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)."
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