Recent research by Australian scientists found that anti-amyloid-beta (anti-Aβ) drugs, used to manage Alzheimer’s disease (AD), could compromise long-term brain health by accelerating brain atrophy, “shrinking” the organ.
After a comprehensive meta-analysis of MRI data from clinical trials, the team said that depending on the anti-Aβ drug class, they could speed up loss of whole brain and hippocampal volume as well as increase ventricular volume. This has been shown for some of the beta-secretase inhibitors and with several of the anti-amyloid monoclonal antibodies, they wrote in the study, which was published in Neurology.
“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 is that volume changes are a surrogate for disease progression,” study investigator Scott Ayton, from The Florey Institute of Neuroscience and Mental Health, University of Melbourne, 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, and actively monitor them for this.”
Earlier progression from MCI to AD?
The team evaluated brain volume changes in 31 clinical trials of anti-Aβ drugs that showed a favourable 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 reported.
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 modelled 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 eight 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 (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.
The team calls 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”.
They suggested 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, Dr Frederik Barkhof, with Amsterdam University Medical Centres, Netherlands, and Dr David Knopman, from Mayo Clinic Alzheimer’s Disease Research Centre, 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.”
Study details
Accelerated Brain Volume Loss Caused by Anti–β-Amyloid Drugs: A Systematic Review and Meta-analysis
Francesca Alves, Pawel Kallinowski, Scott Ayton.
Published in Neurology on 27 March 2023.
Abstract
Objectives
To evaluate brain volume changes caused by different sub-classes of anti-amyloid beta (Aβ) drugs trialled in patients with Alzheimer’s disease.
Methods
PubMed, Embase and Clinicaltrial.gov databases were searched for clinical trials of anti-Aβ drugs. This systematic review and meta-analysis included adults enrolled in randomised controlled trials of anti-Aβ drugs (n=8062 to 10279). The inclusion criteria were as follows: (1) randomised controlled trials of patients treated with anti-Aβ drugs that have demonstrated to favourably change at least one biomarker of pathological Aβ; and (2) detailed MRI data sufficient to assess the volumetric changes in at least one brain region. MRI brain volumes were used as the primary outcome measure; brain regions commonly reported include the hippocampus, lateral ventricle and whole brain. Amyloid-Related Imaging Abnormalities (ARIA) were investigated when reported in clinical trials. Of the 145 trials reviewed, 31 were included in the final analyses.
Results
A meta-analysis on the highest dose of each trial on hippocampus, ventricle, and whole brain revealed drug-induced acceleration of volume changes that varied by anti-Aβ drug class. Secretase inhibitors accelerated atrophy to the hippocampus (mean difference: -37.1 µL [-19.6% relative to change in placebo]; 95% confidence interval: -47.0 to -27.1) and whole brain (-3.3mL [-21.8% relative to change in placebo]; 95% confidence interval: -4.1 to 2.5). Conversely, ARIA-inducing monoclonal antibodies accelerated ventricular enlargement (mean difference: +2.1mL [+38.7% relative to change in placebo]; 95% confidence interval: 1.5 to 2.8) where a striking correlation between ventricular volume and ARIA frequency was observed (r=0.86, p=6.22×10-7). Mild Cognitively Impaired participants treated with anti-Aβ drugs were projected to have a material regression toward brain volumes typical of Alzheimer’s dementia ∼8 months earlier than if they were untreated.
Conclusions
These findings reveal the potential for anti-Aβ therapies to compromise long-term brain health by accelerating brain atrophy, and provide new insight into the adverse impact of ARIA. Six recommendations emerge from these findings.
Medscape article – Anti-Amyloids Linked to Accelerated Brain Atrophy
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