PGx donanemab

APOE encodes apolipoprotein E, a key regulator of amyloid-β metabolism in the brain. The ε4 isoform is the strongest common genetic risk factor for sporadic and is linked to an increased burden of cerebral amyloid angiopathy. Donanemab targets amyloid-β plaques in the brain. Upon binding to amyloid aggregates, it enhances microglial clearance mechanisms, leading to a reduction of plaque burden. The therapeutic goal is to attenuate the rate of cognitive and functional decline in patients with early-stage disease. Treatment may be associated with amyloid-related imaging abnormalities (ARIA), a notable MRI-defined adverse event. ARIA comprises vasogenic edema and effusions (ARIA-E) as well as hemorrhagic changes (ARIA-H), such as cerebral microbleeds and superficial siderosis. ARIA risk rises with ε4 dosage. Due to the elevated risk of severe adverse events observed in APOE ε4 homozygous individuals, treatment is restricted to patients with either one or no APOE ε4 allele. APOE ε4 genotyping therefore represents an essential risk-stratification measure and contributes to safer treatment administration. Pre-treatment cerebral microhaemorrhage and superficial siderosis are further risk factors for ARIA, and baseline superficial siderosis or more than four microhaemorrhages, among other MRI findings, are contraindications in the EU whatever the genotype.

The APOE ε2, ε3 and ε4 isoforms are defined by two coding single-nucleotide variants, rs429358 and rs7412. Genotyping determines both positions and reports the genotype, from which the ApoE ε4 status follows: non-carrier (ε2/ε2, ε2/ε3 or ε3/ε3), heterozygote (one ε4 allele) or homozygote (ε4/ε4), the three groups used in the EU product information.

The result is reported as the APOE genotype and the derived ApoE ε4 status: non-carrier, heterozygote or homozygote. A homozygous result falls outside the European licence, because the EU indication covers only heterozygotes and non-carriers. A heterozygous or non-carrier result is compatible with the indication, provided the other criteria are met, and stratifies the expected ARIA risk.

The assay determines APOE ε2, ε3, and ε4 status based solely on rs429358 and rs7412 and does not identify sequence variants beyond these sites. The genotype is one eligibility criterion among several, alongside confirmed amyloid pathology and the clinical stage. A non-carrier result does not exclude ARIA.

The EU product information makes ApoE ε4 testing mandatory before donanemab is started, after counselling and consent, with a CE-marked in vitro diagnostic of the corresponding intended purpose or, where none is available, an alternative validated test. Treatment is initiated through a central registration system within a controlled access programme. An additional MRI at one year of treatment is foreseen in patients with ARIA risk factors such as ε4 heterozygosity.

For current, actionable guidance, see the and the .

Results are interpreted in the individual clinical context, and the treatment decision rests with the treating physician.

Content reviewed against the current guidelines on 22 October 2026. Pharmacogenomic classifications are periodically revised; the linked databases above hold the day-current version.

• European Medicines Agency. Kisunla (donanemab) EPAR product information, sections 4.1, 4.2, 4.3, 4.4, 4.8, 5.1 and Annex II. Current 26 February 2026. Available from:
• US Food and Drug Administration. KISUNLA (donanemab-azbt) US prescribing information, indications and boxed warning (BLA761248, version 8). Effective 30 December 2025. Available from: