Genetic Testing for Familial Alzheimer’s Disease

Name of Policy:

Genetic Testing for Familial Alzheimer’s Disease

Policy #: 011 Latest Review Date: October 2015
Category: Laboratory/Pathology Policy Grade: A

Background/Definitions:

As a general rule, benefits are payable under Blue Cross and Blue Shield of Alabama health
plans only in cases of medical necessity and only if services or supplies are not investigational,
provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be
considered for coverage:

1. The technology must have final approval from the appropriate government regulatory
bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology
on health outcomes;

3. The technology must improve the net health outcome;
4. The technology must be as beneficial as any established alternatives;
5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies,
devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment,
would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an
illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and
2. Clinically appropriate in terms of type, frequency, extent, site and duration and

considered effective for the patient’s illness, injury or disease; and
3. Not primarily for the convenience of the patient, physician or other health care provider;

and
4. Not more costly than an alternative service or sequence of services at least as likely to

produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of
that patient’s illness, injury or disease.

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Description of Procedure or Service:

Alzheimer’s disease (AD) is the most common cause of dementia in elderly patients. Early-onset
AD is much less common, but can occur in non-elderly individuals. For late-onset AD, there is a
component of risk that runs in families, suggesting the contribution of genetic factors. Early
onset Alzheimer’s has a stronger component of family risk, with clustering in families, thus
suggesting an inherited genetic mutation.

Alzheimer’s’ disease (AD) is commonly associated with a family history; 40% of patients with
AD have at least one 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.

Susceptibility Polymorphism at the Apolipoprotein E (APOE) Gene
The APOE lipoprotein is a carrier of cholesterol produced in the liver and brain glial cells. The
APOE gene has three alleles—epsilon 2, 3, and 4—with the epsilon 3 allele being the most
common. Individuals carry two APOE alleles. The presence of at least one epsilon 4 allele is
associated with a 1.2- to three-fold increased risk of AD depending on the ethnic group. Among
those homozygous for epsilon 4 (about 2% of the population), the risk of AD is higher than for
those heterozygous for epsilon 4. The mean age of onset of AD is about 68 years for epsilon 4
homozygotes, about 77 years for heterozygotes, and about 85 years for those with no epsilon 4
alleles. About half of patients with sporadic AD carry an epsilon 4 allele. However, not all
patients with the allele develop AD. The epsilon 4 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 two- to four-fold greater risk of
developing AD than the general population. There is evidence of possible interactions between
epsilon 4 alleles, other risk factors for AD (e.g., risk factors for cerebrovascular disease such as
smoking, hypertension, hypercholesterolemia, and diabetes), 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.

Genetic Mutations
Individuals with early onset familial AD (i.e., 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 three genes have been identified in
affected families: amyloid-beta precursor protein gene (APP), 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 in patients presenting with symptoms suggestive of AD, or a technique for risk
assessment in asymptomatic patients with a family history of AD. Mutations in PSEN1 and

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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 (TREM2)
Gene
Recent studies identified rs75932628-T, a rare functional substitution for R47H of TREM2, as a
heterozygous risk variant for late-onset AD. On chromosome 6p21.1, at position 47 (R47H), the
T allele of rs75932628, encodes a histidine substitute for arginine in the gene that encodes
TREM2.

TREM2 is highly expressed in the brain and is known to have a role in regulating inflammation
and phagocytosis. TREM2 may serve a protective role in the brain by suppressing inflammation
and clearing it of cell debris, amyloids and toxic products. A decrease in the function of TREM2
would allow inflammation in the brain to increase and may be a factor in the development of
AD. The effect size of the TREM2 variant confers a risk of AD that is similar to the APOE
epsilon 4 allele, although it occurs less frequently.

Diagnosis of Alzheimer Disease (AD)
The diagnosis of AD is divided into three categories: possible, probable, and definite AD. 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. 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. 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
• Cognitive impairment established by history from patient and a knowledgeable
informant, plus objective assessment by bedside mental status examination or
neuropsychological testing
• Cognitive impairment involving a minimum of two 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
• 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.

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• Clinical course
• Insidious onset
• Clear-cut history of worsening over time
• Interference with ability to function at work or usual activities
• Decline from previous level of functioning and performing

• Exclusion of other disorders
• Cognitive decline not explained by delirium or major psychiatric disorder
• No evidence of other active neurologic disease, including substantial
cerebrovascular disease or dementia with Lewy bodies.
• Lack of prominent features of variant frontotemporal dementia or primary
progressive aphasia.
• 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. This may consist of an atypical
onset (e.g., 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. Features of MCI are evidence of impairment in one 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 (e.g., neuroimaging,
laboratory studies, and neuropsychological assessment) to rule out vascular, traumatic, and
medical causes of cognitive decline and to evaluate genetic factors.

Biomarker evidence has been integrated into the diagnostic criteria for probable and possible AD
for use in research settings. Other diagnostic tests for AD include cerebrospinal (CSF) fluid
levels of Tau protein or beta-amyloid precursor protein, as well as positron emission tomography
(PET) amyloid imaging.

Policy:

Genetic Testing for the diagnosis or risk assessment of Alzheimer’s disease does not meet
Blue Cross and Blue Shield of Alabama’s medical criteria for coverage and is considered
investigational. Genetic testing includes, but not limited to, testing for the apolipoprotein E
epsilon 4allele, presenilin genes, amyloid precursor gene or TREM2.

Blue Cross and Blue Shield of Alabama does not approve or deny procedures, services, testing,
or equipment for our members. Our decisions concern coverage only. The decision of whether
or not to have a certain test, treatment or procedure is one made between the physician and
his/her patient. Blue Cross and Blue Shield of Alabama administers benefits based on the
member’s contract and corporate medical policies. Physicians should always exercise their best

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medical judgment in providing the care they feel is most appropriate for their patients. Needed
care should not be delayed or refused because of a coverage determination.

Key Points:

The most recent update was performed through September 4, 2015.

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 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, with associations between late-onset Alzheimer disease (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 late-
onset AD. 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 nine 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 (APOE) Gene
The association of the APOE e4 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.

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.

The association of APOE genotype with response to AD therapy has also been examined. The
USA-1 Study group found APOE genotype did not predict therapeutic response. Rigaud et al
followed 117 individuals with AD over 36 weeks in an open-label trial of donepezil; 80 (68%)
completed the trial. They found no statistically significant effect of APOE genotype on change
in cognition (assessed by ADAS-Cog). 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(TREM2) Gene
Jonsson et al evaluated 3,550 subjects with AD and found a genome-wide association with only
one marker, the T allele of rs75932628 (excluding the ApoE locus and the A673T variant in

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APP11). The frequency of rs75932628 (TREM2) was then tested in a general population of

110,050 Icelanders of all ages and 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 8,888
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; p=3.42×10(−10)). In 1,236 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 and colleagues also found a strong association of the R47H TREM2 variant with AD
(p=0,001), Using three 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 1,994 AD patients, and 4,062 controls 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. 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 one-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 endpoint.

No clinical trials were identified that address 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 that patients may take following knowledge of a mutation. Changes in
lifestyle factors such as diet and exercise, and/or incorporation of “brain training” exercises may
occur, but there is no evidence that these types of intervention 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 Alzheimer’s Disease
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.

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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
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, i.e. Sanger sequencing and/or next-generation sequencing.

Clinical Validity
Genetic testing for PSEN1 detects 30–60% of familial early onset AD. A number of mutations
have been reported scattered throughout the presenilin 1 (PSEN1) gene, 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 APP and 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 AD in an unaffected family member from 50% to either 0% or 100%.
Testing for 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.

However, it is not uncommon to discover previously unreported PSEN1 mutations in an
individual, and without additional family information, these 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, defining 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
have small sample sizes and retrospective designs, and the research was conducted in different
countries, which may limit the generalizability of the findings.

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There is no evidence that early intervention for asymptomatic mutation carriers can delay or
mitigate future disease. There are many actions that patients may take following knowledge of a
mutation: changes in lifestyle factors such as diet and exercise, and incorporation of “brain
training” exercises may occur, but there is no evidence that these types of intervention 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 al cite a proposed framework by Khoury and colleagues for the continuum of
translational research that is required to move genomics research findings in Alzheimer’s disease
to clinical and public health applications that benefit population health. The four 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 Alzheimer’s Disease
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.

Summary
The evidence on genetic testing in individuals who are asymptomatic and at risk for developing
Alzheimer disease includes studies on gene associations, test accuracy, and effects on health
outcomes. Relevant outcomes include 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 effect of the technology on health outcomes.

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Practice Guidelines and Position Statements
The American College of Medical Genetics and Genomics
The American College of Medical Genetics and Genomics lists genetic testing for APOE alleles
as one of five recommendations in the Choosing Wisely initiative. 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 Alzheimer disease (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 recommendations:

• Routine use of APOE genotyping in patients with suspected AD is not recommended at
this time (Guideline).

• 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 (EFNS)
The European Federation of Neurological Sciences made the following recommendations:

• 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 pre-
symptomatic testing.
• Routine Apo E genotyping is not recommended.

Fourth Canadian Consensus Conference on Diagnosis and Treatment of Dementia (CCCDTD)
The 2012 Canadian Consensus Conference on Dementia was held in May 2012 to update the
third consensus guidelines referenced below. Previous recommendations were endorsed if there
weren’t any changes in the literature. Full articles written by the CCCDTD workgroups
providing complete background information for the consensus conference are available online at:
www.healthplexus.net/article/2012-canadian-consensus-conference-dementia.

A summary of consensus recommendations from the CCCDTD4 was published by Gauthier and
colleagues in 2012. 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:

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“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 (CCCDTD)
The CCCDTD conference recommended the following predictive genetic testing for
asymptomatic “at risk” 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
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.

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American College of Genetics and the National Society of Genetic Counselors
The American College of Genetics and the National Society of Genetic Counselors issued the
following joint practice guidelines:

• 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.
o Symptomatic patients: Genetic counseling for symptomatic patients should be
performed in the presence of the individual’s legal guardian or family member.
o 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 APOE testing is not advised.
• 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:

o The lifetime risk of AD in the general population is approximately 10 to 12% in a
75–80 year lifespan.

o The effect(s) of ethnicity on risk is still unclear.
o 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:
o 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).
o Autosomal dominant family history of dementia with one or more cases of
EOAD.
o A relative with a mutation consistent with EOAD (currently PSEN1/2 or
APP).

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• 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.
o 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.
o 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.

In 1998, the Alzheimer Disease Working Group of the Stanford Program in Genomics, Ethics,
and Society suggested that “predictive or diagnostic genetic testing for highly penetrant
mutations (e.g., 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 three affected members in two 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 (i.e., 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.

U.S. Preventive Services Task Force Recommendations
Genetic testing for AD is not a preventive service.

Key Words:

Apolipoprotein E (APOE), Gene Testing for Alzheimer’s, presenilin, Gene Testing for
Alzheimer’s, Amyloid Precursor Gene Testing for Alzheimer’s, APOE genetic testing, APOE
alleles, ADmark™ profile

Approved by Governing Bodies:

No U.S. Food and Drug Administration (FDA)-cleared genotyping tests were found. The U.S.
Food and Drug Administration (FDA) has not regulated these tests to date. Thus, genotyping is
offered as a laboratory-developed test. Clinical laboratories may develop and validate tests in-

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An Independent Licensee of the Blue Cross and Blue Shield Association

Medical Policy #011

house (“home-brew”) and market them as a laboratory service; such tests must meet the general
regulatory standards of the Clinical Laboratory Improvement Act (CLIA).

Benefit Application:

Coverage is subject to member’s specific benefits. Group specific policy will supersede this
policy when applicable.

ITS: Covered if covered by the Participating Home Plan
FEP: Special benefit consideration may apply. Refer to member’s benefit plan`FEP does not
consider investigational if FDA approved and will be reviewed for medical necessity.

Current Coding: Molecular pathology procedure, Level 2 (e.g., 2-10 SNPs, 1
methylated variant, or 1 somatic variant [typically using
CPT codes: nonsequencing target variant analysis], or detection of a dynamic
81401 mutation disorder/triplet repeat) – includes APOE (apolipoprotein
E) (e.g., hyperlipoproteinemia type III, cardiovascular disease,
81405 Alzheimer disease), common variants (e.g., *2, *3, *4)
Molecular pathology procedure, Level 6 (e.g., analysis of 6-10
81406 exons by DNA sequence analysis, mutation scanning or
duplication/deletion variants of 11-25 exons) – includes PSEN1
HCPCS: (presenilin 1) (e.g., Alzheimer disease), full gene sequence
Molecular pathology procedure, Level 7 (e.g., analysis of 11-25
S3852 exons by DNA sequence analysis, mutation scanning or
duplication/deletion variants of 26-50 exons, cytogenomic array
analysis for neoplasia) – includes APP (amyloid beta [A4]
precursor protein) (e.g., Alzheimer disease), full gene sequence,
and PSEN2 (presenilin 2 [Alzheimer disease 4]) (e.g., Alzheimer
disease), full gene sequence.

DNA analysis for APOE epsilon 4 allele for susceptibility to
Alzheimer’s disease

Previous Coding: Genetic testing for detection of mutations in the presenilin – 1 gene
(Deleted 01/01/15)
S3855

Genetic testing for Alzheimer’s disease may be offered along with cerebrospinal fluid
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, MA).
(Deleted 01/01/2013)

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Medical Policy #011

A combination of the molecular diagnostic CPT codes (83890-83914) are identified by
Athena diagnostics as those used to identify the multiple laboratory steps in testing for
apolipoprotein epsilon (APOE) alleles or mutations in the presenilin genes. (Deleted
01/01/13)

References:

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 2011; 7(3):270-9. Available online at:
download.journals.elsevierhealth.com/pdfs/journals/1552-
5260/PIIS155252601100104X.pdf. Last accessed August 2015.

2. American College of Medical Genetics and Genomics. Choosing Wisely. 2015;
www.choosingwisely.org/societies/american-college-of-medical-genetics-and-genomics/.
Accessed October, 2015.

3. Bertram L and Tanzi RE. Thirty years of Alzheimer’s disease genetics: The implications of
systematic meta-analyses. Nat Rev Neurosci, October 2008; 9(10): 768-778.

4. Bird TD. Genetic aspects of Alzheimer disease. Genet Med, April 2008; 10(4): 231-239.
5. Bird TD. Gene Reviews: Alzheimer Disease Overview. 2015;

www.ncbi.nlm.nih.gov/books/NBK1161/. Accessed October, 2015.
6. 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.
7. Caselli RJ, Doeck AC, Locke DE et al. Cerebrovascular risk factors and preclinical memory
decline in healthy APOE ε4 homozygotes. Neurology 2011; 76(12):1078-84.
8. Chao S, Roberts JS, Mateau TM, et al. Health behavior changes after genetic risk
assessment for Alzheimer disease: The REVEAL Study. Alzheimer Dis Assoc Disord, Jan-
Mar 2008; 22(1): 94-97.
9. Chertkow H. Diagnosis and treatment of dementia: Introduction. Introducing a series based
on the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia.
CMAJ, January 2008; 178(3): 316-321.
10. 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 2012; 15(4):120-6.
11. Goldman JS, Hahn SE, et al. Genetic counseling and testing for Alzheimer’s disease: Joint
practice guidelines of the American College of Medical Genetics and the National Society
of Genetic Counselors. Genet Med, 2011 Jun; 13(6):597-605.
12. Guerreiro R, Wojtas A, Bras J et al. TREM2 variants in Alzheimer's disease. N Engl J Med
2013; 368(2):117-27.
13. 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):1236–48.
14. 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 [Research Support, N.I.H., Extramural Research Support, Non-U.S.
Gov't]. 2012; 8(1):1-13. Available online at:

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Proprietary Information of Blue Cross and Blue Shield of Alabama
An Independent Licensee of the Blue Cross and Blue Shield Association

Medical Policy #011

www.ncbi.nlm.nih.gov/pmc/articles/PMC3266529/pdf/nihms334821.pdf. Last accessed
August 2015.
15. Jonsson T, Stefansson H, Steinberg S et al. Variant of TREM2 associated with the risk of
Alzheimer's disease. N Engl J Med 2013; 368(2):107-16.
16. 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 2007; 9(10):665-74.
17. Knopman DS, DeKosky ST, Cummings JL, et al. Practice parameter: Diagnosis of
dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the
American Academy of Neurology. Neurology 2001; 56(9): 1143-1153.
18. McConnell LM, Koenig BA, Greely HT and Raffin TA. Genetic testing and Alzheimer
disease: Has the time come? Alzheimer Disease Working Group of the Stanford Program in
Genomics, Ethics & Society. Nature Medicine 1998; 4(7): 757-759.
19. 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; 7(3):263-9. Available online at:
download.journals.elsevierhealth.com/pdfs/journals/1552-
5260/PIIS1552526011001014.pdf. Last accessed August 2015.
20. 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):967–80.
21. 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):1394-1404.
22. 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.
23. Raschetti R, Albanese E, Vanacore N and Maggini M. Cholinesterase inhibitors in mild
cognitive impairment: A systematic review of randomized trials. PLoS Med, November
2007; 4(11): e338.
24. Raskind MA, Peskind ER, Wessel T, et.al. The Galantamine USA-1 Study Group.
Neurology, June 2000; 54(12): 2261-2268.
25. 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, July 2002; 12(5): 415-420.
26. Seshadri S, Fitzpatrick AL, et al. Genome-wide Analysis of Genetic Loci Associated with
Alzheimer’s Disease. JAMA, 2010 May 12; 303(18):1832-1840.
27. 3rd Canadian Consensus Conference on Diagnosis and Treatment of Dementia (approved
July 2007). Available online at //www.cccdtd.ca/. Last accessed August 2015.
28. Tsuang D, Larson EB, Bowen J, et al. The utility of apolipoprotein E genotyping in the
diagnosis of Alzheimer disease in a community-based case series. Arch Neurol, December
1999; 56(12): 1489-1495.
29. Waldemar G, Dubois B, Emere M, Georges J, et al. Recommendations for the diagnosis and
management of Alzheimer’s disease and other disorders associated with dementia: EFNS
guideline. Eur J Neurology, January 2007; 14(1): e1-26.

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An Independent Licensee of the Blue Cross and Blue Shield Association

Medical Policy #011

30. Zetzsche T, Rujescu D, et al. Advances and perspectives from genetic research:
development of biological markers in Alzheimer’s disease. Expert Rev Mol Diagn, 2010
Jul; 10(5):667-90.

Policy History:

Medical Policy Reference Manual, 2.04.13
Medical Policy Group, April 2001 (2)
Medical Policy Administration Committee, July 2001
Medical Policy Group, May 2003
Medical Policy Administration Committee, May 2003
Medical Policy Group, May 2005 (1)
Medical Policy Group, May 2007 (1)
Medical Policy Group, May 2009 (1)
Medical Policy Group, July 2011 (1): Update to Description, Key Points and References
Medical Policy Group, December 2012 (3): 2013 Coding Update – Deleted the following codes:
83891, 83892, 83894, 83896, 83898, 83900, 83901, 83902, 83904, 83907, 83908, 83909, 83912,
83914 effective January 1, 2013; addition of codes 81401, 81405 and 81406
Medical Policy Panel, September 2012
Medical Policy Group, January 2013 (1): Update to Descriptions, Key Points, Coding and
References; no change in policy statement
Medical Policy Panel, September 2013
Medical Policy Group, September 2013 (1): Update to Key Points and References; no change to
policy statement
Medical Policy Panel, September 2014
Medical Policy Group, September 2014(1): Update Key Points; no change to policy statement.
Medical Policy Group, November 2014: 2015 Annual Coding Update. Moved deleted HCPC
code S3855 to previous coding.
Medical Policy Panel, October 2015
Medical Policy Group, October 2015 (3): Updates to Description, Key Points & References; no
change in policy statement. Change to Title removing “Familial”

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-
by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i)
research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date
hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels
of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure
review) in Blue Cross and Blue Shield’s administration of plan contracts.

Page 16 of 16

Proprietary Information of Blue Cross and Blue Shield of Alabama
An Independent Licensee of the Blue Cross and Blue Shield Association

Medical Policy #011