Clinical trials for Alzheimer's drugs Leqembi and Kisunla, developed by Eisai and Eli Lilly respectively, are facing ethical scrutiny over the disclosure of genetic risk information to trial participants. An investigation revealed that critical data regarding the ApoE4 gene and its association with increased risk of brain bleeding (ARIA) was not fully disclosed to volunteers during the trials. This has sparked debate about informed consent and patient safety in Alzheimer's research.
The trials, conducted between 2021 and 2024, aimed to assess the efficacy of these drugs in slowing cognitive decline by targeting amyloid plaques in the brain. However, it was found that participants with the ApoE4 gene, especially those with two copies (homozygotes), were at a significantly higher risk of experiencing ARIA, including brain swelling and hemorrhaging. Despite this, the companies did not routinely inform participants of their ApoE4 status during the trial, a decision now under ethical review.
Ethical Concerns and Informed Consent
The core of the controversy lies in the concept of informed consent. Participants in clinical trials are entitled to comprehensive information about potential risks, benefits, and uncertainties associated with the treatment. Critics argue that withholding ApoE4 status from participants undermined their ability to make fully informed decisions about participating in the trials. Dr. George Perry, editor of the Journal of Alzheimer’s Disease, described the decision as "ethically fraught."
Eli Lilly, in a statement to the Times, indicated that participants were given the option to learn their genetic profiles only after the trial ended, advising them to "assume they have the higher risk" at the outset. Eisai defended their practice by stating that not informing study participants about their ApoE4 genetic test results was consistent with other Alzheimer’s disease clinical trials being conducted at the time.
The Role of ApoE4 and ARIA
The ApoE4 gene is a known risk factor for Alzheimer's disease, and subsequent research has clarified its association with ARIA in individuals undergoing anti-amyloid therapies. While the link between ApoE4 and ARIA was less established during the initial trial phases, accumulating evidence has made it a standard practice to disclose ApoE4 status to potential participants in current trials.
Balancing Scientific Rigor and Patient Safety
The decision to withhold genetic information was reportedly influenced by concerns that disclosing ApoE4 status could introduce bias into the trial results. However, this rationale has been challenged by bioethicists and patient advocates who prioritize patient autonomy and the right to make informed decisions about their health.
Current Practices and Future Directions
Today, it is standard practice to inform participants about their ApoE4 risk. Scott Roberts, a professor at the University of Michigan involved in the REVEAL study, stated, "I’m glad it seems like the field has moved towards this model of disclosure up front."
This shift reflects a growing recognition of the importance of transparency and patient empowerment in clinical research, ensuring that individuals can weigh the potential risks and benefits of participating in Alzheimer's drug trials with full knowledge of their genetic predispositions.
