What are the recommendations and implications for Alzheimer's genetic testing?

From the Guidelines

Genetic testing for Alzheimer's disease should be approached with caution and is generally recommended only for individuals with a strong family history of early-onset Alzheimer's disease (occurring before age 65). Testing should always be accompanied by comprehensive genetic counseling both before and after testing to help individuals understand the implications of results, as emphasized by the Alzheimer's Association clinical practice guideline 1. Currently, testing focuses primarily on mutations in three genes associated with early-onset Alzheimer's: APP, PSEN1, and PSEN2, as well as the APOE gene (particularly the ε4 allele) which increases risk for late-onset Alzheimer's but is not deterministic.

Key Considerations

• The decision to perform genetic testing should be made in partnership with the patient and family after appropriate education regarding the potential implications of such testing for the patient and blood relatives, highlighting the need for specialized expertise and proficiency in genetic counseling 1.
• The psychological impact of learning genetic risk status can be significant, potentially causing anxiety or depression, while results may also affect family planning decisions, insurance coverage, and long-term care planning.
• Currently, there are no proven preventive measures specifically for those with genetic risk, though general recommendations include maintaining cardiovascular health, regular exercise, cognitive stimulation, and a healthy diet.
• The field is evolving rapidly with new treatments like lecanemab and donanemab showing promise in clinical trials, making the landscape of genetic testing implications increasingly complex.

Recommendations for Practice

• Genetic testing for susceptibility loci (e.g., APOE) is not clinically recommended due to limited clinical utility and poor predictive value, as noted in guidelines from the American College of Medical Genetics and the National Society of Genetic Counselors 1.
• Testing for genes associated with early-onset autosomal dominant AD should be offered in specific situations, including a symptomatic individual with early-onset AD or a relative with a mutation consistent with early-onset AD 1.
• 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 1.

Future Directions

• The use of AD biomarkers and communication of results are neither recommended for asymptomatic individuals nor individuals with subjective cognitive decline in clinical practice, particularly because there is no treatment available for preclinical stages 1.
• Professionals are faced with complex and partially conflicting recommendations regarding the diagnostic process, and the uncertainty about reimbursement of biomarker tests often arises, underscoring the need for interdisciplinary perspectives and consensus regarding recommendations for the use of predictive diagnoses in AD 1.

From the Research

Recommendations for Alzheimer's Genetic Testing

• Genetic testing for Alzheimer's disease is available for individuals with a family history of early-onset disease, particularly those with a known mutation in the APP, PSEN1, or PSEN2 genes 2, 3.
• The goal of genetic testing is to identify at-risk individuals and facilitate early and effective treatments, as well as strategies to delay the onset of disease in presymptomatic mutation carriers 2.
• However, genetic testing is not recommended for presymptomatic individuals with a family history of late-onset disease, as the APOE4 allele may only confer greater risk for disease, but its presence is not conclusive for the development of AD 2, 3.

Implications of Alzheimer's Genetic Testing

• Genetic testing for Alzheimer's disease can have significant psychological and behavioral impacts, including anxiety, depression, and distress, particularly if individuals are not adequately prepared or supported 4, 5.
• The majority of individuals who undergo genetic testing for APOE genotype report positive attitudes and interest in testing, with motivations including future planning and learning about their own and their children's risks of developing AD 4.
• Decision aids, such as online tools, can be effective in helping individuals make informed decisions about whether to undergo APOE genetic testing, increasing knowledge and facilitating discussions with healthcare providers 6.

Considerations for Genetic Testing

• Genetic testing for Alzheimer's disease should be performed under guidelines developed by professional organizations, with appropriate pretest and post-test counseling, education, and support 3.
• The interpretation of genetic test results should be done with caution, considering the complexity of the disease and the potential for coexistence of other forms of dementia 2, 3.
• Further research is needed to fully understand the implications of genetic testing for Alzheimer's disease and to develop effective strategies for supporting individuals who undergo testing 4, 5.