Brain volume change following anti-amyloid β immunotherapy for Alzheimer's disease: amyloid-removal-related
Christopher R S Belder1, Delphine Boche2, James A R Nicoll2
1Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London, London, UK; UK Dementia Research Institute at UCL, University College London, London, UK; Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.
Abstract:
Progressive cerebral volume loss on MRI is a hallmark of Alzheimer's disease and has been widely used as an outcome measure in clinical trials, with the prediction that disease-modifying treatments would slow loss. However, in trials of anti-amyloid immunotherapy, the participants who received treatment had excess volume loss. Explanations for this observation range from reduction of amyloid β plaque burden and related inflammatory changes through to treatment-induced toxicity. The excess volume changes are characteristic of only those immunotherapies that achieve amyloid β lowering; are compatible with plaque removal; and evidence to date does not suggest an association with harmful effects. Based on the current evidence, we suggest that these changes can be described as amyloid-removal-related pseudo-atrophy. Better understanding of the causes and consequences of these changes is important to enable informed decisions about treatments. Patient-level analyses of data from the trials are urgently needed, along with longitudinal follow-up and neuroimaging data, to determine the long-term trajectory of these volume changes and their clinical correlates. Post-mortem examination of cerebral tissue from treated patients and evaluation of potential correlation with antemortem neuroimaging findings are key priorities.
Insights
Anti-amyloid immunotherapy in Alzheimer's trials caused unexpected brain volume loss. This "amyloid-removal-related pseudo-atrophy" may reflect plaque reduction, not harm, warranting further investigation.
Area of Science:
- Neurology
- Neuroimaging
- Immunotherapy
Background:
- Progressive cerebral volume loss is a key indicator in Alzheimer's disease (AD) and a common clinical trial outcome measure.
- Anti-amyloid immunotherapy trials have paradoxically shown increased brain volume loss in treated participants.
Purpose of the Study:
- To investigate the nature of increased cerebral volume loss observed in anti-amyloid immunotherapy trials for Alzheimer's disease.
- To propose a novel interpretation of these observed volume changes.
Main Methods:
- Analysis of neuroimaging data from anti-amyloid immunotherapy clinical trials.
- Review of existing evidence regarding treatment effects and potential mechanisms.
Main Results:
- The observed excess volume loss is specific to immunotherapies that effectively lower amyloid-beta (Aβ) plaque burden.
- These volume changes are consistent with plaque removal and do not appear to be associated with harmful effects.
- The phenomenon is termed "amyloid-removal-related pseudo-atrophy".
Conclusions:
- Amyloid-removal-related pseudo-atrophy is a potential explanation for increased brain volume loss in AD immunotherapy trials.
- Further research, including patient-level data analysis and post-mortem studies, is crucial to understand the long-term implications.
- Clarifying these changes is essential for informed treatment decisions in Alzheimer's disease management.
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