carriers can delay or mitigate future disease.
There are many actions patients may take following knowledge of a mutation. Changes in
lifestyle factors (eg, diet, exercise) and/or incorporation of “brain training” exercises can be
made, but there is no evidence that these interventions impact clinical disease.
Reproductive planning may be affected as well, but it is unclear whether outcomes would be
improved. Testing for a disease that will not manifest for many decades includes uncertainty
about whether treatments for AD will be available at that future time point. This leads to
uncertainties about whether reproductive interventions now will reduce the future incidence or
severity of disease.
Section Summary: Genetic Testing for Late-Onset AD
Both the APOE gene and the triggering receptor gene have shown strong statistical associations
with AD, thus demonstrating some degree of clinical validity. However, the clinical sensitivity
and specificity of APOE ε4 is poor, and there is a lack of evidence on the clinical sensitivity and
specificity of the triggering receptor gene.
No studies were identified that address how the use of the APOE or TREM2 variant might be
incorporated into clinical practice. It is not clear how management of asymptomatic patients with
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these genes would change in a way that improves outcomes. Therefore, clinical utility has not
been demonstrated for these tests.
Genetic Testing for Early-Onset Familial AD
Analytic Validity
There is a lack of published evidence on the analytic validity of genetic testing for early-onset
familial AD. Analytic validity is expected to be high when current methods of sequencing are
performed, ie Sanger sequencing and/or next-generation sequencing.
Clinical Validity
Genetic testing for presenilin 1 (PSEN1) detects 30% to 60% of familial early-onset AD. A
number of mutations scattered throughout the PSEN1 gene have been reported, requiring
sequencing of the entire gene when the first affected member of a family with an autosomal
dominant pattern of AD inheritance is tested. Mutations in amyloid-beta precursor protein (APP)
and presenilin 2 (PSEN2) genes account for only a small fraction of cases; it is likely that other
causative genes will be discovered.
The nearly complete penetrance of a PSEN1 disease‒associated mutation would change the
probability of developing familial AD in an unaffected family member from 50% to either 0% or
100%. However, there is evidence that clinical expressivity is variable, ie, the presence of
PSEN1 mutations is not useful in predicting age of onset (although it is usually similar to age of
onset in affected family members), severity, type of symptoms, or rate of progression in
asymptomatic individuals.
It is not uncommon to discover previously unreported PSEN1 mutations in an individual, and
without additional family information, they may reflect mutations not associated with disease, or
new causative mutations restricted to a single family (private mutation). Thus, interpretation of
test results of asymptomatic individuals without identification of a mutation in affected family
members may be inconclusive in a significant proportion of patients.
Clinical Utility
The potential clinical utility of testing is in early identification of asymptomatic patients who are
at risk for developing early-onset AD. Genetic testing will in most cases lead to better risk
stratification, distinguishing patients who will develop the disease from those who will not. If
early identification of patients at risk leads to interventions to delay or mitigate clinical disease,
then clinical utility will be established. Identification of asymptomatic, young adult carriers
could impact reproductive planning. And clinical utility may be demonstrated if testing leads to
informed reproductive planning that improves outcomes. Alternatively, clinical utility could be
demonstrated if knowledge of mutation status leads to beneficial changes in psychological
outcomes.
A systematic review on the psychological and behavioral impact of genetic testing for AD found
few studies on the impact of testing for early-onset familial AD. The existing studies generally
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have small sample sizes and retrospective designs, and the research was conducted in different
countries, which may limit the generalizability of the findings.17
There is no evidence that early intervention for asymptomatic mutation carriers can delay or
mitigate future disease. There are many actions patients may take following knowledge of a
mutation: changes in lifestyle factors (eg, diet, exercise) and incorporation of “brain training”
exercises; but there is no evidence that these interventions impact clinical disease.
Reproductive planning may be affected as well, but it is unclear whether outcomes would be
improved. Testing for a disease that will not manifest for more than several decades includes
uncertainty about whether treatments for AD will be available. This leads to uncertainties about
whether reproductive interventions now will reduce the future incidence or severity of disease.
Mihaescu et al18 cite the framework proposed by Khoury et al19 for the continuum of
translational research that is required to move genomics research findings in AD into clinical and
public health applications that benefit population health. The 4 phases of translation research
include: (1) translation of basic genomics research into a potential health care application; (2)
evaluation of the application for the development of evidence-based guidelines; (3) evaluation of
the implementation and use of the application in health care practice; and (4) evaluation of the
achieved population health impact. The authors concluded that genetic testing for AD is still in
the first phase.
Section Summary: Genetic Testing for Early-Onset AD
A substantial percentage of patients with early-onset AD will have a pathogenic mutation;
however, up to 40% will test negative. Therefore, the clinical sensitivity is suboptimal. The
mutations are also found in some individuals who do not have a family history of familial AD,
but the false-positive rate and clinical specificity is not well-defined.
For those from families with early-onset, familial AD, there are currently no known preventive
measures or treatments that can mitigate the effect of the disease. It is not clear how management
of asymptomatic patients with these genes would change in a way that improves outcomes.
Therefore, clinical utility has not been demonstrated for these tests.
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 1
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Table 1. Summary of Key Trials
NCTNo.
Trial Name
Planned
Enrollment
Completion
Date
3000
700
June 2016
Dec 2016
210
Dec 2019
500,000
Dec 2030
Ongoing
NCT 00064870
NCT02198586
National Cell Reposttory for Alzheimers Disease (NCRAD)
Impact Study on Brain Structure and Function. in a Population
45 to 75 Years Old
NCT 01 760005
A Phase urnI Randomized, Double-Blind, Placebo-Controlled MultiCenter Study of 2 Potential Disease Modifying Therapies in
Individuals at Risk for and With Dominantly Inherited Alzheimer
s
Disease
NCT 02564692
Alzheimer's Prevention Registry *HQH0DWFKP rogram
NCT: national clinical trial.
Apoe
Summary of Evidence
The evidence for genetic testing in individuals who are asymptomatic and at risk for developing
Alzheimer disease (AD) includes studies on gene associations, test accuracy, and effects on
health outcomes. Relevant outcomes are test accuracy, test validity, change in disease status, and
health status measures. Many genes, including apolipoprotein E (APOE), CR1, BIN1, PICALM,
and TREM2, are associated with late-onset AD. However, the sensitivity and specificity of
genetic testing for indicating which individuals will progress to AD is low, and numerous other
factors can affect progression. Overall, genetic testing has not been shown to add value to the
diagnosis of AD made clinically. For individuals with early-onset AD, mutations in the
presenilin 1 (PSEN1) and amyloid-beta precursor protein (APP) genes are found in a substantial
number of patients. However, there is no direct or indirect evidence to establish that clinical
outcomes are improved as a result of genetic testing for these mutations. The current lack of
effective methods to prevent the onset of AD or to target AD treatments based on genetic
characteristics limits the clinical benefit for genetic testing. The evidence is insufficient to
determine the effects of the technology on health outcomes.
Practice Guidelines and Position Statements
American College of Medical Genetics and Genomics
The American College of Medical Genetics and Genomics lists genetic testing for APOE alleles
as one of 5 recommendations in the Choosing Wisely initiative.13 The recommendation is “Don’t
order APOE genetic testing as a predictive test for Alzheimer disease.” The stated rationale is
that APOE is a susceptibility gene for later-onset AD, the most common cause of dementia.
These recommendations stated that “The presence of an ε4 allele is neither necessary nor
sufficient to cause AD. The relative risk conferred by the ε4 allele is confounded by the presence
of other risk alleles, gender, environment and possibly ethnicity, and the APOE genotyping for
AD risk prediction has limited clinical utility and poor predictive value.”
American Academy of Neurology
The American Academy of Neurology made the following recommendations20:
Routine use of APOE genotyping in patients with suspected AD is not recommended at this
time (Guideline).
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There are no other genetic markers recommended for routine use in the diagnosis of AD
(Guideline).
This guideline is currently being updated as of October 6, 2015.
European Federation of Neurological Sciences
The European Federation of Neurological Sciences made the following recommendations21:
Recommendations: genetic testing (level of evidence not reported)
Screening for known pathogenic mutations can be undertaken in patients with appropriate
phenotype or a family history of an autosomal dominant dementia. Testing of patients
with familial dementia and of unaffected at-risk-relatives should be accompanied by
neurogenetic counseling and undertaken only after full consent and by specialist centers.
Presymptomatic testing may be performed in at-risk members of family-carrying
mutation. It is recommended that the Huntington’s disease protocol is followed for presymptomatic testing.
Routine Apo E genotyping is not recommended.
Fourth Canadian Consensus Conference on Diagnosis and Treatment of Dementia
The 2012 Canadian Consensus Conference on Diagnosis and Treatment of Dementia (CCCDTD)
was held in May 2012 to update the third consensus guidelines referenced next. Previous
recommendations were endorsed if there were no changes in the literature. Full articles written
by CCCDTD workgroups providing complete background information for the consensus
conference are available online (http://www.healthplexus.net/article/2012-canadian-consensusconference-dementia).
A summary of consensus recommendations from the CCCDTD4 was published by Gauthier et al
in 2012.22 It is noted in the summary that: “Despite a large number of important advances, the
CCCDTD4 concluded that fundamental changes in dementia diagnosis and management have
not yet arrived.” The 2012 CCCDTD4 summary recommends:
“Testing and longitudinal follow-up of asymptomatic individuals or patients with subjective
cognitive impairments not meeting MCI [mild cognitive impairment] criteria, or at-risk
individuals (e.g., gene mutation carriers, family history of AD, APOE epsilon 4) should be
restricted to research.”
Third Canadian Consensus Conference on Diagnosis and Treatment of Dementia
The CCCDTD23 recommended the following predictive genetic testing for asymptomatic “atrisk” individuals with an apparent autosomal dominant inheritance and a family-specific
mutation has been identified:
1. With appropriate pre- and post-testing counseling, predictive genetic testing (PGT) can
be offered to “at-risk” individuals (Grade B, Level 2**). Examples:
a) First-degree relatives of an affected individual with the mutation (e.g., children and
siblings);
b) First cousins of an affected individual if the common ancestors (parents who were
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siblings) died before the average age of onset of dementia in the family;
c) Nieces and nephews of affected individuals whose parent (sibling of the affected
individual) died well before the average age of onset of dementia in the family;
d) PGT in minors is not generally offered in Canada, but occasionally may be
considered on a case-by-case basis by the relevant medical ethics committee(s);
e) Individuals who are not “at risk” for the inherited disease do not require testing.
2. In young persons (60 years or younger) presenting with an early onset dementia, it is
sometimes worthwhile to test for the most common mutations based on the “best estimate”
diagnosis (e.g., in early onset AD, one might test for the most common mutations in PS1,
APP). (Grade B, Level 2**) If a mutation is identified, it would have direct implications
for offspring of the individual (if a de novo mutation is assumed). Conversely, it would
also be important to test other family members such as parents and siblings for possible
non-penetrance of a mutation.
Genetic screening with APOE genotype in asymptomatic individuals in the general
population is not recommended because of the low specificity and sensitivity. (Grade E,
Level 2**)
Genetic testing with APOE genotype is not recommended for the purpose of diagnosing
AD because the positive and negative predictive values are low. (Grade E, Level 2**)
** CCCDTD Evidence Ratings
Grade (B) There is fair evidence to support this maneuver.
Grade (E) There is good evidence to recommend against this procedure.
Level 2: (1) Evidence obtained from well-designed controlled trial without randomization,
or (2) Evidence obtained from well-designed cohort or case control analytic studies,
preferably from more than one center, or (3) Evidence obtained from comparisons between
times or places with or without intervention. Dramatic results in uncontrolled experiments
are included in this category.
American College of Genetics and National Society of Genetic Counselors
The American College of Genetics and the National Society of Genetic Counselors issued the
following joint practice guidelines2:
Pediatric testing for AD should not occur. Prenatal testing for AD is not advised if the patient
intends to continue a pregnancy with a mutation.
Genetic testing for AD should only occur in the context of genetic counseling (in person or
through videoconference) and support by someone with expertise in this area.
Symptomatic patients: Genetic counseling for symptomatic patients should be performed
in the presence of the individual’s legal guardian or family member.
Asymptomatic patients: A protocol based on the International Huntington Association
and World Federation of Neurology Research Group on Huntington’s Chorea
Guidelines is recommended.
DTC [direct-to-consumer] APOE testing is not advised.
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A ≥3-generation family history should be obtained, with specific attention to the age of onset
of any neurologic and/or psychiatric symptoms, type of dementia and method of
diagnosis, current ages, or ages at death (especially unaffected relatives), and causes of
death. Medical records should be used to confirm AD diagnosis when feasible. The
history of additional relatives may prove useful, especially in small families or those with
a preponderance of early death that may mask a history of dementia.
A risk assessment should be performed by pedigree analysis to determine whether the family
history is consistent with EOAD [early-onset AD] or LOAD [late-onset AD] and with
autosomal dominant (with or without complete penetrance), familial, or sporadic
inheritance.
Patients should be informed that currently there are no proven pharmacologic or lifestyle
choices that reduce the risk of developing AD or stop its progression.
The following potential genetic contributions to AD should be reviewed:
The lifetime risk of AD in the general population is approximately 10–12% in a 75–80
year lifespan.
The effect(s) of ethnicity on risk is still unclear.
Although some genes are known, there are very likely others (susceptibility,
deterministic, and protective) whose presence and effects are currently unknown.
For families in which an autosomal dominant AD gene mutation is a possibility:
Discuss the risk of inheriting a mutation from a parent affected with autosomal dominant AD
is 50%. In the absence of identifying a mutation in apparent autosomal dominant
families, risk to offspring could be as high as 50% but may be less.
Testing for genes associated with early onset autosomal dominant AD should be offered in
the following situations:
A symptomatic individual with EOAD in the setting of a family history of dementia or in
the setting of an unknown family history (e.g., adoption).
Autosomal dominant family history of dementia with one or more cases of EOAD.
A relative with a mutation consistent with EOAD (currently PSEN1/2 or APP).
The Alzheimer Disease & Frontotemporal Dementia Mutation Database should be consulted
(available online at: www.molgen.ua.ac.be/ADMutations/) before disclosure of genetic
test results, and specific genotypes should not be used to predict the phenotype in
diagnostic or predictive testing.
Discuss the likelihood of identifying a mutation in PSEN1, PSEN2, or APP, noting that
current experience indicates that this likelihood decreases with lower proportions of
affected family members and/or older ages of onset.
Ideally, an affected family member should be tested first. If no affected family member is
available for testing and an asymptomatic individual remains interested in testing
despite counseling about the low likelihood of an informative result (a positive result
for a pathogenic mutation), he/she should be counseled according to the
recommended protocol. If the affected relative, or their next of kin, is uninterested in
pursuing testing, the option of DNA banking should be discussed.
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Stanford Program in Genomics, Ethics, and Society
In 1998, the Alzheimer Disease Working Group of the Stanford Program in Genomics, Ethics,
and Society24 suggested that “predictive or diagnostic genetic testing for highly penetrant
mutations (eg, APP, PSEN1, PSEN2) may be appropriate for individuals from families with a
clear autosomal dominant pattern of inheritance, particularly those with a family history of early
onset of symptoms.” Such families generally have 3 affected members in 2 generations. In the
case of diagnostic testing of clearly symptomatic individuals, testing would do little to change
diagnostic confidence; however, it might assist excluding other causes of early-onset dementia,
as potentially treatable contributory causes would still require exploring. In cases of early
detection of questionably symptomatic individuals (ie, those with mild cognitive impairment,
MCI) mutation identification might secure a diagnosis and lead to early treatment. The
possibility that earlier diagnosis might lead to improved outcomes, while plausible, is not based
on current evidence. Pharmacologic interventions for MCI have not demonstrated benefit in
reducing progression to AD.25
U.S. Preventive Services Task Force Recommendations
Not applicable.
Medicare National Coverage
There is no national coverage determination (NCD).
Biochemical Markers of Alzheimer’s Disease
The clinical purposes of testing for Alzheimer disease (AD)‒related biomarkers are to improve
diagnostic accuracy or to predict conversion from mild cognitive impairment (MCI) to AD.
Evidence of health benefit or clinical utility from testing requires demonstrating:
incremental improvement in diagnostic or prognostic accuracy over current practice and
that incremental improvements lead to improved health outcomes (eg, by informing clinical
management decisions) and generalizability.
A framework for evaluating evidence supporting health benefit from testing requires
consideration of the following: appropriate reference standard; requirements for predicting
conversion from MCI to AD; how better diagnostic accuracy or prediction of conversion would
lead to improved health outcomes; appropriate data analysis, including assay cutoffs; patient
sample composition (inclusion and exclusion criteria); and validation of accuracy or prediction in
independent samples as evidence of generalizability.
Criterion Standard. Accuracy of clinical AD diagnostic criteria has been established by
comparison with autopsy, the criterion standard. Therefore, comparison with autopsy is most
appropriate to validly assess incremental diagnostic improvement of biomarkers.
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Predicting Conversion From MCI to AD. Predicting conversion from MCI to AD may rely
on clinical diagnosis, albeit with some attendant error and misclassification, because the
prediction of interest is conversion and not the criterion standard diagnosis.
Incremental Diagnostic Improvement. Incremental diagnostic or prognostic improvement
is best demonstrated by evidence that the proposed predictor can correctly reclassify patients
with and without AD, or those with MCI who will and will not progress to AD.9 Alternative
approaches such as classical receiver operating characteristic (ROC) analyses, while
providing insight, do not allow one to directly translate improvements in diagnostic or
prognostic accuracy to changes in health outcomes.10
Test Cutoffs. Almost all studies employ optimal (data-driven) test cutoffs to define test
accuracy (sensitivity and specificity). This approach is typically accompanied by a degree of
optimism, in turn overstating test accuracy.
Sample Definition. Clear description of whether samples included consecutive patients or
were selective is required to evaluate potential bias—including verification bias (exclusion of
cases without postmortem autopsy)11—and generalizability.
Validation. Validation in independent samples is required to establish generalizability of
markers.
Relevant evidence and guidelines were identified by a MEDLINE search through July 30, 2015.
Diagnostic Accuracy of Cerebrospinal Fluid Markers Versus Clinical Diagnosis
Most studies have relied on clinically diagnosed AD as the criterion standard. These studies are
described next; the results are summarized in Error! Reference source not found..
Rosa et al (2014) conducted a systematic review with meta-analysis of studies of cerebrospinal
fluid (CSF) amyloid-β peptide-1-42 (AB-42) in patients with clinically diagnosed AD.12
Literature was searched to May 2013, and 41 prospective or retrospective, cohort, case-control,
and cross-sectional studies were included (total N=5086; 2932 AD, 2154 nondemented controls).
Patients with MCI were excluded. Seventy-six percent of studies satisfied all quality domains of
the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Publication bias was
detected. A summary ROC curve was generated from all reported thresholds. Pooled sensitivity
and specificity were 84% (95% confidence interval [CI], 81 to 85) and 79% (95% CI, 77 to 81),
respectively. Positive and negative likelihood ratios were 4.5 (95% CI, 3.7 to 5.4) and 0.18 (95%
CI, 0.14 to 0.22), respectively, and their ratio, the diagnostic odds ratio, was 29 (95% CI, 21 to
40). Statistical heterogeneity was substantial (I2=68%); studies varied in test cutoffs used and
severity of AD across patient samples. Eleven studies (total N=1459; 830 AD, 629 controls)
reported AB-42 CSF levels. Mean (SD) CSF AB-42 was 467 (189) pg/mL in patients with AD
and 925 (414) pg/mL in controls (weighted mean difference, 450 pg/mL; 95% CI, -600 to -289;
p<0.001). However, statistical heterogeneity was considerable (I2=99%).
Ferreira et al (2014) published a meta-review of systematic reviews with meta-analyses to assess
the use of CSF biomarker tests for AD after publication of revised AD diagnostic criteria13 in
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2011.14 Literature was searched in September 2013, and 7 systematic reviews were included.
None was published after introduction of the revised AD diagnostic criteria, so primary studies
were searched. Twenty-six prospective or retrospective case-control, cross-sectional, or
longitudinal studies were included. Most included studies used clinical criteria for AD diagnosis
or did not specify. Results for both the systematic reviews and the individual studies are
summarized in Error! Reference source not found.. For differentiating AD from nondemented
controls, positive and negative likelihood ratios for all 3 biomarkers ranged from 4 to 8 and from
0.1 to 0.3, respectively. For differentiating AD from other dementias, 1 systematic review of 7
studies reported positive and negative likelihood ratios of 46 and 0.09, respectively, for
differentiating AD (n=175) from Creutzfeldt-Jakob disease (n=110).15 With this systematic
review excluded, positive and negative likelihood ratios ranged from 2 to 7 and from 0.15 to 0.4,
respectively.
A 2011 meta-analysis included 119 studies on biomarkers and diagnostic imaging in AD.16
Sensitivity and specificity were calculated for distinguishing AD from nondemented controls,
and for distinguishing AD from non-AD dementias with and without MCI, if available. Included
studies of CSF biomarkers used a variety of thresholds, with clinical diagnosis or autopsy as the
reference standard. Twenty studies of the AB-42 CSF marker were included; pooled analysis
resulted in sensitivity of 76% and specificity of 77%. CSF total tau was evaluated in 30 studies
with a resulting sensitivity of 79% and specificity of 85%. CSF P-tau was evaluated in 24 studies
resulting in a pooled sensitivity of 78% and specificity of 81%. Six studies evaluated CSF P-tau
as a biomarker to distinguish AD patients from patients with MCI, with a pooled sensitivity of
73% and specificity of 69%. The combination of total tau and AB-42 was evaluated in 12 studies
with a pooled sensitivity of 80% and specificity of 76%. In a comparison of CSF biomarkers,
area under the ROC curve was highest for P-tau alone (0.85). Study heterogeneity was due to use
of different test thresholds and different assay kits. Sensitivity analysis including studies that
used autopsy as the reference standard for P-tau resulted in slightly higher sensitivity (82%) and
lower specificity (57%).
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Table 1. CSF Biomarkers Performance for Distinguishing Alzheimer Disease From Controls
Nondemented Contro ls
Sensitivity
Specificity
AB-42
14
80% (73 to 85)
82% (74 to 88)
Ferreira (2014), SR
14
Ferreira (2014), IS
63%-97%
67%-92%
12
84% (81 to 85)
79% (77 to 81)
Rosa (2013)
10
76%
77%
Mattson (2011 )
NR
NR
Formichi (2006) 17
T-tau
14
Ferreira (2014), SR
82% (76 to 87)
90% (86 to 93)
61%-91%
Ferreira (20'14), IS
53%-97%
10
79%
Mattson (2011 )
85%
Formichi (2006) 17
NR
NR
P-tau
Ferreira (2014), 14 SR
78%-80%
83%-88%
14
Ferreira (2014), IS
61%-89%
37%-92%
10
Mattson (2011 )
78%
81%
Formichi (2006) 17
NR
NR
Values in parentheses are 95% confidence intervals unless otheUwise noted.
a
Contro ls With Dementia
Sensitivity
Specificity
73% (67 to 78)
82%-95%
NR
NR
55%-100%
67% (62 to 72)
22%-80%
NR
NR
80%-100%
73%-91%
61%-92%
NR
52%-100%
75%-98%
40%-93%
NR
50%-100%
72%-88%
77%-88%
NR
37%-100%
78%-83%
56%-88%
NR
80%-100%
CSF: cerebrospinal fluid; IS: individual studies; NR: not reported; P-tau: phosphorylated tau protein; SR: systematic
review; T-tau: total tau protein. a Or unspecified.
In a 2006 review of studies using clinical diagnosis as the criterion standard, Formichi et al17
identified studies examining diagnostic accuracy of the following CSF markers for AD: total tau
protein (T-tau) (41 studies; 2287 AD patients, 1384 controls; sensitivity, 52%-100%; specificity,
50%-100%), phosphorylated tau protein (P-tau) (12 studies; 760 AD patients, 396 controls;
sensitivity, 37%-100%; specificity, 80%-100%), and amyloid-β peptide 1 to 42 (AB-42) (14
studies; 688 AD patients, 477 controls; sensitivity, 55%-100%; specificity, 80%-100%).
Although primarily a descriptive review, test accuracies varied widely and only 1 study included
a majority of autopsy-confirmed AD diagnoses.
Section Summary: Diagnostic Accuracy of Cerebrospinal Fluid Markers Versus Clinical
Diagnosis
Several studies have examined the diagnostic performance of CSF biomarkers for distinguishing
probable AD from nondemented controls and from patients with other types of dementia. The
range of reported sensitivities and specificities is broad; in systematic reviews with metaanalyses, sensitivity and specificity were 80% to 82% and 82% to 90%, respectively, for
differentiating AD from nondemented controls, and 73% and 67%, respectively, for
differentiating AD from other dementias. Positive and negative likelihood ratios were 2 to 8 and
0.2 to 0.4, respectively, in either setting. This evidence does not indicate that CSF biomarkers
improve the accuracy of clinical diagnostic criteria.
Diagnostic Accuracy of CSF Markers With AD Autopsy Confirmation
Engelborghs et al (2008) assayed P-tau and AB-42 in banked CSF.18 Samples were examined
from 100 patients with and 100 without dementing illness seen between 1992 and 2003. All
dementia diagnoses were autopsy-proven (67 pure AD, 6 mixed, 27 non-AD dementias). Details
of the sample selection were not provided; whether CSF testing was routine or selective was not
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indicated. Of those with dementia, 76 were evaluated in a memory clinic and the remainder in
referring centers; all underwent clinical, neuropsychological, and imaging evaluations. The
nondemented group was substantially younger (mean age, 47 years vs 76 years). Laboratory
technicians performing assays were blinded to clinical diagnoses. Samples from 52 patients
required retesting due to unreliable results. Sensitivity and specificity of clinical evaluation for a
pure AD diagnosis was 83% and 75%, respectively, and of P-tau and AB-42 in combination,
80% and 93%, respectively. In logistic regression models, CSF biomarkers did not provide
incremental diagnostic accuracy over clinical diagnosis; as the authors stated: “[A]lthough
biomarkers did not perform significantly better comparing all unique clinical diagnoses, they
were also not significantly worse, and could therefore add certainty to an established diagnosis.”
Four of 7 listed authors were employees of the test manufacturer (Innogenetics [now Fujirebio],
Ghent, Belgium).
Clark et al (2003) examined CSF from 106 patients with autopsy-confirmed dementia who were
evaluated at 10 referral clinics, and 73 controls (4 pathologically examined).19 Laboratory
technicians were blinded to clinical diagnoses. An optimal cutoff of 234 pg/mL for total tau had
sensitivity and specificity of 85% and 84%, respectively, for distinguishing those with AD
(n=73) from cognitively normal people (n=74); AB-42 offered no incremental diagnostic value
to total tau in ROC analyses. An optimal cutoff for total tau of 361 pg/mL had sensitivity and
specificity of 72% and 69%, respectively, for distinguishing AD (n=74) from frontotemporal
dementia (FTD) (n=3) and dementia with Lewy bodies (DLB) (n=10).
Bian et al (2008) assembled from 2 institutions a sample of 30 patients with FTD (19 autopsyproven, 11 with known causal genetic mutations) and autopsy-proven AD (n=19).20 Using an
optimal cutoff of 403 pg/mL, total tau had sensitivity and specificity of 68% and 90%,
respectively, for distinguishing FTD from AD. A tau/AB-42 ratio of 1.06 had 97% specificity for
distinguishing FTD from AD.
Cure et al (2014) conducted a systematic review with meta-analysis of CSF and imaging studies
for the diagnosis of definite AD (autopsy-confirmed).21 Literature was searched in January 2012,
and 3 studies of CSF markers (P-tau, T-tau, AB-42, AB-40) were identified (total N=337).
Pooled sensitivity of all CSF tests was 82% (95% CI, 72 to 92), and pooled specificity was 75%
(95% CI, 60 to 90). Statistical heterogeneity was not reported, but studies varied in AD
definitions, controls (nondemented patients or patients with dementia due to other causes), and
test thresholds. Area under the summary ROC curve constructed using multiple test thresholds
was 0.84.
Section Summary: Diagnostic Accuracy of CSF Markers With AD Autopsy Confirmation
There is limited evidence examining incremental diagnostic accuracy of CSF biomarkers for AD
diagnosis employing autopsy as a criterion standard. Current evidence does not demonstrate
improvement over a clinical diagnosis, or whether diagnosis using CSF biomarkers would lead to
improved health outcomes.
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CSF Markers in Combination
As previously noted, for patients with clinically diagnosed AD, some have suggested that the
tau/AB-42 ratio is a more accurate predictor than either alone. For example, using optimal
cutoffs, de Jong et al (2006) reported sensitivity and specificity of 95% and 90% in a sample
with clinically diagnosed AD (n=61) and vascular dementia (VaD) (n=61).22 In contrast, Le
Bastard et al (2007) found the P-tau/AB-42 ratio lacked specificity to distinguish AD from VaD
in a sample of 85 patients (VaD [n=64], AD [n=21]; 76/85 autopsy-confirmed diagnoses);
specificity was 52% and sensitivity ranged from 91% to 95%.23
CSF AB-42 level normalized to CSF AB-40 (ie, the AB-42/AB-40 ratio) is being investigated as
a marker for patients with uncertain clinical diagnosis. Because AB-40 is not incorporated into
amyloid plaques, CSF levels are more stable than those of AB-42. Sauvee et al (2014) examined
the AB-42/AB-40 ratio in 122 patients with atypical dementia who had discordant CSF
biomarker results (ie, tau, P-tau, AB-42).24 Using 0.05 as the ratio threshold, biological profiles
were clarified in 72 (59%) of 122 patients with the addition of the AB-42/AB-40 ratio. However,
of 35 patients diagnosed with AD by biological profile, 9 (26%) did not meet clinical criteria for
AD or mixed dementia.
Section Summary: CSF Markers in Combination
The clinical utility of CSF biomarkers used in combination has not been demonstrated.
Neural Thread Protein
Zhang et al (2014) conducted a systematic review and meta-analysis of urinary AD-associated
neural thread protein for diagnosing AD in patients with suspected AD.25 Nine studies were
included (total N=841 patients with probable or possible AD, 37 patients with MCI, 992 non-AD
demented or nondemented controls). For probable AD, pooled sensitivity and specificity were
89% (95% CI, 86 to 92) and 90% (95% CI, 88 to 92), respectively. Pooled positive and negative
likelihood ratios were 8.9 (95% CI, 7.1 1 to 11.1) and 0.12 (95% CI, 0.09 to 0.16), respectively.
Kahle et al (2000) reported on the diagnostic potential of CSF levels of total tau protein and
neural thread protein in a group of 35 patients with dementia (30 with probable or definite AD),
5 patients with DLB, 29 patients with Parkinson disease, and 16 elderly healthy control
patients.26 Levels of both tau and neural thread protein were elevated in patients with AD
compared with controls; sensitivity and specificity were 63% and 93%, respectively, for tau, and
70% and 80%, respectively, for neural thread protein.
In a prospective multicenter study conducted at 8 sites, Goodman et al (2007) enrolled 168
patients with recent referrals to memory clinics.27 The Urinary Neural Thread Protein Test was
91.4% sensitive for a diagnosis of probable AD (32/35) and 90.1% specific among healthy
patients. However, it was unclear whether the marker changed management or what the potential
consequences of a 9.9% false-positive rate might be.
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Section Summary: CSF Markers in Combination
Data on neural thread protein as a marker for AD are limited. In 2 studies and 1 meta-analysis,
estimated sensitivity and specificity ranged from 70% to 91% and from 80% to 90%,
respectively. The clinical utility of neural thread protein testing has not been demonstrated.
CSF Markers and Progression of MCI
Studies also have evaluated the prognostic value of markers for progression of MCI and
conversion to clinically manifest AD.
Ritchie et al (2014) published a Cochrane review of CSF amyloid-β protein (primarily AB-42)
for detecting which patients with MCI would progress to AD or other dementias.28 Literature
was searched in December 2012, and 14 prospective or retrospective cohort studies of AD,
including 1 discussed next,29 were included (total N=1349 patients with MCI). Studies that
enrolled patients younger than 50 years of age or with less than 2 years of follow-up were
excluded. Risk of bias was moderate to high in most studies. AD, diagnosed by clinical criteria,
developed in 436 (32%) of 1349 patients. Sensitivity ranged from 36% to 100%, and specificity
from 29% to 91%. Due to heterogeneity of thresholds used, summary sensitivity and specificity
were not calculated. However, a summary ROC curve was generated using the median
specificity of 64%; pooled sensitivity was 81% (95% CI, 72 to 87). Positive and negative
likelihood ratios were 2.2 (95% CI, 2.0 to 2.5) and 0.31 (95% CI, 0.21 to 0.48), respectively.
Analysis of the pre- and posttest probabilities of conversion to AD among patients with MCI in
primary and secondary care settings showed little incremental value of AB-42 testing in either
setting.
The 2014 meta-review of systematic reviews by Ferriera et al (previously discussed) included
studies of CSF biomarkers for differentiating patients with MCI who progress to AD from those
who do not.14 In systematic reviews with meta-analyses, sensitivity and specificity of AB-42
were 67% (95% CI, 59 to 75) and 71% (95% CI, 65 to 78), respectively; for T-tau, 82% (95%
CI, 76 to 86) and 70% (95% CI, 65 to 85), respectively; and for P-tau, 81% (95% CI, 69% to
91%) and 65% to 76%, respectively. Positive and negative likelihood ratios for all 3 tests ranged
from 2 to 3 and from 0.3 to 0.5, respectively.
Mattsson et al (2009) recruited from 12 U.S. and European centers patients with MCI (n=750) or
AD (n=529) and controls (n=304).30 Those with MCI were followed a minimum of 2 years or to
disease progression. Development of probable AD was associated with lower CSF AB-42 and
higher T-tau and P-tau. Using cutoffs defined in the AD and control groups for a diagnostic
sensitivity of 85%, combining AB-42/P-tau and T-tau yielded sensitivity for AD conversion of
83% (95% CI, 78 to 88); specificity, 72% (95% CI, 68 to 76); positive predictive value, 62%;
and negative predictive value, 88%. Type of MCI (amnestic or nonamnestic) was not specified.
Herukka et al (2007) reported on a sample of 106 patients evaluated at a university neurology
department and 33 patients “from an ongoing prospective population-based study”; selection
criteria other than agreeing to a lumbar puncture were not further described.31 Seventy-nine
patients were diagnosed with MCI, 47 with amnestic type, and 33 converting to dementia; 60
patients were included as controls. Average follow-up was 3.5 years (MCI converters), 3.9 years
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(controls), and 4.6 years (stable MCI). CSF AB-42, P-tau, and total tau were measured.
Graphical representation of AB-42, P-tau, and total tau suggested considerable overlap between
controls, those with stable MCI, and progressive MCI. Test accuracy was not reported.
Hansson et al (2006) obtained 137 CSF samples from a larger group of 180 consecutive patients
with MCI who were evaluated at a referral memory clinic between 1998 and 2001.32 CSF also
was obtained from 39 controls. In the analytical sample (n=137), patients were 50 to 86 years of
age at baseline, and 55% were female. Median follow-up was 5.2 years; 57 (42%) progressed to
AD. Using a predictor comprising T-tau and AB-42/P-tau with optimal cutoffs, sensitivity and
specificity for progression to clinical AD were 95% (95% CI, 86 to 98) and 87% (95% CI, 78 to
93), respectively. Patients were not categorized by the presence of amnestic MCI conferring
increased risk of conversion to AD.33
From 4 international clinical research centers, Ewers et al (2007) retrospectively assembled a
sample of 88 patients with amnestic MCI based on both the availability of CSF samples and at
least 1 follow-up visit between 1 and 3 years after initial evaluation; 57 healthy controls with
baseline evaluations only also were included.34 Forty-three patients (49%) in the MCI group
converted to AD over an average 1.5-year follow-up. Using a cutoff of 27.3 pg/mL, sensitivity
and specificity of P-tau for conversion were 87% (95% CI, 73 to 93) and 73% (95% CI, 55 to
84), respectively. It should be noted that the conversion rate to AD in the sample was between 2and 3-fold higher than the typical 15% found in amnestic MCI.
Andreasen et al (2005) studied 32 controls and 44 patients with MCI who, after a 1-year followup, had progressed to probable AD.35 At the start of the study, investigators evaluated total and
P-tau and AB-42 levels. At baseline, 79.5%, 70.4%, and 77.3% had abnormal levels of total tau,
P-tau, and AB-42, respectively. These results would have been more informative if patients with
MCI who did not progress to AD were included for comparison.
Bouwman et al (2007) followed 59 patients with MCI for a mean of 19 months (range, 4-45),
obtaining baseline CSF AB-42 and tau.36 Abnormal AB-42 (<495 pg/mL) and total tau (>356
pg/mL) were accompanied by increased, but imprecise, relative risks for progression to AD (5.0
[95% CI, 1.4 to 18.0] and 5.3 [95% CI, 1.5 to 19.2], respectively).
Parnetti et al (2006) examined 55 patients with MCI.29 Baseline CSF AB-42, total tau, and P-tau
were measured; 38% had abnormal values. After 1 year, 4 (12%) of 33 stable patients had
abnormal markers. Of 11 patients who progressed to AD, DLB, or familial FTD, 10 (91%) had 2
or more abnormal markers. Although results from these studies are consistent with potential
prognostic utility of markers, sample sizes were small. Additionally, the type of MCI (amnestic
or nonamnestic) was not specified but has important predictive value for progression to
dementia.
Section Summary: CSF Markers and Progression of MCI
Evidence suggests that biomarker testing may identify increased risk of conversion from MCI to
AD. Evidence that earlier diagnosis leads to improved health outcomes through delay of AD
onset or improved quality of life is lacking.
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Alzheimer Disease Neuroimaging Initiative
In 2003, the Alzheimer Disease Neuroimaging Initiative (ADNI) initiated a public-private effort
designed to aid researchers and clinicians to develop new treatments and monitor their
effectiveness, as well as to lessen the time and cost of clinical trials. Participants have been
recruited across the United States and Canada with follow-up every 6 months for approximately
10 years. Participants undergo neuropsychological testing, imaging, and biomarker evaluations
to determine whether these measures can be combined to monitor the progression of MCI and
AD. Ongoing results from several studies span diagnostic and prognostic questions addressed
here.
In a 2011 report, Gomar et al evaluated the value of neuropsychological testing, neuroimaging,
and biomarkers (CSF AB and tau) for diagnosing AD in all participants in the ADNI database
who had a lumbar puncture.37 This included 105 normal controls, 179 patients with MCI, and 91
patients with AD. Neuropsychological testing and magnetic resonance imaging (MRI) were
found to be the most informative techniques, with 84% and 82% correct classification,
respectively. CSF assessments had 73% correct classification and did not add diagnostic
information when all techniques were combined. CSF assessments were less informative in
patients aged 75 years and older (70% correct classification vs 77% for patients ≤75 years).
Two reports from 2009 compared MRI scans and CSF biomarkers for diagnosis and prognosis
among 399 participants undergoing both exams (109 normal, 192 amnestic MCI, 98 AD).38,39 In
ROC analyses, C statistics for MRI as diagnostic of probable AD compared with normal and for
P-tau/AB-42 were 0.90 and 0.84, respectively.38 In longitudinal evaluation, both MRI and
biomarkers were associated with conversion to AD; c-indices were 0.69 for MRI and 0.62 for Ttau/AB-42.39 Reclassification measures were not reported. In these studies, MRI appeared to
provide greater diagnostic (for probable AD) and prognostic information.
In a 2012 report, Schmand et al evaluated the value of neuropsychological testing, neuroimaging,
and biomarkers (AB and tau in CSF) for predicting conversion to AD in 175 patients with
MCI.40 With a mean follow-up of 2.7 years (range, 0.5-4.6), 81 patients (46%) converted to AD.
Neuropsychological testing and MRI predicted conversion with 63% to 67% classification
success both in patients younger and older than 75 years. CSF biomarkers correctly classified
64% of patients younger than 75 years and 60% of patients 75 years of age or older. Difference
in prediction for markers in combination (70%) was not significantly better than for individual
markers.
Landau et al (2010) examined predictors of conversion to clinically diagnosed AD and cognitive
decline in 85 patients with amnestic MCI in the ADNI.41 Twenty-eight patients developed AD
over a mean 1.9-year follow-up. In multivariate models, CSF markers (P-tau, T-tau, P-tau/AB42, T-tau/AB-42) were not associated with conversion to AD.
De Meyer et al (2010) developed a model using biomarkers (CSF AB-42/P-tau) in the U.S.ADNI sample (114 cognitively normal, 200 MCI, 102 AD patients).42 Sensitivity and specificity
in the development set were 90% and 64%, respectively; one-third of cognitively normal people
had false-positive results. The model was then validated in a Belgian data set of 73 patients with
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autopsy-confirmed dementia and correctly identified 64 (94%) of 68 AD patients. In a separate
data set of 57 patients with MCI, the model identified all patients who progressed to AD.
Ewers et al (2012) evaluated CSF AB-42, amyloid PET, fluorodeoxyglucose-positron emission
testing (FDG-PET), and MRI in 211 ADNI patients with at least 1 detected amyloid biomarker.43
Using the most recent diagnostic criteria, in 92 patients undergoing all tests, AB-42 had 94%
sensitivity for a positive FDG-PET or MRI. The authors concluded, “[m]ore correlation and
validation studies of biomarkers in the AD population will be essential to understand biomarker
performance and correlation with autopsy data.”
In 181 ADNI patients with MCI, Richard et al (2013) found neither MRI nor CSF biomarkers
improved classification of patients who developed AD compared with a brief memory test.44 Net
reclassification improvement obtained by adding MRI results to the memory test were 1.1% and
for CSF AB-42/P-tau, 2.2%.
Improved Health Outcomes (Clinical Utility)
Although not without controversy because of modest efficacy, cholinesterase inhibitors are used
to treat mild-to-moderate AD.45,46 Memantine, an N-methyl-D-aspartate receptor antagonist,
appears to provide a small benefit in those with moderate-to-advanced disease.45,47 Given
available therapies, in principle, more accurate diagnosis might allow targeting treatment to those
most likely to benefit. However, clinical trial entry criteria and benefit have been based on
clinical diagnosis. While the possibility that more accurate diagnosis may lead to improved
outcomes is plausible, it is not based on current evidence. Pharmacologic interventions for MCI
have not demonstrated benefit in reducing progression to AD.48-51
Ongoing and Unpublished Clinical Trials
A search of ClinicalTrials.gov in June 2015 did not identify any ongoing or unpublished trials
that would likely influence this review.
Summary of Evidence
The evidence for testing for Alzheimer disease (AD)‒related biomarkers in patients who have
dementia or mild cognitive impairment includes systematic reviews, meta-analyses, and case
series. Relevant outcomes are test accuracy, test validity, symptoms, change in disease status,
morbid events, quality of life, medication use, and resource utilization. Most studies derive from
select patient samples and define optimal test cutoffs without validation; thus, generalizability of
results is uncertain. For the diagnosis of AD, evidence does not demonstrate incremental
improvement in diagnostic accuracy over clinical testing. For predicting conversion from mild
cognitive impairment (MCI) to AD, limited evidence, including that from the Alzheimer Disease
Neuroimaging Initiative, suggests that testing may define increased risk. Whether earlier
diagnosis leads to improved health outcomes through delay of AD onset or improved quality of
life is unknown. Therefore, the evidence is insufficient to determine the effects of the technology
on health outcomes.
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Practice Guidelines and Position Statements
National Institute of Neurological and Communicative Disorders and Stroke and
Alzheimer Disease and Related Disorders Association
In 1984, National Institute of Neurological and Communicative Disorders and Stroke (NINCDS)
and Alzheimer Disease and Related Disorders Association (ADRDA) developed clinical criteria
for the diagnosis of AD.52 Although evidence to date has used NINCDS/ADRDA’s AD
classification, in 2011, the National Institute on Aging and the Alzheimer’s Association
workgroup revised diagnostic criteria for dementia due to AD.13
In the 1984 guidelines, diagnostic categories were defined as follows.
Possible Alzheimer Disease
Clinical diagnosis of possible AD:
A. 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, the presentation, or the clinical course.
B. 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.
C. 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 Disease
Criteria for the clinical diagnosis of probable AD included:
A. 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;
B. Deficits in 2 or more areas of cognition;
C. Progressive worsening of memory and other cognitive functions;
D. No disturbance of consciousness;
E. Onset between ages 40 and 90 years, most often after the age of 65 years; and
F. 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:
A. Progressive deterioration of specific cognitive functions such as language (aphasia),
motor skills (apraxia), and perception (agnosia);
B. Impaired activities of daily living and altered patterns of behavior;
C. Family history of similar disorders, particularly if confirmed neuropathologically; and
D. Laboratory results: normal lumbar puncture as evaluated by standard techniques, normal
pattern or nonspecific changes in the electroencephalogram (EEG), and evidence of
cerebral atrophy on computed tomography (CT) scanning with progression documented
by serial observation.
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Other clinical features consistent with the diagnosis of probable AD, after exclusion of causes of
dementia other than AD, include
A. Plateaus in the course of progression of the illness;
B. Associated symptoms of depression, insomnia, incontinence, delusions, illusions,
hallucinations, sexual disorders, weight loss, and catastrophic verbal, emotional, or
physical outbursts;
C. Other neurological abnormalities in some patients, especially with more advanced disease
and including motor signs such as increased muscle tone, myoclonus, or gait disorder;
and
D. Seizures in advanced disease CT normal for age.
Features that make the diagnosis of probable AD uncertain or unlikely include:
A. Sudden apoplectic onset;
B. Focal neurological findings such as hemiparesis, sensory loss, visual field deficits, and
incoordination early in the course of the illness; and
C. Seizures or gait disturbances at the onset or very early in the course of the illness.
Definite Alzheimer Disease
Criteria for diagnosis of definite AD are:
A. Clinical criteria for probable Alzheimer disease; AND
B. Histopathologic evidence obtained from a biopsy or autopsy.
National Institute on Aging and the Alzheimer’s Association
As of 2011, probable AD is defined by the National Institute on Aging and the Alzheimer’s
Association workgroup according to the following diagnostic criteria13:
“Meets criteria for dementia…and in addition, has the following characteristics:
A. Insidious onset. Symptoms have a gradual onset over months to years, not sudden over
hours or days;
B. Clear-cut history of worsening of cognition by report or observation; and
C. The initial and most prominent cognitive deficits are evident on history and examination
in one of the following categories.
a. Amnestic presentation: It is the most common syndromic presentation of AD
dementia. The deficits should include impairment in learning and recall of recently
learned information. There should also be evidence of cognitive dysfunction in at
least one other cognitive domain, as defined earlier in the text.
b. Nonamnestic presentations: Language presentation: The most prominent deficits are
in word-finding, but deficits in other cognitive domains should be present.
Visuospatial presentation: The most prominent deficits are in spatial cognition,
including object agnosia, impaired face recognition, simultanagnosia, and alexia.
Deficits in other cognitive domains should be present. Executive dysfunction: The
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most prominent deficits are impaired reasoning, judgment, and problem solving.
Deficits in other cognitive domains should be present.
D. The diagnosis of probable AD dementia should not be applied when there is evidence of:
a. Substantial concomitant cerebrovascular disease, defined by a history of a stroke
temporally related to the onset or worsening of cognitive impairment; or the presence
of multiple or extensive infarcts or severe white matter hyperintensity burden; or
b. Core features of dementia with Lewy bodies other than dementia itself; or
c. Prominent features of behavioral variant frontotemporal dementia; or
d. Prominent features of semantic variant primary progressive aphasia or
nonfluent/agrammatic variant primary progressive aphasia; or
e. Evidence for another concurrent, active neurological disease, or a non-neurological
medical comorbidity or use of medication that could have a substantial effect on
cognition.”
All probable AD by NINCDS-ADRDA criteria are subsumed in the revised probable AD
criteria. Revised criteria include a category of “Probable AD dementia with increased level of
certainty” due to documented decline or having a causative AD genetic mutation. Additionally, a
category “Probable AD dementia with evidence of the AD pathophysiological process” has been
added. Evidence of the AD pathophysiologic process is supported by detection of low
cerebrospinal fluid (CSF) AB-42, positive positron emission tomography (PET) amyloid
imaging, or elevated CSF tau, and decreased 18-F fluorodeoxyglucose uptake on PET in the
temporoparietal cortex with accompanying atrophy by magnetic resonance imaging in relevant
structures. Detection of the “pathophysiological process” is further divided according to when in
the disease natural history markers are expected to be detectable.
Note on Revised AD Criteria and Biomarkers
The biomarkers considered in this evidence review included in a category among revisions to the
2011 updated AD diagnostic criteria, “probable AD dementia with evidence of the AD
pathophysiological process.”13 However, the diagnostic criteria workgroup noted that
“we do not advocate the use of AD biomarker tests for routine diagnostic purposes at the
present time. There are several reasons for this limitation: 1) the core clinical criteria
provide very good diagnostic accuracy and utility in most patients; 2) more research needs
to be done to ensure that criteria that include the use of biomarkers have been appropriately
designed, 3) there is limited standardization of biomarkers from one locale to another, and
4) access to biomarkers is limited to varying degrees in community settings. Presently, the
use of biomarkers to enhance certainty of AD pathophysiological process may be useful in
3 circumstances: investigational studies, clinical trials, and as optional clinical tools for use
where available and when deemed appropriate by the clinician.”13
Alzheimer’s Association
In 2009, the Alzheimer’s Association (AA) initiated a quality control program for CSF markers,
noting that “Measurements of CSF AD biomarkers show large between laboratory variability,
likely caused by factors related to analytical procedures and the analytical kits. Standardization
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of laboratory procedures and efforts by kit vendors to increase kit performance might lower
variability, and will likely increase the usefulness of CSF AD biomarkers.”8 In 2012, the
Alzheimer's Biomarkers Standardization Initiative published consensus recommendations for
standardization of preanalytical aspects (eg, fasting, tube types, centrifugation, storage time,
temperature) of CSF biomarker testing.53
In 2013, AA published recommendations for operationalizing the detection of cognitive
impairment during the Medicare annual wellness visit in primary care settings.54 The
recommended algorithm for cognitive assessment was based on “current validated tools and
commonly used rule-out assessments.” Guideline authors noted that use of biomarkers (eg, CSF
tau and β-amyloid proteins) “was not considered as these measures are not currently approved or
widely available for clinical use.”
The 4th Canadian Consensus Conference on Diagnosis and Treatment of Dementia
The 4th Canadian Consensus Conference on Diagnosis and Treatment of Dementia published
updated evidence-based consensus recommendations in 2012.55,56 There was consensus that
plasma AB-42 measurement is unreliable and is not recommended for clinical practice. There
was lack of consensus for measurement of CSF AB-42 and tau levels in patients with atypical
dementia. Conference participants concluded that “for now, measurement of CSF AB1-42 and
tau have no clinical utility in Canada, although they are part of research protocols in
observational and therapeutic studies.”
European Federation of Neurological Societies and European Neurological Society
In 2012, European Federation of Neurological Societies and European Neurological Society
published updated evidence-based consensus guidelines on the diagnosis and management of
disorders associated with dementia.57 A level B recommendation (probably effective based on
class 3 [unblinded] evidence) that CSF AB-42/tau/p-tau assessment helps to differentiate AD
was included.
U.S. Preventive Services Task Force Recommendations
Not applicable.
Medicare National Coverage
There is no national coverage determination (NCD).
V. DEFINITIONS
TOP
ALLELE refers to one of two or more different genes containing specific inheritable
characteristics that occupy corresponding positions (loci) on paired chromosomes.
AUTOSOMAL DOMINANT INHERITANCE refers to a pattern of inheritance in which the
transmission of a dominant allele on an autosome causes a trait to be expressed.
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BIOCHEMICAL MARKER refers to any biochemical compound such as an antigen, antibody,
abnormal enzyme, or hormone that is sufficiently altered in a disease to serve as an aid in
diagnosing or in predicting susceptibility to disease.
FIRST-DEGREE RELATIVE refers to parent, sibling, or child.
GENE is the basic unit of heredity, made of DNA, the code for a specific protein.
LIPOPROTEIN refers to conjugated chemicals in the bloodstream consisting of simple
proteins bound to fat. Cholesterol, phospholipids and triglycerides are all fatty components
of lipoproteins.
NEUROFIBRIL refers to any of the many tiny fibrils that extend in every direction of the
nerve cell body. They extend into the axon and dendrites of the cell.
NEURON refers to a nerve cell, the structural and functional unit of the nervous system.
VI. BENEFIT VARIATIONS
TOP
The existence of this medical policy does not mean that this service is a covered benefit
under the member's contract. Benefit determinations should be based in all cases on the
applicable contract language. Medical policies do not constitute a description of benefits.
A member’s individual or group customer benefits govern which services are covered,
which are excluded, and which are subject to benefit limits and which require
preauthorization. Members and providers should consult the member’s benefit information
or contact Capital for benefit information.
VII. DISCLAIMER
TOP
Capital’s medical policies are developed to assist in administering a member’s benefits, do not constitute
medical advice and are subject to change. Treating providers are solely responsible for medical advice and
treatment of members. Members should discuss any medical policy related to their coverage or condition
with their provider and consult their benefit information to determine if the service is covered. If there is a
discrepancy between this medical policy and a member’s benefit information, the benefit information will
govern. Capital considers the information contained in this medical policy to be proprietary and it may only
be disseminated as permitted by law.
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VIII. CODING INFORMATION
TOP
Note: This list of codes may not be all-inclusive, and codes are subject to change at any time. The
identification of a code in this section does not denote coverage as coverage is determined
by the terms of member benefit information. In addition, not all covered services are
eligible for separate reimbursement.
Investigational; therefore not covered when used for genetic testing and/or biochemical
markers for the diagnosis or risk assessment of Alzheimer’s disease:
CPT Codes ®
81099
81401
81405
81406
83520
86849
Current Procedural Terminology (CPT) copyrighted by American Medical Association. All Rights Reserved.
HCPCS
Codes
S3852
Description
DNA analysis for APOE epsilon 4 allele for susceptibility to Alzheimer's disease
IX. REFERENCES
TOP
Genetic Testing for Alzheimer’s Disease
1. Bird TD. Genetic aspects of Alzheimer disease. Genet Med. 2008;10(4):231-239.
2. Goldman JS, Hahn SE, Catania JW, et al. Genetic testing and counseling for Alzheimer’s
disease: Joint Practice Guidelines of the American College of Genetics and the National
Society of Genetic Counselors. Genet Med. 2011;13(6):597-605.
3. Caselli RJ, Doeck AC, Locke DE, et al. Cerebrovascular risk factors and preclinical memory
decline in healthy APOE e4 homozygotes. Neurology. 2011;76(12):1078-1084.
4. Jonsson T, Stefansson H, Steinberg S, et al. Variant of TREM2 associated with the risk of
Alzheimer's disease. N Engl J Med. Jan 10 2013;368(2):107-116. PMID 23150908
5. Guerreiro R, Wojtas A, Bras J, et al. TREM2 variants in Alzheimer's disease. N Engl J Med.
Jan 10 2013;368(2):117-127. PMID 23150934
6. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to
Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's
Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers
Dement 2011; 263-269. Available at:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3312024/. Accessed Aug. 6, 2015.
7. Hyman BT, Phelps CH, Beach TG, et al. National Institute on Aging-Alzheimer's Association
guidelines for the neuropathologic assessment of Alzheimer's disease. Alzheimers Dement
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2012; 2012/01/24:1-13. Available at:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266529/pdf/nihms334821.pdf. Accessed
Aug. 6, 2015.
8. Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to
Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's
Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers
Dement 2011; 270-279. Available at:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3312024/. Accessed Aug. 6, 2015.
9. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Genetic
Testing for Alzheimer’s Disease: APOE Epsilon 4 Allele. TEC Assessments 1999; Volume 14,
Tab 7.
10. Bertram L, Tanzi RE. Thirty years of Alzheimer's disease genetics: the implications of
systematic meta-analyses. Nat Rev Neurosci. 2008;9(10):768-778.
11. Naj AC, Jun G, Reitz C, et al. Effects of multiple genetic loci on age at onset in late-onset
Alzheimer disease: a genome-wide association study. JAMA Neurol. Nov 2014;71(11):13941404. PMID 25199842
12. Bird TD. Gene Reviews: Alzheimer Disease Overview. 2015;
http://www.ncbi.nlm.nih.gov/books/NBK1161/. Accessed October 8, 2015.
13. American College of Medical Genetics and Genomics. Choosing Wisely. 2015;
http://www.choosingwisely.org/societies/american-college-of-medical-genetics-andgenomics/. Accessed October 6, 2015.
14. Raskind MA, Peskind ER, Wessel TGiADamr, et al. The Galantamine USA-1 Study Group.
Neurology. 2000;54(12):2261-2268.
15. Rigaud AS, Traykov L, Latour F, et al. Presence or absence of at least one epsilon 4 allele
and gender are not predictive for the response to donepezil treatment in Alzheimer's disease.
Pharmacogenetics. 2002;12(5):415-420.
16. Chao S, Roberts JS, Marteau TM, et al. Health behavior changes after genetic risk
assessment for Alzheimer disease: the REVEAL Study. Alzheimer Dis Assoc Disord.
2008;22(1):94-97.
17. Rahman B, Meiser B, Sachdev P, et al. To know or not to know: An update of the literature
on the psychological and behavioral impact of genetic testing for Alzheimer Disease risk.
Genet Test Mol Biomarkers. 2012;16(8):1-8.
18. Mihaescu R, Detmar SB, Cornel MC, et al. Translational research in genomics of
Alzheimer’s disease: a review of current practice and future perspectives. J Alzheimers Dis.
2010;20(4):967–980.
19. Khoury MJ, Gwinn M, Yoon PW, et al. The continuum of translation research in genomic
medicine: how can we accelerate the appropriate integration of human genome discoveries
into health care and disease prevention? Genet Med. Oct 2007;9(10):665-674. PMID
18073579
20. Knopman DS, DeKosky ST, Cummings JL, et al. Report of the Quality Standards
Subcommittee of the American Academy of Neurology Practice parameter diagnosis of
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dementia. 2001 Neurology; 56(9)1143-53. (reaffirmed 2/13/2004). 2001;
http://www.neurology.org/content/56/9/1143.full. Accessed October 6, 2015.
21. Hort J, O’Brien JT, Gainotti G, et al. EFNS guidelines for the diagnosis and management of
Alzheimer’s disease. Eur J Neurol. 2010;17(10):1236–1248.
22. Gauthier S, Patterson C, Chertkow H, et al. Recommendations of the 4th Canadian
Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD4). Can
Geriatr J. Dec 2012;15(4):120-126. PMID 23259025
23. 3rd Canadian Consensus Conference on Diagnosis and Treatment of Dementia (approved
July 2007). New Consensus Guidlines on Management of Dementia. 2008;
http://www.google.com/url?url=http://www.grhosp.on.ca/uploads/Careers,%2520volunteers
%2520and%2520students/PhysiciansEducationDay/May72008/new_consensus_guidelines_o
n_management_of_dementia.ppt&rct=j&frm=1&q=&esrc=s&sa=U&ei=hqzU5mcLoac8QGWv4DIAQ&ved=0CDMQFjAF&usg=AFQjCNH6omHWOIGe4qzrHAEY
S25As6-TJg. Accessed Aug. 6, 2015.
24. McConnell LM, Koenig BA, Greely HT, et al. Genetic testing and Alzheimer disease: has the
time come? Alzheimer Disease Working Group of the Stanford Program in Genomics, Ethics
& Society. Nat Med. 1998;4(7):757-759.
25. Raschetti R, Albanese E, Vanacore N, et al. Cholinesterase inhibitors in mild cognitive
impairment: a systematic review of randomised trials. PLoS Med. 2007;4(11):e338.
Biochemical Markers of Alzheimer’s Disease
1. Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to
Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's
Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers
Dement. May 2011;7(3):270-279. PMID 21514249
2. Hyman BT, Phelps CH, Beach TG, et al. National Institute on Aging-Alzheimer's Association
guidelines for the neuropathologic assessment of Alzheimer's disease. Alzheimers Dement.
Jan 2012;8(1):1-13. PMID 22265587
3. Galasko D, Clark C, Chang L, et al. Assessment of CSF levels of tau protein in mildly
demented patients with Alzheimer's disease. Neurology. Mar 1997;48(3):632-635. PMID
9065538
4. Motter R, Vigo-Pelfrey C, Kholodenko D, et al. Reduction of beta-amyloid peptide42 in the
cerebrospinal fluid of patients with Alzheimer's disease. Ann Neurol. Oct 1995;38(4):643648. PMID 7574461
5. Zhang J, Peng M, Jia J. Plasma amyloid-beta oligomers and soluble tumor necrosis factor
receptors as potential biomarkers of AD. Curr Alzheimer Res. Mar 16 2014. PMID
24635842
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6. Maddalena A, Papassotiropoulos A, Muller-Tillmanns B, et al. Biochemical diagnosis of
Alzheimer disease by measuring the cerebrospinal fluid ratio of phosphorylated tau protein
to beta-amyloid peptide42. Arch Neurol. Sep 2003;60(9):1202-1206. PMID 12975284
7. Dumurgier J, Vercruysse O, Paquet C, et al. Intersite variability of CSF Alzheimer's disease
biomarkers in clinical setting. Alzheimers Dement. Jul 2013;9(4):406-413. PMID 23141384
8. Bloudek LM, Spackman DE, Blankenburg M, et al. Review and meta-analysis of biomarkers
and diagnostic imaging in Alzheimer's disease. J Alzheimers Dis. 2011;26(4):627-645.
PMID 21694448
9. Pencina MJ, D'Agostino RB, Sr., D'Agostino RB, Jr., et al. Evaluating the added predictive
ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat
Med. Jan 30 2008;27(2):157-172; discussion 207-112. PMID 17569110
10. Vickers AJ. Decision analysis for the evaluation of diagnostic tests, prediction models and
molecular markers. Am Stat. 2008;62(4):314-320. PMID 19132141
11. Bowler JV, Munoz DG, Merskey H, et al. Fallacies in the pathological confirmation of the
diagnosis of Alzheimer's disease. J Neurol Neurosurg Psychiatry. Jan 1998;64(1):18-24.
PMID 9436722
12. Rosa MI, Perucchi J, Medeiros LR, et al. Accuracy of cerebrospinal fluid Abeta(1-42) for
Alzheimer's disease diagnosis: a systematic review and meta-analysis. J Alzheimers Dis.
2014;40(2):443-454. PMID 24448789
13. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to
Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's
Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers
Dement. May 2011;7(3):263-269. PMID 21514250
14. Ferreira D, Perestelo-Perez L, Westman E, et al. Meta-review of CSF core biomarkers in
Alzheimer's disease: the state-of-the-art after the new revised diagnostic criteria. Front
Aging Neurosci. 2014;6:47. PMID 24715863
15. van Harten AC, Kester MI, Visser PJ, et al. Tau and p-tau as CSF biomarkers in dementia: a
meta-analysis. Clin Chem Lab Med. Mar 2011;49(3):353-366. PMID 21342021
16. Mattsson N, Andreasson U, Persson S, et al. The Alzheimer's Association external quality
control program for cerebrospinal fluid biomarkers. Alzheimers Dement. Jul 2011;7(4):386395 e386. PMID 21784349
17. Formichi P, Battisti C, Radi E, et al. Cerebrospinal fluid tau, A beta, and phosphorylated tau
protein for the diagnosis of Alzheimer's disease. J Cell Physiol. Jul 2006;208(1):39-46.
PMID 16447254
18. Engelborghs S, De Vreese K, Van de Casteele T, et al. Diagnostic performance of a CSFbiomarker panel in autopsy-confirmed dementia. Neurobiol Aging. Aug 2008;29(8):11431159. PMID 17428581
19. Clark CM, Xie S, Chittams J, et al. Cerebrospinal fluid tau and beta-amyloid: how well do
these biomarkers reflect autopsy-confirmed dementia diagnoses? Arch Neurol. Dec
2003;60(12):1696-1702. PMID 14676043
Page 33
MEDICAL POLICY
POLICY TITLE
DIAGNOSTIC TESTING AND RISK ASSESSMENT FOR ALZHEIMER'S
DISEASE (BIOCHEMICAL AND GENETIC)
POLICY NUMBER
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20. Bian H, Van Swieten JC, Leight S, et al. CSF biomarkers in frontotemporal lobar
degeneration with known pathology. Neurology. May 6 2008;70(19 Pt 2):1827-1835. PMID
18458217
21. Cure S, Abrams K, Belger M, et al. Systematic literature review and meta-analysis of
diagnostic test accuracy in Alzheimer's disease and other dementia using autopsy as
standard of truth. J Alzheimers Dis. May 19 2014. PMID 24840572
22. de Jong D, Jansen RW, Kremer BP, et al. Cerebrospinal fluid amyloid
beta42/phosphorylated tau ratio discriminates between Alzheimer's disease and vascular
dementia. J Gerontol A Biol Sci Med Sci. Jul 2006;61(7):755-758. PMID 16870640
23. Le Bastard N, Van Buggenhout M, De Leenheir E, et al. LOW specificity limits the use of the
cerebrospinal fluid AB1-42/P-TAU181P ratio to discriminate alzheimer's disease from
vascular dementia. J Gerontol A Biol Sci Med Sci. Aug 2007;62(8):923-924; author reply
924-925. PMID 17702886
24. Sauvee M, DidierLaurent G, Latarche C, et al. Additional use of abeta42/abeta40 ratio with
cerebrospinal fluid biomarkers p-tau and abeta42 increases the level of evidence of
Alzheimer's disease pathophysiological process in routine practice. J Alzheimers Dis.
2014;41(2):377-386. PMID 24614902
25. Zhang J, Zhang CH, Li RJ, et al. Accuracy of urinary AD7c-NTP for diagnosing Alzheimer's
disease: a systematic review and meta-analysis. J Alzheimers Dis. 2014;40(1):153-159.
PMID 24346218
26. Kahle PJ, Jakowec M, Teipel SJ, et al. Combined assessment of tau and neuronal thread
protein in Alzheimer's disease CSF. Neurology. Apr 11 2000;54(7):1498-1504. PMID
10751266
27. Goodman I, Golden G, Flitman S, et al. A multi-center blinded prospective study of urine
neural thread protein measurements in patients with suspected Alzheimer's disease. J Am
Med Dir Assoc. Jan 2007;8(1):21-30. PMID 17210499
28. Ritchie C, Smailagic N, Noel-Storr AH, et al. Plasma and cerebrospinal fluid amyloid beta
for the diagnosis of Alzheimer's disease dementia and other dementias in people with mild
cognitive impairment (MCI). Cochrane Database Syst Rev. 2014;6:CD008782. PMID
24913723
29. Parnetti L, Lanari A, Silvestrelli G, et al. Diagnosing prodromal Alzheimer's disease: role of
CSF biochemical markers. Mech Ageing Dev. Feb 2006;127(2):129-132. PMID 16274728
30. Mattsson N, Zetterberg H, Hansson O, et al. CSF biomarkers and incipient Alzheimer
disease in patients with mild cognitive impairment. JAMA. Jul 22 2009;302(4):385-393.
PMID 19622817
31. Herukka SK, Helisalmi S, Hallikainen M, et al. CSF Abeta42, Tau and phosphorylated Tau,
APOE epsilon4 allele and MCI type in progressive MCI. Neurobiol Aging. Apr
2007;28(4):507-514. PMID 16546302
32. Hansson O, Zetterberg H, Buchhave P, et al. Association between CSF biomarkers and
incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study.
Lancet Neurol. Mar 2006;5(3):228-234. PMID 16488378
Page 34
MEDICAL POLICY
POLICY TITLE
DIAGNOSTIC TESTING AND RISK ASSESSMENT FOR ALZHEIMER'S
DISEASE (BIOCHEMICAL AND GENETIC)
POLICY NUMBER
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33. Ganguli M, Dodge HH, Shen C, et al. Mild cognitive impairment, amnestic type: an
epidemiologic study. Neurology. Jul 13 2004;63(1):115-121. PMID 15249620
34. Ewers M, Buerger K, Teipel SJ, et al. Multicenter assessment of CSF-phosphorylated tau for
the prediction of conversion of MCI. Neurology. Dec 11 2007;69(24):2205-2212. PMID
18071141
35. Andreasen N, Blennow K. CSF biomarkers for mild cognitive impairment and early
Alzheimer's disease. Clin Neurol Neurosurg. Apr 2005;107(3):165-173. PMID 15823670
36. Bouwman FH, Schoonenboom SN, van der Flier WM, et al. CSF biomarkers and medial
temporal lobe atrophy predict dementia in mild cognitive impairment. Neurobiol Aging. Jul
2007;28(7):1070-1074. PMID 16782233
37. Gomar JJ, Bobes-Bascaran MT, Conejero-Goldberg C, et al. Utility of combinations of
biomarkers, cognitive markers, and risk factors to predict conversion from mild cognitive
impairment to Alzheimer disease in patients in the Alzheimer's disease neuroimaging
initiative. Arch Gen Psychiatry. Sep 2011;68(9):961-969. PMID 21893661
38. Vemuri P, Wiste HJ, Weigand SD, et al. MRI and CSF biomarkers in normal, MCI, and AD
subjects: predicting future clinical change. Neurology. Jul 28 2009;73(4):294-301. PMID
19636049
39. Vemuri P, Wiste HJ, Weigand SD, et al. MRI and CSF biomarkers in normal, MCI, and AD
subjects: diagnostic discrimination and cognitive correlations. Neurology. Jul 28
2009;73(4):287-293. PMID 19636048
40. Schmand B, Eikelenboom P, van Gool WA. Value of diagnostic tests to predict conversion to
Alzheimer's disease in young and old patients with amnestic mild cognitive impairment. J
Alzheimers Dis. 2012;29(3):641-648. PMID 22297644
41. Landau SM, Harvey D, Madison CM, et al. Comparing predictors of conversion and decline
in mild cognitive impairment. Neurology. Jul 20 2010;75(3):230-238. PMID 20592257
42. De Meyer G, Shapiro F, Vanderstichele H, et al. Diagnosis-independent Alzheimer disease
biomarker signature in cognitively normal elderly people. Arch Neurol. Aug 2010;67(8):949956. PMID 20697045
43. Ewers M, Walsh C, Trojanowski JQ, et al. Prediction of conversion from mild cognitive
impairment to Alzheimer's disease dementia based upon biomarkers and neuropsychological
test performance. Neurobiol Aging. Jul 2012;33(7):1203-1214. PMID 21159408
44. Richard E, Schmand BA, Eikelenboom P, et al. MRI and cerebrospinal fluid biomarkers for
predicting progression to Alzheimer's disease in patients with mild cognitive impairment: a
diagnostic accuracy study. BMJ Open. 2013;3(6). PMID 23794572
45. Raina P, Santaguida P, Ismaila A, et al. Effectiveness of cholinesterase inhibitors and
memantine for treating dementia: evidence review for a clinical practice guideline. Ann
Intern Med. Mar 4 2008;148(5):379-397. PMID 18316756
46. Kaduszkiewicz H, Zimmermann T, Beck-Bornholdt HP, et al. Cholinesterase inhibitors for
patients with Alzheimer's disease: systematic review of randomised clinical trials. BMJ. Aug
6 2005;331(7512):321-327. PMID 16081444
47. McShane R, Areosa Sastre A, Minakaran N. Memantine for dementia. Cochrane Database
Syst Rev. 2006(2):CD003154. PMID 16625572
Page 35
MEDICAL POLICY
POLICY TITLE
DIAGNOSTIC TESTING AND RISK ASSESSMENT FOR ALZHEIMER'S
DISEASE (BIOCHEMICAL AND GENETIC)
POLICY NUMBER
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48. Schneider LS, Mangialasche F, Andreasen N, et al. Clinical trials and late-stage drug
development for Alzheimer's disease: an appraisal from 1984 to 2014. J Intern Med. Mar
2014;275(3):251-283. PMID 24605808
49. Feldman HH, Ferris S, Winblad B, et al. Effect of rivastigmine on delay to diagnosis of
Alzheimer's disease from mild cognitive impairment: the InDDEx study. Lancet Neurol. Jun
2007;6(6):501-512. PMID 17509485
50. Winblad B, Gauthier S, Scinto L, et al. Safety and efficacy of galantamine in subjects with
mild cognitive impairment. Neurology. May 27 2008;70(22):2024-2035. PMID 18322263
51. Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and donepezil for the treatment of
mild cognitive impairment. N Engl J Med. Jun 9 2005;352(23):2379-2388. PMID 15829527
52. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer's disease:
report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and
Human Services Task Force on Alzheimer's Disease. Neurology. Jul 1984;34(7):939-944.
PMID 6610841
53. Vanderstichele H, Bibl M, Engelborghs S, et al. Standardization of preanalytical aspects of
cerebrospinal fluid biomarker testing for Alzheimer's disease diagnosis: a consensus paper
from the Alzheimer's Biomarkers Standardization Initiative. Alzheimers Dement. Jan
2012;8(1):65-73. PMID 22047631
54. Cordell CB, Borson S, Boustani M, et al. Alzheimer's Association recommendations for
operationalizing the detection of cognitive impairment during the Medicare Annual Wellness
Visit in a primary care setting. Alzheimers Dement. Mar 2013;9(2):141-150. PMID
23265826
55. Gauthier S, Patterson C, Chertkow H, et al. Recommendations of the 4th Canadian
Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD4). Can
Geriatr J. Dec 2012;15(4):120-126. PMID 23259025
56. Rosa-Neto P, Hsiung GY, Masellis M. Fluid biomarkers for diagnosing dementia: rationale
and the Canadian Consensus on Diagnosis and Treatment of Dementia recommendations for
Canadian physicians. Alzheimers Res Ther. Nov 25 2013;5(Suppl 1):S8. PMID 24565514
57. Sorbi S, Hort J, Erkinjuntti T, et al. EFNS-ENS Guidelines on the diagnosis and management
of disorders associated with dementia. Eur J Neurol. Sep 2012;19(9):1159-1179. PMID
22891773
X. POLICY HISTORY
MP-2.050
TOP
CAC 5/27/03
CAC 4/26/05
CAC 6/28/05
CAC 5/30/06
CAC 4/24/07 Consensus
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CAC 5/27/08
CAC 5/26/09
CAC 5/25/10 Adopted BCBSA Criteria
CAC 7/26/2011 Added BCBSA policy statement regarding biochemical markers.
Measurement of cerebrospinal fluid and urinary biomarkers of Alzheimer’s disease is
investigational. Other policy statements unchanged.
CAC 10/30/12 Consensus review. References updated but no changes to the
policy statements. FEP variation added for this review. Codes reviewed
10/26/12
02/27/2013- Admin code changes, deleted codes removed- skb
CAC 9/24/13 Consensus review. References updated but no changes to the
policy statements. Rationale and guidelines added.
CAC 5/20/14 Consensus review. For genetic testing for diagnosis of
alzheimer’s disease, TREM2 added as another example of a test considered
investigational. References and rationale updated. Codes reviewed.
CAC 6/2/15 Consensus review. No changes to the policy statements.
Background, references and rationale updated. Coding reviewed.
CAC 5/31/16 Consensus review. No changes to the policy statements.
Background, references, and rationale updated. Appendix added. Coding
reviewed.
Administrative Update 11/15/16 -Variation reformatting 10/21/16.
TOP
Health care benefit programs issued or administered by Capital BlueCross and/or its subsidiaries, Capital Advantage Insurance
Company®, Capital Advantage Assurance Company® and Keystone Health Plan® Central. Independent licensees of the
BlueCross BlueShield Association. Communications issued by Capital BlueCross in its capacity as administrator of programs
and provider relations for all companies.
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APPENDIX
Appendix Table 1. Categories of Genetic Testing Addressed in Genetic Testing for Alzheimer's
Disease
Category
1. Testing of an affected individual's germline to benefit the individual
1a. Diagnostic
1b. Prognostic
1c. Therapeutic
2. Testing cancer cells from an affected individual to benefit tne individual
2a. Diagnostic
2b. Prognostic
2c. Therapeutic
3. Testing an asymptomatic individual to determine Mure risk of disease
4. Testing of an affected individual's germline to benefit family members
S. Reproductive testing
5a. carrier testing: preconception
Sb. carrier testing: prenatal
5C. In utero testing: aneuploidy
5d. In utero testing: mutations
5e. In utero testing: other
Sf. Preimplantation testing with in vitro fertilization
Addressed
x
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