In a recent study, researchers discovered that anti-amyloid drugs used to treat Alzheimer’s can lead to brain atrophy.
Different types of drugs have varying effects on different areas of the brain. Secretase inhibitors caused shrinkage throughout the entire brain, particularly in the hippocampus, while monoclonal antibodies increased the volume of ventricles (hollow parts of the brain). Some monoclonal antibody drugs also caused a decrease in whole-brain volume.
According to the researchers, those who take these drugs end up with dementia-like reduced brain volumes eight months sooner than those who go untreated:
“Mild Cognitively Impaired participants treated with anti-[amyloid] drugs were projected to have a material regression toward brain volumes typical of Alzheimer’s dementia ~8 months earlier than if they were untreated.”
The study was carried out by Francesca Alves, Pawel Kallinowski, and Scott Ayton at the Florey Institute of Neuroscience and Mental Health, University of Melbourne, Australia, and published in the journal Neurology.
A History of Anti-Amyloid Alzheimer’s Drugs
Anti-amyloid Alzheimer’s drugs are designed to reduce amyloid plaques, which have been associated in some studies with Alzheimer’s disease. However, researchers have also noted that amyloid reduction has never been associated with clinical improvement, and dozens of amyloid-reducing drugs have failed to improve clinical outcomes in the past few decades.
These drugs have been in the news repeatedly over the past few years after the FDA approved Biogen’s monoclonal antibody drug aducanumab (Aduhelm). Aducanumab failed its two phase-3 clinical trials, which were terminated early because the drug did not improve clinical outcomes and caused brain bleeding (known as ARIA) in more than a third of patients. However, the FDA worked with Biogen for several years to reanalyze the data from these failed, incomplete trials.
The FDA’s advisory committee voted against the approval of aducanumab (10–0, with one “uncertain”) Nonetheless, the FDA approved the drug. Three of the advisory committee members resigned in protest, with one writing that this was “the worst drug approval decision in recent U.S. history.”
Then, in January, just after a congressional investigation concluded that the FDA acted inappropriately in approving aducanumab, the FDA approved a second controversial drug from Biogen called lecanemab. At the time of its approval, lecanemab was already linked to three deaths from brain bleeding.
A meta-analysis last year, which included the data on aducanumab, found that anti-amyloid drugs did not improve cognition.
The Current Study
The Neurology study by Alves, Kallinowski, and Ayton was a meta-analysis of 31 clinical trials of various anti-amyloid Alzheimer’s drugs. The drugs included secretase inhibitors, monoclonal antibodies (including aducanumab and lecanemab), and drugs they grouped as “other.“
All of the drugs, taken as a whole, reduced brain volume (compared with those who did not take the drugs). However, the researchers noted that the results were broken down by drug class.
The secretase inhibitors reduced hippocampus volume, as well as whole-brain volume. The monoclonal antibodies were found to increase the size of the brain ventricles (a type of atrophy since the ventricles are hollow). The researchers found that this ventricular atrophy was particularly associated with the frequency of ARIA. That is, for monoclonal antibodies, it seems that the drugs that caused the most frequent brain bleeding also caused the most brain atrophy.
The researchers write:
“These data reveal the potential for anti-Aβ therapies to compromise long-term brain health by materially accelerating brain atrophy and provide new insight into the adverse impact of ARIA.”
The study was not designed to assess whether any of these drugs have a clinical effect on cognition or dementia symptoms—only to assess whether they cause brain atrophy. The drugs included in the study had to modify amyloid but were not required actually to have a clinically useful effect.
The group of people most at risk of Alzheimer’s disease are those with the APOE4 gene. In the trials of aducanumab, this group of people—the ones most in need of treatment—were also at the highest risk for brain bleeding. The current study, in which ARIA frequency is linked with brain atrophy, demonstrates that these patients may also be the most likely to experience brain shrinkage after taking these drugs.
According to the researchers, proponents of these drugs argue that the brain atrophy is actually a good thing because it may represent the destruction of amyloid plaque structures. However, Alves, Kallinowski, and Ayton note that the brain shrinkage was not directly linked to the amount of amyloid reduction, and the link to ARIA also clouds the issue. They also suggest that even if this were true, the reduction of functional amyloid—which is present even in the healthy brain—could cause worsened cognition.
Alves, Kallinowski, and Ayton write that, frustratingly, much of the data from the clinical trials of these drugs remains hidden behind the fortress of the pharmaceutical industry. Their requests for this data were not granted. And, they add, it seems that the FDA did not consider this data during the approval process for aducanumab—even though they listed it as “a key pharmacodynamic endpoint.”
The researchers write:
“Potentially adverse volumetric changes caused by anti-Aβ drugs have hardly been investigated (publicly) by the pharmaceutical companies that control the data. We have been unsuccessful in our requests to access these data. There is also no publicly available evidence that the FDA reviewed volumetric data for aducanumab when they approved the drug. The Clinical Review of aducanumab by the FDA’s Centre for Drug Evaluation and Research lists changes in volume to brain structures as a key pharmacodynamic endpoint (safety and efficacy), but they do not comment on the result in an otherwise exhaustive analysis of the trial data.”
The researchers close with some recommendations. First, clinicians should tell patients that brain atrophy is a real risk with these drugs and incorporate that into the risk/benefit analysis of ongoing treatment. And researchers and ethics boards must assess and make public this data to determine the true danger these drugs pose to cognitive functioning.
- Clinicians that prescribe ARIA-inducing anti-Aβ monoclonal antibodies should inform current and new patients that these drugs have been shown to accelerate markers of neurodegeneration (for example, ventricular enlargement).
- Clinicians should review the volumetric data from the clinical trials of ARIA-inducing anti-Aβ monoclonal antibodies when assessing these therapies’ risk/benefit profiles.
- Clinicians should monitor brain volume changes of individual patients that receive ARIA-inducing anti-Aβ monoclonal antibodies to determine whether continued treatment is appropriate.
- The data safety monitoring boards (DSMB) serving current clinical trials of anti-Aβ drugs should review volumetric data to determine if patient safety is at risk, particularly in patients that develop ARIA.
- Ethics boards that approve trials for anti-Aβ drugs should request that volume changes be actively monitored. Long-term follow-up of brain volumes should be factored into the trial designs to determine if brain atrophy is progressive, particularly in patients who develop ARIA.
- Pharmaceutical companies that have conducted trials of anti-Aβ drugs should interrogate prior data on brain volume (e.g., stratifications by ARIA, analysis of additional brain structures), report the findings, and release the data for researchers to investigate.
Alves, F., Kallinowski, P., & Ayton, S. (2023). Accelerated brain volume loss caused by anti–β-amyloid drugs: A systematic review and meta-analysis. Neurology. First published March 27, 2023, DOI: https://doi.org/10.1212/WNL.0000000000207156 (Link)