Can a new test tell who is prone to side effects? …C0NTINUE READING HERE >>>
Share on PinterestScientists have found a link between genetics and the likelihood of experiencing side effects from Alzheimer’s drugs. RichVintage/Getty ImagesSince July 2023, three anti-amyloid medications have been FDA-approved for the treatment of Alzheimer’s disease with more in development. A potential and serious side effect of anti-amyloid medications is amyloid-related imaging abnormalities (ARIA), where swelling or small bleeding areas of the brain occur. People who carry the apolipoprotein E-E4 gene (APOE-e4) are at a higher risk of developing ARIA when taking anti-amyloid drugs.Researchers have developed a new test to help determine which APOE variants a person may have to potentially predict whether or not they would have a negative reaction to taking anti-amyloid medications.
In July 2023, the U.S. The Food and Drug Administration (FDA) approved lecanemab, sold under the brand name Leqembi — the first anti-amyloid medication for the treatment of Alzheimer’s disease.
Since then, the anti-amyloid medication — donanemab (Kisunla) has also received FDA approval, with more still in development.
A potential and serious side effect of anti-amyloid medications is called amyloid-related imaging abnormalities (ARIA), where swelling or small bleeding areas of the brain occur.
One of the risk factors for developing ARIA is if a person is a positive carrier of the apolipoprotein E-E4 gene (APOE-e4).
To help mitigate any serious side effects from taking anti-amyloid medications, researchers at Revvity’s EUROIMMUN have developed a test to help determine which APOE variants a person may have to potentially predict whether or not they would have a negative reaction to taking these types of drugs.
The study was recently presented at the Association for Diagnostics & Laboratory Medicine (ADLM) 2024, but the results are yet to be published in a peer-reviewed journal.
This new test called the EURORealTime APOE test is a real-time PCR (polymerase chain reaction) test that works by amplifying genomic DNA isolated from whole blood to detect the three APOE alleles that a person has in its genome, Maite Sabalza, PhD, senior scientific affairs manager at EUROIMMUN US and poster presenter of this study at ADLM 2024 told Medical News Today.
“In humans, there are three versions, called alleles, of the gene that makes this protein: APOE-e2, APOE-e3, and APOE-e4. Each person inherits two copies of these genes, one from each parent. These copies can be the same — homozygous, like having two APOE-e4 alleles — or different — heterozygous, like having one APOE-e4 and one APOE-e3 allelles. As a consequence, there are six APOE genotypes that result (in) combinations of the three alleles.”
— Maite Sabalza, PhD
“The APOE-e4 allele is the most important for Alzheimer’s disease risk,” she continued. “About 25% of people in the U.S. have at least one APOE-e4 allele and about 5% have two copies of it. Having two APOE-e4 alleles can increase the risk of developing Alzheimer’s disease by up to 15 times.”
In addition to having an increased risk for Alzheimer’s disease, Sabalza said people with the APOE-e4 allele are also more likely to experience the ARIA side effect when treated with anti-amyloid drugs for Alzheimer’s.
“ARIA involves brain swelling or small bleeding in the brain,” she explained. “This side effect might be more common and severe in people with two copies of the APOE-e4 allele. ARIA can develop within the first few weeks or months of treatment, thereby limiting the optimal dose.”
According to Sabalza, there are two forms of ARIA:
Amyloid-Related Imaging Abnormalities – Edema (ARIA-E) where there is the development of brain swelling or edema, which can lead to symptoms like headache or confusion. Sabalza said experts believe it relates to the removal of amyloid plaques from the brain Amyloid-Related Imaging Abnormalities – Hemorrhage (ARIA-H) occurs when small bleeding events in the brain occur, and imaging can detect them. Researchers also believe these hemorrhages are associated with amyloid-targeting treatments, Sabalza said.
“Although ARIA is typically asymptomatic, serious and life-threatening events may occur, and as such, are included as warnings on prescribing information for anti-amyloid drugs,” Sabalza continued.
“ARIA-E from aducanumab has caused one death, and ARIA-H from donanemab has also resulted in one death. Due to these potential side effects, it is recommended to screen patients for APOE genotypes before starting such treatments to discuss the potential risks of ARIA.”
Right now, Sabalza said the EURORealTime APOE test is currently available for research use only.
“The next steps would involve more research and clinical studies to better understand a person’s risk of developing ARIA when treated with anti-amyloid drugs for Alzheimer’s disease,” she continued.
“Additionally, APOE genotyping can be utilized for patient stratification, helping to determine inclusion criteria for clinical trials as more treatments are developed and additional biomarkers are identified. This approach not only enhances the precision of clinical trials but also ensures that patients receive the most appropriate and effective treatments based on their genetic profile. These steps are crucial for advancing personalized medicine and improving outcomes for patients with Alzheimer’s disease,” she added.
After reviewing this study, Verna Porter, MD, a board certified neurologist and director of the Dementia, Alzheimer’s Disease, and Neurocognitive Disorders at Pacific Neuroscience Institute in Santa Monica, CA told MNT her first reaction is one of cautious optimism at the idea of being able to accurately genotype APOE in patients with this test.
“The EURORealTime APOE test appears to offer a sensitive and reliable method for determining APOE alleles, potentially making it a valuable tool for improving risk stratification for potential anti-amyloid therapeutic treatments,” Porter explained. “This new technique holds significant promise as a means of accurately identifying patients at risk for severe side effects from anti-amyloid drugs.”
“Given the serious nature of side effects like brain swelling (ARIA) and microhemorrhages, having a reliable method to predict these risks is a notable step forward. This advancement may enable us to tailor treatments more precisely, enhancing both the safety and efficacy of Alzheimer’s disease therapies.”
— Verna Porter, MD
“The next steps for this research should include larger, more diverse clinical trials to further validate the test’s accuracy and reliability across different populations,” Porter added. “Additionally, integrating this genotyping test into routine clinical practice and developing guidelines for its use in treatment planning would be beneficial. Exploring the test’s cost-effectiveness and accessibility will also be important to ensure widespread adoption.”
MNT also spoke with Rehan Aziz, MD, program director of the Psychiatry Residency Program associate program director of the Geriatric Psychiatry Fellowship Program at Hackensack Meridian Jersey Shore University Medical Center, and associate professor of Psychiatry and Neurology at Hackensack Meridian School of Medicine in New Jersey about this research.
“In the coming years, there will likely be high utilization of anti-amyloid medications like lecanemab and donanemab in patients with either mild cognitive impairment or mild dementia due to Alzheimer’s disease, as they are the first disease-modifying drugs for Alzheimer’s disease,” Aziz said.
“[Anti-amyloid medications for Alzheimer’s] medications carry a high risk of brain edema and hemorrhages, called ARIA. The risk is highest in people who carry the APOE-e4/e4 genotype. This test is able to determine whether someone is a carrier of this genotype with 100% accuracy, helping doctors appropriately assess risk before prescribing these medications.”
— Rehan Aziz, MD
“It is important for doctors to know if a patient is at high risk for having a bad reaction to the new anti-amyloid drugs in order to prevent or reduce the risk of brain swelling and bleeding. ARIA can be (a) significant event (that) can worsen symptoms, (and) lead to hospitalization or even death. It is also unknown what are the long-term risks of these events. So, the best strategy is to minimize ARIA as much as possible,” he continued.
“Other APOE genotyping methods exist, so in order for this one to be widely adopted it will need to be broadly available, covered by insurance, and cost-effective,” Aziz added.
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