APOE. Genotyping alleles E2, E3 and E4 (pharmacogenetics) [1 gene]

Allele 4 of the APOE gene has been traditionally referred to in the literature as APOE4, epsilon 4 (APOE ε4), or p.C112R (NP_000032.1: p.Cys130Arg). It represents the best documented genetic risk factor in association with Alzheimer’s disease (AD). However, its presence is neither necessary nor sufficient for disease development. Likewise, its presence or absence does not exclude the possibility that the patient could carry any other genetic alterations that can cause dementia, nor is it useful to differentiate AD from other dementia types.

In patients treated with anti-amyloid beta monoclonal antibodies, the APOE ε4 allele has been described to be associated with an increased risk of amyloid-related imaging abnormalities (ARIA), with a dose-dependent effect according to the number of alleles present (PMID: 40112274; PMID: 38165296).

Due to this increased risk, genotyping of the APOE gene is required before starting treatment with anti-amyloid monoclonal antibodies. In the European Union, United Kingdom, and Australia, these treatments are not indicated in homozygous patients for APOE ε4 due to a higher incidence of ARIA, while in the United States, the FDA has authorized the use of lecanemab and donanemab independently of the APOE genotype (PMID: 40997839; PMID: 37495380).

The APOE genotype provides a complementary value to be considered when diagnosing patients with clinical features compatible with Alzheimer’s disease. Moreover, it is worth mentioning that it can be useful for therapeutic patient management. The use of drugs such as lecanemab is generally not recommended in patients with the APOE4/4 genotype due to the risk of adverse events [https://www.ema.europa.eu/en/medicines/human/EPAR/leqembi].

Although the E4 allele of the APOE gene constitutes the main genetic risk factor for AD, its presence is neither necessary nor sufficient for disease development. Likewise, its presence or absence does not exclude the possibility that the patient could carry any other genetic alterations that can cause dementia, nor is it useful to differentiate AD from other dementia types. Its use for the assessment of asymptomatic patients is generally not recommended.