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Anti-Amyloids Linked to Accelerated Brain Atrophy

Anti-amyloid-beta (anti-Aβ) drugs, which are used in the management of Alzheimer’s disease (AD), have the potential to compromise long-term brain health by accelerating brain atrophy, a comprehensive meta-analysis of MRI data from clinical trials suggests.

Depending on the anti-Aβ drug class, these agents can accelerate loss of whole brain and hippocampal volume and increase ventricular volume. This has been shown for some of the beta-secretase inhibitors and with several of the anti-amyloid monoclonal antibodies, researchers note.

“These data warrant concern, but we can’t make any firm conclusions yet. It is possible that the finding is not detrimental, but the usual interpretation of this finding is that volume changes are a surrogate for disease progression,” study investigator Scott Ayton, PhD, The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Australia, told Medscape Medical News.

“These data should be factored into the decisions by clinicians when they consider prescribing anti-amyloid therapies. Like any side effect, clinicians should inform patients regarding the risk of brain atrophy. Patients should be actively monitored for this side effect,” Ayton said.

The study was published online March 27 in Neurology.

Earlier Progression From MCI to AD?

Ayton and colleagues evaluated brain volume changes in 31 clinical trials of anti-Aβ drugs that demonstrated a favorable change in at least one biomarker of pathological Aβ and included detailed MRI data sufficient to assess the volumetric changes in at least one brain region.

A meta-analysis on the highest dose in each trial on the hippocampus, ventricles, and whole brain showed drug-induced acceleration of volume changes that varied by anti-Aβ drug class.

Secretase inhibitors accelerated atrophy in the hippocampus (mean difference –37.1 μL; –19.6% relative to change in placebo) and whole brain (mean difference –3.3 mL; –21.8% relative to change in placebo), but not ventricles.

Conversely, monoclonal antibodies caused accelerated ventricular enlargement (mean difference +1.3 mL; +23.8% relative to change in placebo), which was driven by the subset of monoclonal antibodies that induce amyloid-related imaging abnormalities (ARIA) (+2.1 mL; +38.7% relative to change in placebo). There was a “striking correlation between ventricular volume and ARIA frequency,” the investigators report.

The effect of ARIA-inducing monoclonal antibodies on whole brain volume varied, with accelerated whole brain volume loss caused by donanemab (mean difference –4.6 mL; +23% relative to change in placebo) and lecanemab (–5.2 mL; +36.4% relative to change in placebo). This was not observed with aducanumab and bapineuzumab.

Monoclonal antibodies did not cause accelerated volume loss to the hippocampus regardless of whether they caused ARIA.

The researchers also modeled the effect of anti-Aβ drugs on brain volume changes. In this analysis, participants with mild cognitive impairment (MCI) treated with anti-Aβ drugs were projected to have a “material regression” toward brain volumes typical of AD roughly 8 months earlier than untreated peers.

The data, they note, “permit robust conclusions regarding the effect of anti-Aβ drug classes on different brain structures, but the lack of individual patient data (which has yet to be released) limits the interpretations of our findings.”

“Questions like which brain regions are impacted by anti-Aβ drugs and whether the volume changes are related to ARIA, plaque loss, cognitive/noncognitive outcomes, or clinical factors such as age, sex, and APOE ε4 genotype can and should be addressed with available data,” said Ayton.

Ayton and colleagues call on data safety monitoring boards (DSMBs) for current clinical trials of anti-Aβ drugs to review volumetric data to determine if patient safety is at risk, particularly in patients who develop ARIA.

In addition, they note 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.”

Finally, they add that drug companies that have conducted trials of anti-Aβ drugs should interrogate prior data on brain volume, report the findings, and release the data for researchers to investigate.

“I have been banging on about this for years,” said Ayton. “Unfortunately, my raising of this issue has not led to any response. The data are not available, and the basic questions haven’t been asked (publicly).”

Commendable Research

In an accompanying editorial, Frederik Barkhof, MD, PhD, with Amsterdam University Medical Centers, Netherlands, and David Knopman, MD, with Mayo Clinic Alzheimer’s Disease Research Center, Rochester, Minnesota, write that the investigators should be “commended” for their analysis. 

“The reality in 2023 is that the relevance of brain volume reductions in this therapeutic context remains uncertain,” they write.

“Longer periods of observation will be needed to know whether the brain volume losses continue at an accelerated rate or if they attenuate or disappear. Ultimately, it’s the clinical outcomes that matter, regardless of the MRI changes,” Barkhof and Knopman conclude.

The research was supported by funds from the Australian National Health & Medical Research Council. Ayton has reported being a consultant for Eisai in the past 3 years. Barkhof has reported serving on the DSMB for Prothena and the A45-AHEAD studies; being a steering committee member for Merck, Bayer, and Biogen; and being a consultant for IXICO, Roche, Celltrion, Rewind Therapeutics, and Combinostics. Knopman has reported serving on the DSMD for the Dominantly Inherited Alzheimer Network Treatment Unit study; serving on a DSMB for a tau therapeutic for Biogen (until 2021); being an investigator for clinical trials sponsored by Biogen, Lilly Pharmaceuticals, and the University of Southern California. He has reported serving as a consultant for Roche, Samus Therapeutics, Magellan Health, BioVie, and Alzeca Biosciences; and attending an Eisai advisory board meeting for lecanemab in 2022.

Neurology. Published online March 27, 2023. Article, Editorial

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