Introduction
Anti-amyloid medications have shown a modest slowing of Alzheimer's disease (AD) progression. However, concerns exist regarding sustained benefits, especially due to a paradoxical acceleration of brain volume changes observed in patients. AD is characterized by amyloid-β (Aβ) plaque accumulation, neurodegeneration, brain volume loss, and cognitive decline. Anti-Aβ treatments, such as lecanemab and donanemab, demonstrated modest effects in slowing cognitive deterioration in 18-month clinical trials.
Amyloid-Related Imaging Abnormalities (ARIA)
A common side effect observed in these trials was amyloid-related imaging abnormalities (ARIA). ARIA are MRI-detected effects that present as brain swelling (ARIA-E) or small areas of bleeding (ARIA-H). While often asymptomatic, ARIA can cause symptoms like headache, confusion, or visual disturbances. The long-term effects of ARIA, particularly severe cases, are not yet understood.
Accelerated Brain Volume Changes
Brain volume changes, detectable by MRI, serve as an indicator of AD progression. Anti-Aβ therapies have been associated with accelerated volumetric changes, especially in individuals who develop ARIA. The cause of accelerated brain volume change with these medications remains unclear. While clinical outcomes are prioritized, volume changes are noted as potentially important when the clinical significance of the effect is uncertain. Limited release of these data by study sponsors has contributed to uncertainty for patients, physicians, and researchers.
Proposed Explanations Examined
Plaque Removal Hypothesis
Several explanations have been proposed for the accelerated volume changes. Initially, the clearing of Aβ plaque was suggested as a cause. However, quantitative analysis indicates that the volume of Aβ plaque accounts for a minimal fraction of the observed change. Arguments suggesting that non-Aβ components of plaque contribute to this volume are challenged by the required magnitude of such components. Furthermore, a post-mortem study indicated that anti-Aβ therapies primarily reduce plaque in superficial cortical layers, limiting the potential contribution to overall volume change. Temporal and spatial discrepancies also exist, with plaque loss preceding volumetric change and volume loss occurring in areas with minimal plaque, such as white matter. These findings challenge the hypothesis that Aβ or plaque removal is the primary driver of the observed brain volume changes.
Inflammation Resolution Hypothesis
Another proposed mechanism is the resolution of inflammation. This explanation is complicated by the observation that ARIA, which is an inflammatory reaction, correlates with increased volumetric change. Additionally, post-mortem studies of individuals treated with anti-Aβ therapy have indicated increased inflammation, including activation of the immune complement system and upregulation of specific microglial markers. These findings suggest a potential pathway where inflammation triggered by Aβ clearance may lead to neuronal loss. A study investigating neuronal counts after anti-Aβ therapy reported increased neuronal loss.
Interpretation and Data Needs
Volumetric changes are considered safety signals. In AD research, these changes are typically interpreted as neurodegeneration. The lack of data hinders definitive interpretations. If volumetric change indicates neurodegeneration, it does not necessarily negate the drugs' net benefit. It is possible that the treatment removes dysfunctional neurons or causes collateral cellular damage. Such damage could explain a lack of sustained long-term benefits and may represent a mechanism for refinement to minimize harm.
Call for Data Transparency
Uncertainty regarding the observed volume changes could be reduced by analyzing existing clinical trial data. Such analyses could include examining volumetric changes stratified by ARIA status and APOE genotype, assessing the temporal and regional relationship between volume loss and plaque reduction, and evaluating the connection between volumetric changes and clinical outcomes. Researchers are reiterating a call for pharmaceutical companies to transparently release clinical trial data. Despite the lecanemab clinical trial publication over three years prior, specific MRI volumetric data remain unpublished. While preliminary volumetric analysis for donanemab's phase III trial has been released, detailed regional volumetric changes, ARIA stratifications, and associations with clinical outcomes are not yet reported.
Industry Responsibility
The development of effective therapeutics relies on collaboration among scientists, clinicians, and industry. Transparency and Openness Promotion guidelines support verifiable research through replication, preregistration, and open data. These standards are enforced by major journals to ensure credibility and scientific progress. Academic researchers are considered essential for independent data interpretation, free from commercial influences. The pharmaceutical sector has not fully adopted this transparency in this context. Increased data transparency from industry sponsors could inform therapy delivery, improve understanding of safety profiles, and help identify patients who would benefit most. The nature of the observed volumetric changes—whether a safety signal, a physiological response, or an efficacy marker—remains undetermined. Inaccessible clinical trial datasets restrict scientific debate and guidance for patients and clinicians. Pharmaceutical companies are urged to uphold the same transparency standards as the broader research community.