Monoclonal antibodies targeting amyloid-β, i.e., lecanemab and donanemab, have recently been approved for treating early Alzheimer’s disease (AD). Though these antibodies are by many considered milestones in AD therapy, clinical approvals have been inconsistent due to ongoing debates over their clinical benefit and safety. The reported cognitive decline slowing is modest and often below the thresholds for clinically significant differences on outcome scales. Moreover, these therapies are linked to adverse effects, including infusion reactions, headaches, and nausea, as well as more serious issues like amyloid-related imaging abnormalities (ARIAs), the long-term impact of which remains unclear. In this Viewpoint article, we highlight three safety concerns: ARIAs, accelerated brain volume loss, and therapy-related deaths. ARIAs occur much more frequently in treated AD patients than in placebo groups, yet their functional consequences remain poorly understood. Evidence also suggests that treatment with anti-amyloid antibodies may lead to more brain tissue loss than placebo treatments, though this has received limited attention in trials and regulatory evaluations. Finally, reliable data on therapy-related mortality is scarce due to insufficient access to detailed clinical and neuropathological information. These issues underscore significant uncertainties in assessing the risk-benefit profile of anti-amyloid therapies. A more systematic investigation—including routine brain volume monitoring, functional PET imaging, and independent death evaluations—is crucial for a comprehensive understanding of both benefits and risks in regulatory and clinical decisions.