Pharmacogenetics or predictive genetics? APOE testing blurs the lines

Abstract

The integration of pharmacogenetics into personalized medicine enables the optimization of drug selection and dosage, maximizing therapeutic benefits while minimizing the risk of adverse drug reactions. The association between APOE alleles and ARIA, a known adverse reaction in Alzheimer's disease patients treated with anti-amyloid monoclonal antibodies, has led to the inclusion of APOE genotyping among conventional pharmacogenetic tests. Given the dual role of APOE alleles, the widespread implementation of this genetic test requires caution and should be accompanied by appropriate genetic counselling. APOE genotyping is uniquely positioned at the intersection of pharmacogenetics and germline testing: it provides insight not only into drug safety (specifically the risk of Amyloid-Related Imaging Abnormalities) but also into familial risk for developing Alzheimer's disease. Carriers of risk alleles, especially homozygotes, face the highest risk and require close monitoring. While APOE genotyping can inform treatment decisions, it also raises ethical concerns due to the broader implications of disclosing genetic risk information for neurodegenerative diseases. Identifying a high-risk APOE genotype in a patient substantially impacts family members. Therefore, patients considered for treatment with anti-amyloid monoclonal antibodies should receive comprehensive pre- and post-test genetic counseling that goes beyond traditional standards, as currently provided for other peculiar tests. Such counseling ensures that patients are adequately informed about potential outcomes, psychological impacts, and familial implications. It also supports ethical decision-making and facilitates truly informed consent, helping to prevent deterministic or overly simplistic interpretations of genetic risk.

Keywords: APOE; ARIA; alzheimer disease; genetic counselling; monoclonal antibodies; pharmacogenetics; predictive test.