Alzheimer’s Drug Trials: Do Drug Companies Warn You About Your Genetic Risk?

Your genetics could make you more vulnerable to the side effects of the new class of Alzheimer’s drugs.

Carrying two copies of the ApoE4 gene increases the risk of side effects, like brain swelling and small brain bleeds (ARIA), from anti-amyloid drugs like Leqembi and Kisunla. While most cases are mild or asymptomatic, a small percentage of people develop serious complications including, in rare cases, death. But when drugmakers started their Phase 3 trials for these drugs in 2019 and 2020, they didn’t tell trial participants whether they carried the risk. 

The evidence linking people with ApoE4 to ARIA wasn’t clear-cut at the time. Some experts who spoke with Being Patient argued that companies didn’t tell participants as a result. Others argued that participants should have been warned anyway. Now that the risk is clear, has genetic disclosure become standard in anti-amyloid trials? We looked into it. Here’s what we learned.

How are drugmakers dealing with genetic disclosure in trials?

Many clinical trials of anti-amyloid drugs that started in the last few years have allowed participants to know whether they carry the ApoE4 gene at the start of the trial.

Roche

Roche is currently testing the anti-amyloid trontinemab in a phase 1/2 trial that started in 2021. Trontinemab is an anti-amyloid antibody with a brain transporter that helps it sneak across the blood-brain barrier. So far, the drug has a very low rate of brain swelling and bleeding, known as amyloid-related imaging abnormalities, or ARIA, but Roche’s spokesperson told Being Patient that the company needs to collect more data before they know for sure.

However, the drug company did not tell participants whether they carried the ApoE4 gene at the start of the study. 

As of 2022, Roche’s anti-amyloid trials allow participants to learn whether they have the ApoE4 gene at the start of trials. That year, Roche ran a Phase 3 trial of the drug ganterenumab, which was terminated early, allowing participants to learn their ApoE4 status — and whether they were at an elevated risk of ARIA risk — at the start of the trial. 

Moving forward, Roche plans to allow participants to learn whether they carry the ApoE4 gene at the start of its current and future anti-amyloid trials. A spokesperson told Being Patient that the link between ApoE4 carriers “has now been established as a key risk factor for ARIA with standard anti-amyloid monoclonal antibodies” for Alzheimer’s disease, necessitating disclosure.

Eisai

Eisai, the drugmaker that developed Leqembi in partnership with Biogen, is currently running two clinical trials. 

The AHEAD 3-45 study, launched midway through 2020, tests whether Leqembi can prevent Alzheimer’s disease in cognitively healthy people who are at risk. The second study, launched last year, assesses whether a combination treatment of Leqembi and an anti-tau antibody can slow the disease in its early stages.

A spokesperson for the company confirmed that both trials allow participants to find out if they carry the ApoE4 gene at the start of the trial. As for future trials, the spokesperson said that the company “is not planning to conduct any additional anti-amyloid trials.”

Eli Lilly

Eli Lilly’s anti-amyloid drug Kisunla was approved by the FDA last year. 

Lilly is now conducting more clinical trials to test Kisunla and a newer anti-amyloid drug called remternetug. One ongoing remternetug trial and one Kisunla trial, started in 2021 and 2024, respectively, allow participants to learn whether or not they have the ApoE4 gene at the start of the trial.

However, three other active trials don’t provide this option to participants:

• TRAILRUNNER ALZ-1, which started in 2022, to test remternetug in early Alzheimer’s disease.
• TRAILBLAZER ALZ-5, which started in 2022, to test Kisunla in early Alzheimer’s outside the U.S. 
• TRAILBLAZER ALZ-6, which started in 2023, to test whether different dosing regimens of Kisunla lead to a lower risk of brain bleeding and swelling

“Lilly’s trial protocols are based on current science, available evidence, the specific patient population, and our ethical and legal responsibilities,” a spokesperson told Being Patient. “We are committed to following the science and will continue to reassess these factors and adapt our protocols as the science evolves.”

AbbVie

AbbVie started a Phase 2 trial of its anti-amyloid drug, ABBV-916, in late 2022 but terminated the development of the drug in 2024 due to what a spokesperson explained were  “strategic business decisions.”

In the trial, ApoE4 status was determined by a third party, and the information was related to the researchers running the trial. It was up to the researchers, not the company, to decide whether or not to share the information with participants. 

“AbbVie was not involved in this disclosure process,” the spokesperson said.

Overall trends

In our previous reporting, neurologists and experts argued that the link between ApoE4 and ARIA wasn’t as apparent when Eisai and Eli Lilly began planning their pivotal Phase 3 trials, which started in 2019 and 2020, respectively. Now, there is little ambiguity.

As a result, almost all the anti-amyloid trials in the U.S. run by the three major drugmakers—Roche, Eisai, and Eli Lilly—allow participants to find out whether they carry a genetic risk before the start of the trial. Eisai started providing proactive disclosure in newly registered trials in 2020, and Roche began in 2022. In contrast, one of Eli Lilly’s trials, which started recruiting participants abroad in 2022, does not provide proactive disclosure. 

Here’s a breakdown of key anti-amyloid trials and whether they disclose genetic risk to participants: