Alzheimer’s Disease Drugs Aduhelm, Leqembi May Cause Brain Shrinkage: Study

Aduhelm and Leqembi side effects may actually speed up brain atrophy, making Alzheimer’s disease and dementia problems worse, researchers warn.

A controversial new type of Alzheimer’s drug could actually speed up the progression of dementia in some cases by causing brain shrinkage, according to the findings of a new study.

Australian researchers warn that the drugs, Aduhelm and Leqembi, which belong to a subclass of anti-amyloid beta drugs, may cause accelerated dementia in mildly cognitively impaired individuals. Their findings were published last month in the medical journal Neurology.

Aduhelm (aducanumab) became the first novel therapy introduced for the treatment of Alzheimer’s since 2003, after it was granted approval through the FDA’s Accelerated Approval Program in June 2022. The drug is designed to reduce the presence of amyloid beta plaques in the brain, which are believed to be linked to the progression of the disease.

However, the decision to approve Aduhelm immediately raised questions, since it was allowed on the market in the U.S. over the recommendations of an independent FDA advisory panel, which unanimously indicated the drug should not be approved due to questions about Aduhelm’s effectiveness treating Alzheimer’s.

Leqembi (lecanemab), a similar drug, was just approved in January 2023.

Potential Side Effects of Aduhelm and Leqembi

The findings of this new study raise new signals about the potential side effects of Aduhelm and Leqembi, which are especially concerning given existing questions about the lack of benefits provided by the medications.

Researchers from the University of Melbourne, Australia conducted a meta-analysis of clinical trials on this new class of dementia drugs. The report examined 31 clinical trials, looking for changes in the volume of the brain and investigating any Amyloid-Related Imaging Abnormalities (ARIA) detected during those trials. Two types of anti-amyloid beta drugs were compared; secretase inhibitors and ARIA-inducing monoclonal antibodies.

Researchers found patients given the highest doses of these drugs appeared to experience accelerated volume changes to the whole brain, as well as the ventrical and hippocampus portions.

Anti-amyloid drugs are used to reduce amyloid plaques, which some research has linked with Alzheimer’s disease. But reducing amyloid plaque has not been proven to improve the disease, and many anti-amyloid drugs failed to improve the condition in clinical trials.

According to the findings, secretase inhibitors accelerated brain atrophy to the hippocampus by 20% and to the entire brain by 22%. However, ARIA-inducing monoclonal antibodies, which include both Aduhelm and Leqembi, led to roughly 28% more brain shrinkage compared to control groups. Patients using those drugs also experienced a 39% increase in ventricular enlargement or the empty spaces of the brain.

Researchers said the monoclonal drugs led to a level of brain shrinkage, and potential dementia progression, eight months earlier than if they didn’t receive treatment at all. However, they noted the shrinkage was not conclusively linked to the reduction of amyloid plaques.

Critics propose the shrinkage may be linked to a reduction of inflammation in the brain and the clearing of antibodies. That theory is not proven, and brain shrinkage can be an indicator of neurodegeneration and brain damage.

“These findings reveal the potential for anti-amyloid therapies to compromise long-term brain health by accelerating brain atrophy and provide new insight into the adverse impact of ARIA,” wrote study authors.

Aduhelm Approval Controversy

Scrutiny already surrounds Aduhelm after the FDA’s controversial approval of the drug, which came despite evidence from a clinical trial indicating the drug may not be able to slow Alzheimer’s disease. Aduhelm also failed two of the phase-3 clinical trials, which were ended early because the researchers failed to see improvements among patients.

The FDA bucked the unanimous recommendation of its scientific advisory committee and approved the drug for use. Two members of the advisory committee resigned in protest and called the FDA’s move the “worst drug approval decision in recent U.S. history.”

Later, after a congressional committee concluded the FDA approved the drug inappropriately and ignored agency protocol, the agency moved to approve the second Alzheimer’s drug, Leqembi.