Medical Policy Medical Policy
Policy Num: 11.003.040
Policy Name: Genetic Testing for Alzheimer Disease
Policy ID: [11.003.040] [Ac / B / M+ / P+] [2.04.13]
Last Review: November 22, 2024
Next Review: November 20, 2025
Related Policies:
11.001.032 - Cerebrospinal Fluid and Urinary Biomarkers of Alzheimer Disease
05.001.046 - Aducanumab for Alzheimer Disease
06.001.053 - Selected Positron Emission Tomography Technologies for Evaluation of Alzheimer Disease
| Population Reference No. | Populations | Interventions | Comparators | Outcomes |
| 1 | Individuals: · Who are asymptomatic and at risk for developing late-onset Alzheimer disease | Interventions of interest are: · Genetic testing | Comparators of interest are: · Standard clinical management without genetic testing | Relevant outcomes include:
|
| 2 | Individuals: · Who are asymptomatic, at risk for developing early-onset Alzheimer disease, and have a known familial variant | Interventions of interest are: · Targeted familial variant testing | Comparators of interest are: · Standard clinical management without genetic testing | Relevant outcomes include:
|
| 3 | Individuals: · Who are asymptomatic, at risk for developing early-onset Alzheimer disease, and have no known familial variant | Interventions of interest are: · Genetic testing | Comparators of interest are: · Standard clinical management without genetic testing | Relevant outcomes include:
|
| 4 | Individuals: · With a clinical diagnosis of mild cognitive impairment or mild dementia associated with Alzheimer disease, who are considering initiation or discontinuation of an FDA-approved amyloid-beta plaque targeting therapy | Interventions of interest are: · Genetic testing | Comparators of interest are: · Standard clinical management without genetic testing | Relevant outcomes include:
|
Alzheimer 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 non-elderly individuals. Early-onset AD has a stronger component of family risk, with clustering in families, thus suggesting an inherited genetic disease-causing variant.
For individuals who are asymptomatic and at risk for developing late-onset Alzheimer disease (AD) who receive genetic testing, the evidence includes studies on gene associations, test accuracy, and effects on health outcomes. Relevant outcomes are test accuracy and validity, change in disease status, health status measures, and quality of life. Many genes, including 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. The current lack of effective methods to prevent the onset of AD limits the clinical benefit for genetic testing. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.
For individuals who are asymptomatic, at risk for developing early-onset, autosomal dominant AD, and have a known familial variant who receive targeted genetic testing, the evidence includes studies on gene associations and test accuracy. Relevant outcomes are test accuracy and validity, change in disease status, change in reproductive decision making, health status measures, and quality of life. Variants in the PSEN1 and PSEN2 and APP genes are known to cause early-onset AD in an autosomal dominant pattern with almost complete penetrance. The clinical validity for autosomal dominant early-onset AD will be nearly certain when a familial pathogenic variant has previously been identified. Outside the reproductive setting when used for prognosis or prediction, there is insufficient evidence to draw conclusions on the benefits of genetic testing for pathogenic variants. Testing a prospective parent, when performed in conjunction with genetic counseling, provides more accurate information to guide reproductive planning than family history alone. Therefore, the clinical utility for the purposes of reproductive decision making has been demonstrated for these tests. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.
For individuals who are asymptomatic, at risk for developing early-onset, autosomal dominant AD, and have no known familial variant who receive genetic testing, the evidence includes studies on gene associations and test accuracy. Relevant outcomes are test accuracy and validity, change in disease status, change in reproductive decision making, health status measures, and quality of life. Variants in the PSEN1, PSEN2, and APP genes are known to cause early-onset AD in an autosomal dominant pattern with almost complete penetrance. The clinical validity for autosomal dominant early-onset AD will be reasonably certain when a variant found in the database of pathogenic PSEN1, PSEN2, and APP variants are identified. Outside the reproductive setting when used for prognosis or prediction, there is insufficient evidence to draw conclusions on the benefits of genetic testing for pathogenic variants. Testing a prospective parent, when performed in conjunction with genetic counseling, provides more accurate information to guide reproductive planning than family history alone. Therefore, the clinical utility for the purposes of reproductive decision making has been demonstrated for these tests. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.
For individuals with a clinical diagnosis of mild cognitive impairment or mild dementia associated with AD who are considering initiation or discontinuation of an FDA-approved amyloid-beta targeting therapy who receive genetic testing, the evidence includes randomized clinical trials. Relevant outcomes are test accuracy and validity, symptoms, change in disease status, functional outcomes, health status measures, quality of life, and treatment-related morbidity and mortality. The incidence of asymptomatic, symptomatic and serious amyloid-related imaging abnormalities (ARIA) following treatment with the amyloid-beta targeting therapiesis significantly higher in APOE ε4 homozygotes compared to heterozygotes and noncarriers. The boxed warnings in the FDA labels for approved amyloid-beta targeting therapies states that testing for APOE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA..The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.
Clinical input was sought to help determine whether the use of genetic testing for those for individuals with early AD who are considering initiation or discontinuation of an FDA-approved amyloid-beta targeting therapy would provide a clinically meaningful improvement in net health outcome. In response to requests, clinical input was received from 3 respondents; 1 physician-level response identified through a specialty society; 2 physician-level responses (joint response) identified through an academic medical center.
For individuals with early AD who are considering initiation or discontinuation of an FDA-approved amyloid-beta targeting therapy who receive genetic testing, clinical input supports this use provides a clinically meaningful improvement in net health outcome with the criteria described.
Further details from clinical input are included in the Appendix.
The objective of this evidence review is to determine whether genetic testing improves the net health outcome in individuals who are asymptomatic and at risk for developing Alzheimer disease, and to guide initiation or management of a U.S. Food and Drug Administration-approved amyloid-beta targeting therapy.
Targeted genetic testing for a known familial variant in the presenilin (PSEN) genes or amyloid-beta precursor protein (APP) gene associated with autosomal dominant early-onset Alzheimer disease may be considered medically necessary in an asymptomatic individual to determine future risk of disease when the following criteria are met:
The individual has a close relative (ie, first- or second-degree relative) with a known familial variant associated with autosomal dominant early-onset Alzheimer disease (see Policy Guidelines) AND
Results of testing will inform reproductive decision making.
Genetic testing for variants in presenilin (PSEN) genes or amyloid-beta precursor protein (APP) gene associated with autosomal dominant early-onset Alzheimer disease may be considered medically necessary in an asymptomatic individual to determine future risk of disease when the following criteria are met:
The individual has a family history of dementia consistent with autosomal dominant Alzheimer disease for whom the genetic status of the affected family members is unavailable, AND
Results of testing will inform reproductive decision making.
Genetic testing for the apolipoprotein E (APOE) gene to guide initiation or management of a U.S. Food and Drug Administration-approved amyloid-beta targeting therapy is considered medically necessary in individuals with mild cognitive impairment or mild dementia associated with Alzheimer disease.
Genetic testing for the risk assessment of Alzheimer disease in asymptomatic individuals is considered investigational in all other situations. Genetic testing includes, but is not limited to, testing for the apolipoprotein E epsilon 4 (APOE ε4) allele or triggering receptor expressed on myeloid cells 2 (TREM2).
Genetic testing for Alzheimer disease (AD) may be offered along with analysis of cerebral spinal fluid levels of the tau protein and amyloid-beta peptide 1-42 (see evidence review 2.04.14). This group of tests may be collectively referred to as the ADmark™ Profile, offered by Athena Diagnostics.
The 2011 guidelines from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors recommended that genetic testing for early-onset, autosomal dominant AD should only occur in the context of genetic counseling with support by someone expert in the area. In asymptomatic patients, a testing protocol based on the 1994 International Huntington Association and World Federation of Neurology Research Group on Huntington’s Chorea guidelines has been recommended.
A family history of autosomal dominant AD is suggested by 3 affected members in 2 generations. Testing for genes associated with early-onset autosomal dominant AD is appropriate for symptomatic individuals with early-onset Alzheimer disease in the setting of a family history of dementia, the setting of an unknown family history (eg, adoption), or for guiding testing of unaffected family members making reproductive decisions. In individuals at risk of early-onset, autosomal dominant AD, ideally, an affected family member should be tested first to identify the familial variant. Additionally, targeted testing of the parents of a proband with early-onset autosomal dominant AD and a confirmed genetic variant to identify mode of transmission (germline versus de novo) may be considered appropriate in some families, such as families with unaffected parents and no affected closely related family members. If no affected family member is available for testing and an asymptomatic individual remains interested in testing to inform reproductive decision making, then in-depth sequencing of the 3 genes (APP, PSEN1, PSEN2) associated with autosomal dominant AD may be indicated.
The lecanemab (LEQEMBI®) and donanemab (KISUNLA™) product labels include a boxed warning regarding the risk of amyloid-related imaging abnormalities (ARIA). The warning states that providers should discuss the potential risk of serious adverse events associated with ARIA with individuals considering treatment. The warning also states that patients who are APOE ε4 homozygotes have a higher incidence of ARIA and testing for APOE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA.
The Human Genome Variation Society nomenclature is used to report information on variants found in deoxyribonucleic acid (DNA) and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (Table PG1). The Society’s nomenclature is recommended by the Human Variome Project, the Human Genome Organization, and by the Human Genome Variation Society itself.
The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table PG2 shows the recommended standard terminology-“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”-to describe variants identified that cause Mendelian disorders.
| Previous | Updated | Definition |
| Mutation | Disease-associated variant | Disease-associated change in the DNA sequence |
| Variant | Change in the DNA sequence | |
| Familial variant | Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives |
| Variant Classification | Definition |
| Pathogenic | Disease-causing change in the DNA sequence |
| Likely pathogenic | Likely disease-causing change in the DNA sequence |
| Variant of uncertain significance | Change in DNA sequence with uncertain effects on disease |
| Likely benign | Likely benign change in the DNA sequence |
| Benign | Benign change in the DNA sequence |
ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.
Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and understanding risk factors can be difficult for some patients; genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing; further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.
See the Codes table for details.
Some Plans may have contract or benefit exclusions for genetic testing.
Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.
Alzheimer disease (AD) is commonly associated with a family history; 40% of patients with AD have a least 1 other afflicted first-degree relative. Numerous genes have been associated with late-onset AD, while variants in chromosomes 1, 14, and 21 have been associated with early-onset familial AD.1,
Individuals with early-onset familial AD (ie, before age 65 years but as early as 30 years) form a small subset of AD patients. Alzheimer disease within families of these patients may show an autosomal dominant pattern of inheritance. Pathogenic variants in 3 genes have been identified in affected families: the amyloid-beta precursor protein (APP) gene, presenilin 1 (PSEN1) gene, and presenilin 2 (PSEN2) gene. APP and PSEN1 variants have 100% penetrance absent death from other causes, while PSEN2 has 95% penetrance. Variants within these genes have been associated with AD; variants in PSEN1 appear to be the most common. While only 3% to 5% of all patients with AD have early-onset disease, pathogenic variants have been identified in 70% or more of these patients. Identifiable genetic variants are, therefore, rare causes of AD.
Testing for the apolipoprotein E epsilon 4 (APOE ε4) allele among patients with late-onset AD and for APP, PSEN1, or PSEN2 pathogenic variants in the rare patient with early-onset AD has 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. Pathogenic variants in PSEN1 and PSEN2 are specific for AD; APP variants are also found in cerebral hemorrhagic amyloidosis of the Dutch type, a disease in which dementia and brain amyloid plaques are uncommon.
The APOE lipoprotein is a carrier of cholesterol produced in the liver and brain glial cells. The APOE gene has 3 alleles-ε2, 3, and 4-with the ε3 allele being the most common. Individuals carry 2 APOE alleles. The presence of at least one, ε4 allele is associated with a 1.2- to 3-fold increased risk of AD, depending on the ethnic group. Among those homozygous for ε4 (»2% of the population), the risk of AD is higher than for those heterozygous for ε4. Mean age of onset of AD is about age 68 years for ε4 homozygotes, about 77 years for heterozygotes, and about 85 years for those with no ε4 alleles. About half of patients with sporadic AD carry a ε4 allele. However, not all patients with the allele develop AD. The ε4 allele represents a risk factor for AD rather than a disease-associated variant. In the absence of APOE testing, first-degree relatives of an individual with sporadic or familial AD are estimated to have a 2- to 4-fold greater risk of developing AD than the general population.2, There is evidence of possible interactions between ε4 alleles and other risk factors for AD (eg, risk factors for cerebrovascular disease such as smoking, hypertension, hypercholesterolemia, diabetes),3, 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 variants in other genes that may increase the risk of AD.
Studies have also identified rs75932628-T, a rare functional substitution for R47H on the triggering receptor expressed on myeloid cells 2 (TREM2), as a heterozygous risk variant for late-onset AD.4,5, On chromosome 6p21.1, at position 47 (R47H), the T allele of rs75932628 encodes a histidine substitute for arginine in the gene that encodes TREM2.
TREM2 is highly expressed in the brain and is known to have a role in regulating inflammation and phagocytosis. TREM2 may serve a protective role in the brain by suppressing inflammation and clearing it of cell debris, amyloids, and toxic products. A decrease in the function of TREM2 would allow inflammation in the brain to increase and may be a factor in the development of AD. The effect size of the TREM2 variant confers a risk of AD that is similar to the APOE ε4 allele, although it occurs less frequently.
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 amyloid-beta 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 the 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 1 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 the 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 diseases, including substantial cerebrovascular disease or dementia with Lewy bodies;
Lack of prominent features of variant frontotemporal dementia or primary progressive aphasia;
No medication used with substantial effects on cognition.
A diagnosis of possible AD dementia is made when the patient meets most of the AD criteria but has an atypical course or an etiologically mixed presentation.6, This may consist of an atypical onset (eg, sudden onset) or atypical progression. A diagnosis of possible AD is also made when there is another potentially causative systemic or neurologic disorder that is not thought to be the primary etiology of dementia.
Mild cognitive impairment is a precursor of AD in many instances. Mild cognitive impairment may be diagnosed when there is a change in cognition, but insufficient impairment for the diagnosis of dementia.8, Features of mild cognitive impairment are evidence of impairment in 1 or more cognitive domains and preservation of independence in functional abilities. In some patients, mild cognitive impairment may be a predementia phase of AD. Patients with mild cognitive impairment may undergo ancillary testing (eg, neuroimaging, laboratory studies, neuropsychological assessment) to rule out vascular, traumatic, and medical causes of cognitive decline and to evaluate genetic factors.
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 cerebrospinal fluid levels of tau protein or amyloid precursor protein, as well as positron emission tomography amyloid imaging. The cerebrospinal fluid tests are considered separately in evidence review 11.001.032. Positron emission tomography amyloid imaging is considered in evidence review 06.001.053.
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing.
In November 2017, the 23andMe Personal Genome Service (PGS) Test with Genetic Health Risk Report for Late-onset Alzheimer Disease was granted a de novo classification by the U.S. Food and Drug Administration (class II with general and special controls, FDA product code: PTA). This is a direct-to-consumer test that has been evaluated by the FDA for accuracy, reliability, and consumer comprehension. This test reports whether an individual has variants associated with late-onset AD by detecting the presence of the APOE ε4 (rs429353) gene variant.
In January 2023, lecanemab (Leqembi; Eisai) was approved by the FDA for the treatment of AD under accelerated approval based on the reduction in amyloid beta plaques observed in patients treated with lecanemab. On July 6, 2023, the FDA converted the accelerated approval of Leqembi to traditional approval for the treatment of AD in patients with mild cognitive impairment or mild dementia stage of disease. The label includes a boxed warning for amyloid related imaging abnormalities (ARIA), in general, and emphasizing that APOE ε4 homozygotes have a higher incidence of ARIA.
In July 2024, donanemab (Kisunla, Eli Lilly) was approved by the FDA via a traditional approval for the treatment of AD in patients with mild cognitive impairment or mild dementia stage of disease. The label includes a boxed warning for amyloid related imaging abnormalities (ARIA), in general, and emphasizing that APOE ε4 homozygotes have a higher incidence of ARIA.
This evidence review was created in July 1999 with searches of the PubMed database. The most recent literature update was performed through May15, 2024.
Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms are better when the test is used to manage the condition than when another test or no test is used to manage the condition.
The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.
Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.
The purpose of genetic testing in individuals who are asymptomatic and at risk for developing late-onset Alzheimer disease (AD) is potentially to inform management decisions such as early treatment or behavioral changes. Asymptomatic patients at risk of late-onset AD are not generally treated with medical therapy but may choose to make behavioral changes associated with reduced risk of AD.
The following PICO was used to select literature to inform this review.
The relevant population of interest is adults who are asymptomatic and at risk for developing late-onset AD due to a family history of AD or dementia.
The test being considered is genetic testing. It can be performed on a number of candidate genes, individually or collectively. Lists of genes associated with AD and testing laboratories in the U.S. are provided on the Genetic Testing Registry website of the National Center for Biotechnology Information.9,
Genetic testing for variants associated with late-onset AD is complex. Referral for genetic counseling is important for the explanation of the genetic disease, heritability, genetic risk, test performance, and possible outcomes.
The following practice is currently being used: standard clinical management without genetic testing.
The general outcomes of interest are a change in disease status, health status measures, and quality of life. Specific outcomes in each of these categories are listed in Table 1.
The potential beneficial outcomes of primary interest would be change in disease status if changes in management or behavior in asymptomatic patients at risk of late-onset AD are initiated that prevent or slow the progression of cognitive decline. Improvement in health status measures is also important.
Potential harmful outcomes are those resulting from a true- or false-positive test result. Patients might suffer from psychological harm or anxiety after receiving positive test results.
| Outcomes | Details |
| Change in disease status | Incidence or time to Alzheimer disease onset; changes in cognitive test scores |
| Health status measures | Activities of daily living or functional scales such as the 36-Item Short-Form Health Survey, Alzheimer Disease Cooperative Study Activities of Daily Living scale, or Disability Assessment for Dementia |
| Quality of life | EuroQoL EQ-5D; measures of anxiety or depression |
Trials of genetic testing in this population have been sparse and generally included short-term outcomes of distress and anxiety measured within a year. Trials of prevention strategies in AD typically span many years to a decade to detect differences in conversion to AD in asymptomatic, at-risk individuals.
For the evaluation of clinical validity of genetic testing for AD, studies that meet the following eligibility criteria were considered:
Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores);
Included a suitable reference standard (describe the reference standard);
Patient/sample clinical characteristics were described;
Patient/sample selection criteria were described.
Diagnostic tests detect the presence or absence of a condition. Surveillance and treatment monitoring are essentially diagnostic tests over a time frame. Surveillance to see whether a condition develops or progresses is a type of detection. Treatment monitoring is also a type of detection because the purpose is to see if treatment is associated with the disappearance, regression, or progression of the condition.
Prognostic tests predict the risk of developing a condition in the future. Tests to predict response to therapy are also prognostic. Response to therapy is a type of condition and can be either a beneficial response or an adverse response. The term predictive test is often used to refer to the response to therapy. To simplify terms, we use prognostic to refer both to predicting a future condition or predicting a response to therapy.
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).
Many studies have examined the association between the apolipoprotein E epsilon 4 allele (APOE ε4) and AD. The Rotterdam and Framingham studies are examples of large observational studies demonstrating the association. The Rotterdam Study was a prospective cohort study in the city of Rotterdam, the Netherlands, with main objectives of investigating risk factors of cardiovascular, neurologic, ophthalmologic, and endocrine diseases in the elderly.10, In a sample of 6852 participants, carriers of a single ε4 allele had a relative risk of developing AD approximately double that of ε3/ε3 carriers. Carriers of the two, ε4 alleles had a relative risk of developing dementia approximately 8 times that of ε3/ε3 carriers. The Framingham Heart Study was a longitudinal cohort study initiated in 1948 in Framingham, Massachusetts, to identify common risk factors for cardiovascular disease.11, In 1030 participants, the relative risk for developing AD was 3.7 (95% confidence interval [CI], 1.9 to 7.5) for carriers of a single ε4 allele and 30.1 (95% CI, 10.7 to 84.4) for carriers with two ε4 alleles compared with those without a ε4 allele. The association between the APOE ε4 allele and 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,
Associations between late-onset AD and more than 20 non-APOE genes have been suggested. Examples of large studies and meta-analyses on these non-APOE genes are discussed below.
Naj et al (2014) published a genome-wide association study of multiple genetic loci in late-onset AD.13, Genetic data from 9162 white participants with AD, from the Alzheimer Disease Genetics Consortium, were assessed for variants at 10 loci significantly associated with risk of late-onset AD. The analysis confirmed the association between APOE and early-onset and found significant associations for the CR1, BIN1, and PICALM genes. 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 the age of onset by 2.45 years.
Lambert et al (2013) published a large meta-analysis of a genome-wide association study of susceptibility loci for late-onset AD in 17,008 AD cases and 37,154 controls of European ancestry.14, Nineteen loci had genome-wide significance in addition to the APOE locus. The researchers confirmed several genes already reported to be associated with AD (ABCA7, BIN1, CD33, CLU, CR1, CD2AP, EPHA1, MS4A6A-MS4A4E, PICALM). New loci located included HLA-DRB5-HLA-DRB1, PTK2B, SORL1, and SLC24A4-RIN3.
Jonsson et al (2013) evaluated 3550 subjects with AD and found a genome-wide association for only 1 marker, the T allele of rs75932628 (excluding the APOE locus and the APP11 A673T variant).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 developing AD of 0.63% (odds ratio [OR], 2.26; 95% CI, 1.71 to 2.98; p=1.13 x10−8). In the control population of 8,888 patients 85 years of age or older without a diagnosis of AD, the TREM2 frequency was 0.46% (OR, 2.92; 95% CI, 2.09 to 4.09; p=3.42 x10−10). In 1236 cognitively intact controls age 85 or older, the frequency of TREM2 decreased to 0.31% (OR, 4.66; 95% CI, 2.38 to 9.14; p=7.39 x10−6). The decrease in TREM2 frequency in cognitively intact elderly patients supports findings associating TREM2 with increasing risk of AD. Guerriero et al (2013) also found a strong association between the TREM2 R47H variant and AD (p=.001).5, Using 3 imputed data sets of a genome-wide association study, the meta-analysis found a significant association between the variant and AD (p=.002). The authors further reported direct genotyping of R47H in 1994 AD patients and 4062 controls, which detected a highly significant association between the variant and AD (OR, 5.05; 95% CI, 2.77 to 9.16; p=9.0 x10−9).
The effects of APOE and ancestry on AD risk in diverse populations continue to be elucidated.15,
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, more effective therapy, or avoid unnecessary therapy or testing.
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).
There are no RCTs comparing outcomes of asymptomatic adults at risk for developing late-onset AD managed with and without genetic testing for AD.
Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.
The Risk Evaluation and Education for Alzheimer’s Disease (REVEAL) study as reported by Chao et al (2008) was designed to examine the consequences of AD risk assessment by APOE genotype.16, Of 289 eligible participants, 162 were randomized (mean age, 52.8 years; 73% female) to risk assessment based on APOE testing plus 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%), change diet (20% vs. 11% and 7%), or change exercise behaviors (8% vs. 4% and 5%), all respectively. There is insufficient evidence to conclude that these short-term behavioral changes would alter clinical outcomes. Green et al (2009) examined anxiety, depression, and test-related distress at 6 weeks, 6 months, and 1 year in the 162 participants randomized in REVEAL.17, However, there were no significant differences between the group that received the results of APOE testing and the group that did not, in changes in anxiety or depression overall, or the subgroup of participants with the APOE ε4 allele. However, the É4 negative participants had significantly lower test-related distress than É4 positive participants (p=.01).
Christensen et al (2016) examined disclosing associations between APOE genotype and AD risk alone versus AD and coronary artery disease (CAD) risk in an equivalence trial from the REVEAL group.18, Two hundred ninety participants were randomized to AD risk disclosure alone or AD plus CAD risk disclosure. The 257 participants who received their genetic information were included in the analyses. Mean anxiety, depression, and test-related distress scores were below cutoffs for mood disorders at all time points in both disclosure groups and were similar to baseline levels. At the 12-month follow-up, both anxiety (measured by the Beck Anxiety Index) and depression (measured by the Center for Epidemiologic Studies Depression Scale) fell within the equivalence margin indicating no difference between disclosure groups. Among participants with a ε4 allele, distress (measured by Impact of Event Scale) was lower at 12 months in AD plus CAD group than in the AD-only group (difference, -4.8; 95% CI, -8.6 to -1.0; p=.031). AD plus CAD participants also reported more health behavior changes than AD-alone participants, regardless of APOE genotype.
There is no evidence that early intervention for asymptomatic disease-associated variant carriers can delay or mitigate future diseases. There are many actions patients can take following knowledge of a disease-associated variant. Changes in lifestyle factors (eg, diet, exercise) and/or incorporation of “brain training” exercises can be made, but there is no evidence that these interventions impact clinical disease.
The APOE ε4 allele is strongly associated with the incidence of and age at onset of AD; many other genes have shown statistical associations with AD incidence and onset, thus demonstrating some degree of clinical validity. However, the clinical sensitivity and specificity of the APOE ε4 allele is poor,19, and there is a lack of evidence on the clinical sensitivity and specificity of other genes.
It is unclear how changes in the management of asymptomatic patients with these genes would improve outcomes. The REVEAL studies found short-term changes in behaviors following disclosure of APOE genetic testing results in high-risk adults with little increase in anxiety or depression overall, although with a possible increase in distress among É4 allele carriers. It is unclear whether these changes in behaviors would improve clinical outcomes or whether there are long-term effects on psychological outcomes among É4 carriers. Therefore, the clinical utility has not been demonstrated for these tests.
Summary of Evidence
For individuals who are asymptomatic and at risk for developing late-onset Alzheimer disease (AD) who receive genetic testing, the evidence includes studies on gene associations, test accuracy, and effects on health outcomes. Relevant outcomes are test accuracy and validity, change in disease status, health status measures, and quality of life. Many genes, including 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. The current lack of effective methods to prevent the onset of AD limits the clinical benefit for genetic testing. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.
| [ ] MedicallyNecessaryï»ż | [X] Investigationalï»ż |
Population Reference No. 2 & 3
The purpose of genetic testing in individuals who are asymptomatic and at risk for developing early-onset AD is to inform management decisions such as initiation of AD therapy and to inform reproductive decision making. Asymptomatic patients at risk for early-onset AD are not generally treated with medical therapy.
The following PICO was used to select literature to inform this review.
The relevant population of interest is adults who are asymptomatic and at risk for developing early-onset AD due to family history of early-onset AD, specifically those with autosomal dominant AD.
Adults with a family history of early-onset AD caused by a known pathogenic amyloid-beta precursor protein (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2) variant would undergo targeted testing for the specific familial variant. In adults with a family history consistent with autosomal dominant AD but for whom the familial variant is unknown, genetic testing can be performed on the 3 genes (APP, PSEN1, PSEN2) individually or collectively. Multiple variants in these genes can cause early-onset AD, so sequencing the entire coding regions is necessary to comprehensively assess risk when the familial variant is unknown.
The following practice is currently being used: targeted familial variant testing for those with a known familial variant and genetic testing for those without a known familial variant.
The general outcomes of interest are a change in disease status, health status measures, quality of life, and changes in reproductive decision making.
The potential beneficial outcome of primary interest would be change in reproductive decision making. Changes in management in asymptomatic patients at risk of AD might be initiated with the intent to prevent or slow the progression of cognitive decline leading to changes in disease status. Improvement in health status measures is also important.
Potential harmful outcomes are those resulting from a true- or a false-positive test result. Patients might suffer from psychological harm or anxiety after receiving positive test results.
Outcomes of reproductive decision making are relevant during child-bearing years for asymptomatic adults at risk.
For the evaluation of clinical validity of genetic testing for AD, studies that meet the following eligibility criteria were considered:
Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores);
Included a suitable reference standard (describe the reference standard);
Patient/sample clinical characteristics were described;
Patient/sample selection criteria were described.
Diagnostic tests detect the presence or absence of a condition. Surveillance and treatment monitoring are essentially diagnostic tests over a time frame. Surveillance to see whether a condition develops or progresses is a type of detection. Treatment monitoring is also a type of detection because the purpose is to see if treatment is associated with the disappearance, regression, or progression of the condition.
Prognostic tests predict the risk of developing a condition in the future. Tests to predict response to therapy are also prognostic. Response to therapy is a type of condition and can be either a beneficial response or an adverse response. The term predictive test is often used to refer to the response to therapy. To simplify terms, we use prognostic to refer both to predicting a future condition or predicting a response to therapy.
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).
In the scenario of targeted testing of individuals with a known familial pathogenic variant, due to nearly complete penetrance of pathogenic variants, an identified carrier will almost certainly develop the disease unless dying at an age preceding disease onset. Therefore, clinical validity is nearly certain.
In the scenario of genetic testing of individuals with a family history consistent with autosomal dominant early-onset AD but in whom a pathogenic variant has not been found, the testing yield is less certain. Genetic testing for PSEN1 is estimated to detect disease-causing variants in 30% to 60% of individuals with familial early-onset AD,20,21, although estimates vary. A number of variants scattered throughout the PSEN1 gene have been reported, requiring sequencing of the entire gene when the first affected member of a family with an autosomal dominant pattern of AD inheritance is tested. Variants in APP and PSEN2 genes account for another 10% to 20% of cases.
Genetic yields may vary by population. Giau et al (2019) reported on 200 patients with clinically diagnosed early-onset AD from Thailand, Malaysia, the Philippines, and Korea who were genetically screened between 2009 and 2018.22, Thirty-two (16%) patients carried pathogenic APP (8/32 [25%]), PSEN1 (19/32 [59%]), or PSEN2 (5/32 [16%]) variants. However, this analysis included possible and probable pathogenic variants in addition to those classified as definite. Overall, approximately 84% (p=.01) of autosomal dominant pedigrees in the tested Asian population were genetically unexplained.
Clinical and phenotypic expressivity is variable, ie, the presence of PSEN1, PSEN2, or APP variants is not useful in predicting the age of onset (although the age of onset is usually similar in affected family members), severity, type of symptoms, or rate of progression in asymptomatic individuals.23,
A study by Cochran et al (2019) confirmed a high diagnostic yield in early-onset or atypical dementia. Fifty percent (16/32) of patients tested harbored 1 or more genetic variants capable of explaining symptoms, including variants in APP. Nine of 32 patients (28%) had a variant defined as pathogenic or likely pathogenic whereas 6 had 1 or more variants with moderate penetrance. The authors noted this supports a potential oligogenic model for early-onset dementia.24,
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, more effective therapy, or avoid unnecessary therapy or testing.
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.
There are no RCTs comparing outcomes of asymptomatic adults at risk for developing early-onset AD managed with and without genetic testing for AD.
Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.
The potential clinical utility of testing is the early identification of asymptomatic patients who are at risk for developing early-onset AD. Genetic testing will in most cases lead to better risk stratification, distinguishing patients who will develop the disease from those who will not. If the early identification of patients at risk leads to interventions to delay or mitigate clinical disease, then the clinical utility would be established. Identification of asymptomatic, young adult carriers could impact reproductive planning. Additionally, clinical utility may be demonstrated if testing leads to informed reproductive planning that improves outcomes. Alternatively, the clinical utility could be demonstrated if knowledge of variant status leads to beneficial changes in psychological outcomes.
A systematic review, reported by Rahman et al (2012), which assessed 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.25,
There is no evidence that early intervention for asymptomatic pathogenic variant carriers can delay or mitigate future diseases. There are many actions patients may take following knowledge of a pathogenic variant: changes in lifestyle factors (eg, diet, exercise) and incorporation of “brain training” exercises; but there is no evidence that these interventions impact clinical disease.
When a known pathogenic variant is identified in a prospective parent, with reasonable certainty, the disease will develop and there is a 50% risk of an affected offspring. For purposes of informing family planning, when a pathogenic variant is detected in a prospective parent, the prospective parent can choose to refrain from having children or choose medically assisted reproduction during which preimplantation testing would allow a choice to avoid an affected offspring. Identification of a pathogenic variant by genetic testing is more accurate than the alternative of obtaining a family history alone. Therefore, testing in the reproductive setting can improve health outcomes.
The clinical validity for autosomal dominant, early-onset AD will be nearly certain when a pathogenic variant has previously been identified in a family pedigree or the variant database.
For those from families with early-onset, familial AD, when a pathogenic familial variant is known or when the family pedigree is consistent with autosomal dominant AD but the affected family members have not been tested to determine the familial variant, testing a prospective parent when performed in conjunction with genetic counseling provides more accurate information to guide reproductive planning than family history alone. Therefore, the clinical utility for the purposes of reproductive decision making has been demonstrated for these tests. It is not clear how a change in the management of asymptomatic patients with these genes would improve outcomes. Outside of the reproductive setting when used for prognosis or prediction, there is insufficient evidence to draw conclusions on the benefits of genetic testing for pathogenic variants.
Summary of Evidence
For individuals who are asymptomatic, at risk for developing early-onset, autosomal dominant AD, and have a known familial variant who receive targeted genetic testing, the evidence includes studies on gene associations and test accuracy. Relevant outcomes are test accuracy and validity, change in disease status, change in reproductive decision making, health status measures, and quality of life. Variants in the PSEN1 and PSEN2 and APP genes are known to cause early-onset AD in an autosomal dominant pattern with almost complete penetrance. The clinical validity for autosomal dominant early-onset AD will be nearly certain when a familial pathogenic variant has previously been identified. Outside the reproductive setting when used for prognosis or prediction, there is insufficient evidence to draw conclusions on the benefits of genetic testing for pathogenic variants. Testing a prospective parent, when performed in conjunction with genetic counseling, provides more accurate information to guide reproductive planning than family history alone. Therefore, the clinical utility for the purposes of reproductive decision making has been demonstrated for these tests. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.
For individuals who are asymptomatic, at risk for developing early-onset, autosomal dominant AD, and have no known familial variant who receive genetic testing, the evidence includes studies on gene associations and test accuracy. Relevant outcomes are test accuracy and validity, change in disease status, change in reproductive decision making, health status measures, and quality of life. Variants in the PSEN1, PSEN2, and APP genes are known to cause early-onset AD in an autosomal dominant pattern with almost complete penetrance. The clinical validity for autosomal dominant early-onset AD will be reasonably certain when a variant found in the database of pathogenic PSEN1, PSEN2, and APP variants are identified. Outside the reproductive setting when used for prognosis or prediction, there is insufficient evidence to draw conclusions on the benefits of genetic testing for pathogenic variants. Testing a prospective parent, when performed in conjunction with genetic counseling, provides more accurate information to guide reproductive planning than family history alone. Therefore, the clinical utility for the purposes of reproductive decision making has been demonstrated for these tests. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.
| [X] MedicallyNecessaryï»ż | [ ] Investigationalï»ż |
The purpose of genetic testing in individuals with mild cognitive impairment or mild dementia associated with AD who are considering or are currently being treated with an FDA-approved amyloid-beta targeting therapy is to inform management decisions such as initiation, discontinuation, or continuation of therapy.
The following PICO was used to select literature to inform this review.
The relevant population of interest is individuals with mild cognitive impairment or mild dementia associated with AD who are being considered for or are currently being treated with an FDA-approved amyloid-beta targeting therapy (eg, lecanemab and donanemab ).
The intervention of interest is genetic testing, used in addition to clinical diagnosis or assessment of cognitive and functional response to therapy, to inform amyloid-beta targeting therapy management decisions (eg, initiation, discontinuation, or continuation of therapy).
The following practice is currently being used: standard clinical management without genetic testing.
The general outcomes of interest are symptoms, change in disease status, functional outcomes, health status measures, quality of life, and treatment-related morbidity and mortality.
The outcome of primary interest would be changes in treatment decision-making that result in beneficial improvements in health status measures, such as the Clinical Dementia Rating-Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory-10 (NPI-10), Alzheimer’s Disease Assessment Scale – Cognitive 13-Item Scale (ADAS-Cog 13), Alzheimer’s Disease Cooperative Study – Activities of Daily Living – Mild Cognitive Impairment (ADCS-ADL-MCI), Alzheimer’s Disease Composite Score (ADCOMS) and other AD-specific assessment scales.
For the evaluation of clinical validity of genetic testing for AD, studies that meet the following eligibility criteria were considered:
Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores);
Included a suitable reference standard (describe the reference standard);
Patient/sample clinical characteristics were described;
Patient/sample selection criteria were described.
Diagnostic tests detect the presence or absence of a condition. Surveillance and treatment monitoring are essentially diagnostic tests over a time frame. Surveillance to see whether a condition develops or progresses is a type of detection. Treatment monitoring is also a type of detection because the purpose is to see if treatment is associated with the disappearance, regression, or progression of the condition.
Prognostic tests predict the risk of developing a condition in the future. Tests to predict response to therapy are also prognostic. Response to therapy is a type of condition and can be either a beneficial response or an adverse response. The term predictive test is often used to refer to the response to therapy. To simplify terms, we use prognostic to refer both to predicting a future condition or predicting a response to therapy.,
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).
Exploratory analyses of pooled safety data from 2 phase 3 trials of a no longer marketed amyloid-beta targeting therapy, aducanumab, indicate that APOE ε4 carrier status is associated with a higher incidence of amyloid-related imaging abnormalities (ARIA).26,27,28, Specifically, the incidence of ARIA-edema was 43 % versus 20%, in APOE ε4 carriers and non-carriers receiving a 10 mg/kg dose of aducanumab, respectively. The overall incidence of any ARIA ranged from 36-41% in the treatment group compared to 10.3% in the placebo group. The clinical effects of ARIA range from asymptomatic to severe. Although the majority of patients were asymptomatic or had symptoms such as headache, confusion, or dizziness that resolved with temporary stoppage of the drug, 6.2% of participants receiving the high dose of aducanumab discontinued the drug due to ARIA compared to 0.6% in the placebo arm.
The majority of ARIA-edema radiographic events occurred early in treatment (within the first 8 doses), although ARIA can occur at any time. Among patients treated with a planned dose of aducanumab 10 mg/kg who had ARIA-edema, the maximum radiographic severity was mild in 30%, moderate in 58%, and severe in 13% of patients (refer to prescribing label for classification of severity of ARIA). Resolution occurred in 68% of ARIA-edema patients by 12 weeks, 91% by 20 weeks, and 98% overall after detection. Ten percent of all patients who received aducanumab 10 mg/kg had more than 1 episode of ARIA-edema. Radiographic severity and symptomatic status were similar for APOE ε4 carriers and non-carriers.
Lecanemab has been evaluated in 2 double-blind RCTs (Study 201 and Study 301/Clarity AD) with samples sizes of 390 and 1795. Both trials reported an approximately 27% statistically significantly slower rate of decline in the full analysis population for the primary cognitive and functional outcome (ADCOMS for Study 201; CDR-SB for Study 301) for lecanemab versus placebo. In the phase 3 Study 301 (Clarity AD), subgroup analyses for the primary and secondary cognitive outcomes were performed by APOE status. Treatment comparisons favored lecanemab in all subgroups across the outcome measures except for the CDR-SB outcome in ApoE ε4 homozygous participants which favored placebo (n=132 vs, 136 in placebo vs. lecanemab). While results for ADAS-Cog 14 and ADCS-ADL-MCI did favor lecanemab in the APOE ε4 homozygous subgroup, the effect size was attenuated compared to APOE ε4 noncarriers and ε4 heterozygous.29,30,
In Study 201, ARIA was observed in about 12% (20/161) of individuals treated with lecanemab 10 mg/kg biweekly compared to 5% (13/245) in the placebo arm. The incidence of ARIA was higher in APOEε4 homozygotes than in heterozygotes and noncarriers among individuals treated with lecanemab. Of the 5 individuals treated with lecanemab who had symptomatic ARIA, 4 were APOE ε4 homozygotes, 2 of whom experienced severe symptoms.31,
In Study 301 (Clarity AD), ARIA was observed in 21% (191/898) of individuals treated with lecanemab compared to 9% (84/897) of individuals on placebo. ARIA incidence was higher in APOE ε4 homozygotes (45% on lecanemab vs. 22% on placebo) compared to heterozygotes (19% on lecanemab vs. 9% on placebo) and noncarriers (13% on lecanemab vs. 4% on placebo). Rates of symptomatic ARIA were 9.2% for homozygotes, 1.7% for heterozygotes, and 1.4% for noncarriers. Serious events of ARIA were reported in 3% of APOE ε4 homozygotes compared to 1% of heterozygotes and noncarriers.31,
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, more effective therapy, or avoid unnecessary therapy or testing.
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.
There are no RCTs comparing health outcomes of patients who are considering or currently undergoing treatment with amyloid-beta targeting therapy with and without genetic testing for APOE carrier status.
Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.
The potential clinical utility of testing is the identification of patients who are at increased risk of ARIA related to treatment with amyloid-beta targeting therapy. Clinical utility may be demonstrated if testing leads to changes in treatment management decisions (eg, initiation, discontinuation, or continuation of therapy) that leads to beneficial health outcomes.
Individuals who are APOE ε4 homozygotes have a higher incidence of ARIA, symptomatic ARIA and recurrent ARIA. The boxed warnings in the FDA labels for lecanemab and donanemab states that testing for APOE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA.
Randomized clinical trials of amyloid-beta targeting therapy for the treatment of mild cognitive impairment or mild dementia associated with Alzheimer disease demonstrated an increased incidence of ARIA following treatment with the amyloid-beta targeting therapy. For lecanemab, ARIA incidence was higher in APOE ε4 homozygotes (45% on lecanemab vs. 22% on placebo) compared to heterozygotes (19% on lecanemab vs. 9% on placebo) and noncarriers (13% on lecanemab vs. 4% on placebo). Rates of symptomatic ARIA were 9.2%, 1.7%, and 1.4%, respectively. Serious events of ARIA were reported in 3% of homozygotes compared to 1% of heterozygotes and noncarriers. Subgroup analyses suggested that the benefit of lecanemab might also be smaller in APOE ε4 homozygotes. Therefore, individuals considering treatment with an amyloid-beta targeting therapy need to be aware of APOE status in order to inform risk discussions. The boxed warnings in the FDA labels for lecanemab and donanemab states that testing for APOE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA.
For individuals with a clinical diagnosis of mild cognitive impairment or mild dementia associated with AD who are considering initiation or discontinuation of an FDA-approved amyloid-beta targeting therapy who receive genetic testing, the evidence includes randomized clinical trials. Relevant outcomes are test accuracy and validity, symptoms, change in disease status, functional outcomes, health status measures, quality of life, and treatment-related morbidity and mortality. The incidence of asymptomatic, symptomatic and serious amyloid-related imaging abnormalities (ARIA) following treatment with the amyloid-beta targeting therapiesis significantly higher in APOE ε4 homozygotes compared to heterozygotes and noncarriers. The boxed warnings in the FDA labels for approved amyloid-beta targeting therapies states that testing for APOE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA..The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.
| [X] MedicallyNecessaryï»ż | [ ] Investigationalï»ż |
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.
Clinical input was sought to help determine whether the use of genetic testing for those for individuals with early AD who are considering initiation or discontinuation of an FDA-approved amyloid-beta targeting therapy would provide a clinically meaningful improvement in net health outcome. In response to requests, clinical input was received from 3 respondents; 1 physician-level response identified through a specialty society; 2 physician-level responses (joint response) identified through an academic medical center.
For individuals with early AD who are considering initiation or discontinuation of an FDA-approved amyloid-beta targeting therapy who receive genetic testing, clinical input supports this use provides a clinically meaningful improvement in net health outcome with the criteria described.
Further details from clinical input are included in the Appendix.
The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.
Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.
The American College of Medical Genetics and Genomics (ACMG) has listed genetic testing for apolipoprotein E (APOE) alleles as 1 of 5 recommendations in the Choosing Wisely initiative.32, 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 late-onset Alzheimer disease (AD), the most common cause of dementia: “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.”
In 2011, the ACMG, jointly with the National Society of Genetic Counselors issued the following joint practice guidelines:2,
“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 video conference) and support by someone with expertise in this area.
Symptomatic patients: Genetic counseling for symptomatic patients should be performed in the presence of the individual’s legal guardian or family member.
Asymptomatic patients: A protocol based on the International Huntington Association and World Federation of Neurology Research Group on Huntington’s Chorea Guidelines is recommended.
DTC [direct-to-consumer] APOE testing is not advised.
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 the setting of an unknown family history (eg, adoption).
Autosomal dominant family history of dementia with one or more cases of EOAD.
A relative with a mutation consistent with EOAD (currently presenilin [PSEN]1/2 or amyloid-beta precursor protein [APP]).
The Alzheimer Disease & Frontotemporal Dementia Mutation Database should be consulted 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 2019, ACMG reaffirmed its position in the original document. However, an addendum was issued clarifying 2 points:33,
Use of the phrase "pathogenic variant" should be adopted rather than the word "mutation" in discussing pathogenic variants related to autosomal dominant EOAD.
Because the original document no longer meets the criteria for an evidence-based practice guideline by either the ACMG or National Society of Genetic Counselors, both societies have since reclassified it as a Practice Resource.
In 2001 (reaffirmed 2004), the American Academy of Neurology made the following guideline recommendations for the diagnosis of dementia:34,
Routine use of APOE genotyping in patients with suspected AD is not recommended at this time.
There are no other genetic markers recommended for routine use in the diagnosis of AD.
In 2018, the National Institute for Health and Care Excellence (NICE) published guidelines on the assessment, management, and support of people living with dementia.35, The guidelines state that APOE genotyping should not be used to diagnose Alzheimer disease.
Not applicable.
There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.
Some currently ongoing and unpublished trials that might influence this review are listed in Table 2.
| NCT No. | Trial Name | Planned Enrollment | Completion Date |
| Ongoing | |||
| NCT00064870 | National Cell Repository for Alzheimer's Disease (NCRAD) | 10,000 | Jul 2026 (recruiting) |
| NCT01760005a | 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 (DIAN-TU) | 490 | Oct 2027 |
| NCT03876314 | The Effect of Physical Activity on Cognition Relative to APOE Genotype (PAAD-2) | 240 | Dec 2023 |
| NCT04241068a | Phase 3b Open-Label, Multicenter, Safety Study of BIIB037 (Aducanumab) in Subjects With Alzheimer's Disease Who Had Previously Participated in the Aducanumab Studies 221AD103, 221AD301, 221AD302 and 221AD205 (EMBARK) | 1696 | Aug 2024 |
| NCT04770220a | A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Efficacy, Safety and Biomarker Effects of ALZ-801 in Subjects With Early Alzheimer's Disease and APOE4/4 Genotype | 300 | Jun 2024 |
| NCT00869817 | Dominantly Inherited Alzheimer Network (DIAN) | 700 | Jul 2025 |
| NCT04680013 | Genetic Studies in Familial Dementia | 20,000 | Nov 2025 |
| NCT03657732 | A Multi-center Longitudinal Cohort Study of Familial Alzheimer's Disease in China (CFAN) | 40,000 | Jan 2038 |
| Unpublished | |||
| NCT03977584a | Tau PET Longitudinal Substudy Associated With: A Double-Blind, Placebo-Controlled Parallel-Group Study in Preclinical PSEN1 E280A Mutation Carriers Randomized to Crenezumab or Placebo, and in Non-randomized, Placebo-treated Non-carriers From the Same Kindred, to Evaluate the Efficacy and Safety of Crenezumab in the Treatment of Autosomal-Dominant Alzheimer's Disease | 150 | Apr 2022 |
| NCT01998841a | A Double-Blind, Placebo-Controlled Parallel-Group Study in Preclinical PSEN1 E280A Mutation Carriers Randomized to Crenezumab or Placebo, and in Non-Randomized, Placebo-Treated Non-Carriers From the Same Kindred, to Evaluate the Efficacy and Safety of Crenezumab in the Treatment of Autosomal-Dominant Alzheimer's Disease | 252 | Aug 2023 |
NCT: national clinical trial. a Denotes industry-sponsored or cosponsored trial.
| Codes | Number | Description |
|---|---|---|
| CPT | 81401 | Molecular pathology procedure, Level 2 (includes APOE) |
| 81405 | Molecular pathology procedure, Level 6 (includes PSEN1) | |
| 81406 | Molecular pathology procedure, Level 7 (includes APP and PSEN2) | |
| HCPCS | S3852 | DNA analysis for APOE epsilon 4 allele for susceptibility to Alzheimer’s disease |
| ICD-10-CM | F03.90- F03.91 | Unspecified dementia code range |
| 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 | |
| Z31.430 | Encounter of female for testing for genetic disease carrier status for procreative management | |
| Z31.440 | Encounter of male for testing for genetic disease carrier status for procreative management | |
| Z82.0 | Family history of epilepsy and other diseases of the nervous system (Conditions classifiable to G00-G99) | |
| ICD-10-PCS | 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 |
| Date | Action | Description |
|---|---|---|
| 11/22/2024 | Annual Review | Policy updated with literature review through May 15, 2024; references added. Clinical input added. Policy statements changed to medically necessary for APOE testing in individuals with MCI or early AD considering treatment with amyloid targeting therapies. All other testing remains investigational. |
| 11/16/2023 | Annual Review | Minor editorial refinements. Policy statements unchanged. |
| 11/11/2022 | Annual Review | Policy updated with literature review through September 12, 2022; reference added. Policy statements unchanged. |
| 11/30/2021 | Policy update | Policy updated with literature review through September 6, 2021; references added. Investigational policy statement added for initiation or management of amyloid-beta targeting therapy. Policy guidelines updated. |
| 05/28/2021 | Annual Review | Policy updated with literature review through January 11, 2021; reference added. Policy statements unchanged. |
| 05/29/2020 | Annual Review | Policy updated with literature review through January 30, 2020; references added. Policy statement unchanged. |
| 05/28/2019 | Annual Revision | New Policy Format. Updated to BCBSA policy and added PICOS with medical necessity. |
| 11/12/2015 | ||
| 09/17/2013 | ||
| 08/03/2011 | ||
| 01/23/2008 | New policy |