CAM 20413

Genetic Testing for Alzheimer’s Disease

Category:Laboratory   Last Reviewed:July 2018
Department(s):Medical Affairs   Next Review:July 2019
Original Date:April 2013    

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

The evidence on genetic testing in individuals who are asymptomatic and at risk for developing Alzheimer's 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.

Background
Alzheimer's 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 — epsilon 2, 3 and 4 — with the epsilon 3 allele being the most common. Individuals carry 2 APOE alleles. The presence of at least 1 epsilon 4 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 (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 at about age 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 2- to 4-fold greater risk of developing AD than the general population.2 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, 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.

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 3 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 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 epsilon 4 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 
    • 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 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
    • 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
    • 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.6 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.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 (e.g., neuroimaging, laboratory studies, 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.6 Other diagnostic tests for AD include CSF levels of tau protein or beta amyloid precursor protein, as well as PET amyloid imaging. The CSF tests are considered separately in evidence review 20414. PET amyloid imaging is considered in evidence review 60155 on Beta Amyloid Imaging With Positron Emission Tomography for Alzheimer's 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.   

Related Policies
20414 Biochemical Markers of Alzheimer’s Disease

60155 Beta Amyloid Imaging with Positron Emission Tomography (PET) for Alzheimer’s Disease

Policy
Genetic testing for familial Alzheimer’s disease (i.e., early-onset dementia not attributable to other factors) is INVESTIGATIONAL under all situations, including, but not limited to, the following:

  1. Symptomatic individuals with early-onset AD (age <65 years) when there is a family history of dementia, OR
  2. Symptomatic individuals with early-onset AD when there is an unknown family history (adoption), OR
  3. Individuals with a family history of autosomal dominant dementia with one or more instances of early-onset AD, OR
  4. Individuals with a first-degree biological relative with a known mutation in the PSEN1, PSEN2 or APP genes
  5. Testing to confirm a diagnosis of Alzheimer’s disease
  6. Testing for familial Alzheimer’s disease in children
  7. Prenatal testing for Alzheimer’s disease
  8. Testing of APOE gene for purposes of Alzheimer’s disease risk assessment     

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 (see evidence review No. 20414). This group of tests may be collectively referred to as the ADmark Profile, offered by Athena Diagnostics (Worcester, MA).  

Genetic Counseling
Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Coding
Effective in 2013, there is CPT coding to more specifically report PSEN and APP testing.

CPT code 81405 includes: 

PSEN1 (presenilin 1) (e.g., Alzheimer's disease), full gene sequence.

CPT code 81406 includes: 

APP (amyloid beta (A4) precursor protein) (e.g., Alzheimer's disease), full gene sequence, and PSEN2 (presenilin 2 (Alzheimer's disease 4)) (e.g., Alzheimer's disease), full gene sequence.

Effective in 2012, there is CPT coding to more specifically report APOE testing.

CPT code 81401 includes:

APOE (apolipoprotein E) (e.g., hyperlipoproteinemia type III, cardiovascular disease, Alzheimer's disease), common variants (eg, *2, *3, *4).

Prior to 2013, the following series of CPT codes were 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. Some codes would have been used more than once in an individual test.  

APOE

83891: Molecular diagnostics; isolation or extraction of highly purified nucleic acid, each nucleic acid type
83892: enzymatic digestion, each enzyme treatment
83894: separation by gel electrophoresis (e.g., agarose, polyacrylamide), each nucleic acid preparation
83898: amplification, target, each nucleic acid sequence
83912: interpretation and report

Mutations of presenilin genes

83891: Molecular diagnostics; isolation or extraction of highly purified nucleic acid, each nucleic acid type
83898: amplification, target, each nucleic acid sequence
83902: reverse transcription
83904: mutation identification by sequencing, single segment, each segment
83912: interpretation and report

Prior to 2013, there was also a CPT genetic testing code modifier that is specific to APOE and should be appended to the above codes for APOE testing – 7A - APOE, commonly called apolipoprotein E (cardiovascular disease or Alzheimer’s disease).

A HCPCS code specific to APOE epsilon 4 allele testing became effective July 1, 2003 –

S3852: DNA analysis for APOE epsilon 4 allele for susceptibility to Alzheimer’s disease.

Effective 01/1/07, there is also a HCPCS code specific to testing for presenilin-1 mutations: 

S3855: Genetic testing for detection of mutations in the presenilin-1 gene

Benefit Application
BlueCard®/National Account Issues
Some Plans may have contract or benefit exclusions for genetic testing.

Rationale
Genetic Testing for Late-Onset Alzheimer's 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, i.e., 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 Alzheimer's 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.11 Genetic data from 9,162 white race participants with AD from the Alzheimer's 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 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.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 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 Gene
Jonsson et al. evaluated 3,550 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 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 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 1,994 AD patients and 4,062 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 address how the use of the TREM2 rs75932628-Tvariant 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.

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 presenilin 1 (PSEN1) detects 30% to 60% of familial early-onset AD. A number of mutations have been reported, scattered throughout the 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 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, i.e., the presence of a PSEN1 mutation 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.17   

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.18 cite a proposed framework by Khoury et al.19 for the continuum of translational research that is required to move genomics research findings in AD to 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 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.

Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 1. 

Table 1. Summary of Key Trials

NCT No. Trial Name Planned Enrollment Completion Date
Ongoing
NCT00064870

National Cell Repository for Alzheimer's Disease (NCRAD)

3,000 June 2016
NCT02198586 Apoe Impact Study on Brain Structure and Function, in a Population 45 to 75 Years Old 700 Dec 2016
NCT01760005 A Phase II/III Randomized, Double-Blind, Placebo-Controlled Multi-Center Study of 2 Potential Disease Modifying Therapies in Individuals at Risk for and With Dominantly Inherited Alzheimer's Disease 210 December 2019
NCT02564692 Alzheimer's Prevention Registry GeneMatch Program 500,000 December 2030

NCT:  national clinical trial.  

Summary of Evidence
The evidence on genetic testing in individuals who are asymptomatic and at risk for developing Alzheimer's 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.  

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 5 recommendations in the Choosing Wisely initiative.13 The recommendation is: "Don’t order APOE genetic testing as a predictive test for Alzheimer's disease."  The stated rationale is that APOE is a susceptibility gene for later-onset Alzheimer's 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 recommendations20:

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

Fourth Canadian Consensus Conference on Diagnosis and Treatment of Dementia
The 2012 Canadian Consensus Conference on 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-consensus-conference-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 "at risk" individuals with an apparent autosomal dominant inheritance where 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:
    • First-degree relatives of an affected individual with the mutation (e.g., children and siblings); 
    • 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;
    • 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;
    • 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);
    • 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 withAPOE 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. DTC APOE testing is not advised.
    • 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.
  • 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's 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.

In 1998, the Alzheimer's Disease Working Group of the Stanford Program in Genomics, Ethics and Society24 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 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 (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.25  

U.S. Preventive Services Task Force Recommendations
Not applicable.

References  

  1. Bird TD. Genetic aspects of Alzheimer disease. Genet Med. 2008;10(4):231-239. PMID
  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. PMID
  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. PMID
  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 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. PMID
  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. PMID
  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):1394-1404. 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-and-genomics/. 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. PMID
  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. PMID
  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. PMID
  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. PMID
  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. PMID
  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 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. PMID
  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%2520and2520students/PhysiciansEducationDay/May72008/new_consensus_guidelines_on_management_of_dementia.ppt&rct=j&frm=1&q=&esrc=s&sa=U&ei=-hqzU5mcLoac8QGWv4DIAQ&ved=0CDMQFjAF&usg=AFQjCNH6omHWOIGe4qzrHAEYS25As6-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. PMID
  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. PMID

 Coding Section

Codes Number Description
CPT    See Policy Guidelines 
ICD-9 Diagnosis   Investigational for all codes
ICD-9 Procedure    
HCPC S3852 DNA analysis for APOE epsilon 4 allele for susceptibilty to Alzheimer's disease
  S3855 Genetic testing for detection of mutations in the presenilin-1 gene
ICD-10-CM (effective 10/01/15)   Investigational for all codes
  F03 Unspecified dementia
  G30.0-G30.9 Alzheimer's disease code range
  G31.1 Senile degeneration of brain, not elsewhere classified
  R41.0 Disorientation, unspecified
  R41.81 Age-related cognitive decline
  Z13.858 Encounter for screening for other nervous system disorders
ICD-10-PCS (effective 10/01/15)   Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.
Type of Service Pathology/Laboratory  
Place of Service Laboratory/Reference Laboratory  

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

Appendix 

Appendix Table 1. Categories of Genetic Testing Addressed in 20413

Category Addressed

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 the individual  
     2a. Diagnostic  
     2b. Prognostic  
     2c. Therapeutic  
3. Testing an asymptomatic individual to determine future risk of disease X
4. Testing of an affected individual’s germline to benefit family members  
5. Reproductive testing  
     5a. Carrier testing: preconception  
     5b. Carrier testing: prenata  
     5c. In utero testing: aneuploidy  
     5d. In utero testing: mutations  
     5e. In utero testing: other  
     5f. Preimplantation testing with in vitro fertilization  

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

History From 2014 Forward     

08/08/2018 

Corrected formatting issues and Last review date. No other changes. 

07/18/2017 

Annual review, reformatting policy statement for clarity, no other changes to policy intent.

04/25/2017 

Updated category to Laboratory. No other changes 

10/04/2016 

Annual review, no change to policy intent. 

10/29/2015 

Annual review, removing the word familial from the policy title, updated policy verbiage for clarity, no change to intent. Updated background, description, regulatory status, rationale and references. Added guidelines and appendix 1. 

10/08/2014

Annual review, no change to policy intent. Updated rationale and references. Added coding section.

 


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