APOE genotyping recommended prior to Alzheimer’s therapy

New disease-modifying drugs are revolutionizing treatment of Alzheimer’s disease but may cause adverse reactions in some patients. The risk of side effects is linked to the apolipoprotein E (APOE) genotype, with homozygous carriers of the APOE ε4 allele at highest risk. APOE genotyping is therefore recommended prior to treatment with anti-amyloid drugs.

Alzheimer’s pathology and diagnostics

Alzheimer’s disease is the most common form of dementia in old age and is characterized by progressive deterioration in cognitive function and behavior. The hallmark of the disease is the buildup of amyloid-beta aggregates in the brain, which disrupt synaptic activity and lead to destruction of neurons. Further features such as neurofibrillary tangles result from an imbalance between amyloid-beta production and clearance¹. Diagnosis of the disease is based on clinical evaluation, imaging methods such as positron emission tomography (PET), and analysis of biomarkers in cerebrospinal fluid (CSF), including beta-amyloid 1-42 to 1-40 ratio, phosphorylated tau, and total tau. These can be measured, for example, by ELISA or chemiluminescence immunoassays (ChLIA). A panel of assays for robust measurement of these biomarkers is offered by EUROIMMUN to support early diagnosis of Alzheimer’s disease.

New era of therapy

Previously, treatment of Alzheimer’s disease focused on symptom relief and behavioural therapy. The last few years have witnessed the introduction of disease-modifying drugs which can measurably slow disease progression. The monoclonal antibody-based treatments target amyloid-beta plaques in the brain, facilitating their removal. To be effective, the drugs must be implemented in the early stage of mild cognitive decline².

Lecanemab (Leqembi^® from Eisai and Biogen) was approved by the U.S. FDA in 2023 for treatment of patients in the early stage of Alzheimer’s disease with confirmed amyloid pathology as demonstrated by PET or CSF testing. The drug has subsequently been approved in further jurisdictions and is under regulatory review in many countries. The licensing of lecanemab by the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) excludes homozygous e4 carriers from receiving the therapy due to the risk of side effects³. In the recommendations of the European Medicines Agency (EMA), treatment with lecanemab is also restricted to patients who carry no or only one copy of the APOEε4 allele⁴. Another new drug, donanemab (Kisunla^TM from Eli Lilly and Company) has also been approved by the U.S. FDA and some other regulatory authorities. Further antibody-based treatments are in the pipeline.

Side effects of anti-amyloid therapies

In some patients, anti-amyloid therapies can induce potentially life-threatening side effects in the form of brain swelling and bleeding. These are known as amyloid-related imaging abnormalities (ARIA) with edema and/ effusion (ARIA-E) or haemorrhagic changes (ARIA-H)^1,5. They are mainly asymptomatic, but may cause symptoms such as headache, confusion, dizziness, nausea, and gait difficulty. A few cases have been fatal.

The risk of developing ARIA is linked to the APOE genotype. The APOE gene encodes a lipid transporter, which plays a role in Alzheimer’s disease by regulating amyloid-beta aggregation and clearance⁶. There are three alleles of APOE denoted ε2, ε3, and ε4, which code for different isoforms of the ApoE protein. Carriers of the ε4 allele have a greater risk of ARIA, with homozygous carriers considered at highest risk. The rate of ARIA amounted to 5.4% in ε4 non-carriers, 10.9% in heterozygotes, and 32.6% in homozygotes. Rates of symptomatic ARIA were 1.4%, 1.7%, and 9.2%, respectively⁷.

Significance of APOE genotyping

A genetic test to determine the APOE genotype is beneficial prior to treatment with anti-amyloid therapies to assess the risk of adverse reactions. Information about the patient’s APOE genotype can guide a more personalized approach to therapy. In patients receiving lecanemab, post-treatment monitoring is directed principally at detecting ARIA, and heightened vigilance for ARIA is recommended in ε4 carriers, especially homozygotes⁷. In countries that restrict treatment with lecanemab to ε4 noncarriers and heterozygotes, an APOE genetic test is a requisite prior to treatment.

APOE genetic variants

Variant ε3 is the most common of the three APOE alleles. ε3/ε3 is considered the normal genotype and is carried by 63% of the population. The ε4 allele occurs at frequencies of 21% for the heterozygous ε3/ε4 form, 2% for ε2/ε4, and 2% for the homozygous ε4/ε4 form. Whereas ε4 is associated with an increased risk of developing Alzheimer’s disease, the ε2 allele is neuroprotective for the disease. 11% of the population carry the heterozygous ε2/ε3 form and 1% the homozygous ε2/ε2 form⁸. The relative risk of developing late-onset Alzheimer’s disease with respect to the genotype is in ascending order: ε2/ε2, ε2/ε3, ε2/ε4, ε3/ε3, ε3/ε4 and ε4/ε4. The ε4 gene dosage not only affects the disease risk, but also the age of disease onset. Homozygous ε4/ε4 carriers develop the disease at an average of 68 years compared to 76 years for heterozygous carriers and 84 years for ε4 noncarriers⁹.

PCR-based genotyping test

A real-time PCR test to determine the APOE genotype has been developed by EUROIMMUN. The multiplex EURORealTime APOE detects the APOEε2, ε3 and ε4 alleles and deduces the six possible genotypes ε2/ε2, ε2/ε3, ε2/ε4, ε3/ε3, ε3/ε4 and ε4/ε4. The test is performed on genomic DNA (gDNA) isolated from EDTA blood samples, and only one reaction is required per patient sample. The assay is compatible with different real-time PCR cyclers. All data are evaluated, documented and archived automatically using the software EURORealTime Analysis, which displays a simple readout of the patient’s APOE genotype result.

Summary

• New disease-modifying drugs for Alzheimer’s disease can slow disease progression in the early stages
• Carriers of two copies of the APOE ε4 allele have an increased risk of adverse reactions (ARIA)
• ε4/ε4 genotype is an exclusion criterion for anti-amyloid therapy in some countries
• APOE genotyping supports proactive evaluation of the individual ARIA risk

*Regulatory status, precise intended use, and product availability must be verified for the user‘s individual jurisdiction. Please inquire.

References

1. Argwal A et al. Amyloid-related imaging abnormalities in Alzheimer Disease treated with anti-amyloid-β therapy. Radiographics 2023 43:9 doi: 10.1148/rg.230009

2. van Dyck CH et al. Lecanemab in Early Alzheimer’s Disease. N Engl J Med 2023; 388:9-21. doi: 10.1056/NEJMoa2212948

3. Press Release from MHRA. Lecanemab licensed for adult patients in the early stages of Alzheimer’s disease - GOV.UK. Retrieved Feb 12, 2024

4. Leqembi – Opinion from European Medicines Agency. Leqembi | European Medicines Agency (EMA) Retrieved Feb 12, 2024

5. Filippi M et al. Amyloid-Related Imaging Abnormalities and β-Amyloid-Targeting Antibodies: A Systematic Review. JAMA Neurol. 2022 Mar 1;79(3):291-304. doi: 10.1001/jamaneurol.2021.5205

6. Sun YY et al. Roles of ApoE4 on the Pathogenesis in Alzheimer’s Disease and the Potential Therapeutic Approaches. Cell Mol Neurobiol 2023 43:3115–3136 doi: 10.1007/s10571-023-01365-1

7. Cummings J et al. Lecanemab: Appropriate use Recommendations. J Prev Alzheimer’s Dis. 2023;10(3):362-377 doi: 10.14283/jpad.2023.30.

8. Wang YY et al. The Proportion of APOE4 Carriers Among Non-Demented Individuals: A Pooled Analysis of 389,000 Community-Dwellers. J Alzheimers Dis. 2021;81(3):1331-1339. doi: 10.3233/JAD-201606. PMID: 33935087.

9. Corder EH et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.Science (1993), 921-923.