Alzheimer’s disease (AD) represents an unprecedented healthcare challenge, with 6.9 million Americans over 65 currently diagnosed. This neurological burden is projected to increase substantially, as epidemiological models predict 13.8 million cases by 2060 (2024 Alzheimer’s disease facts and figures, 2024). The devastating impact of AD extends beyond individual patients to families, healthcare systems, and societies, with global costs exceeding $1 trillion annually (Skaria, 2022).

Despite decades of research, therapeutic options for AD have remained limited, with most available treatments providing only symptomatic relief rather than addressing the underlying pathology (Passeri et al., 2022; van der Flier et al., 2023). The amyloid hypothesis, which posits that β-amyloid (Aβ) accumulation is central to AD pathogenesis, has driven drug development efforts, though many candidates have failed in clinical trials (Selkoe and Hardy, 2016; Wu et al., 2022).

A breakthrough occurred in 2021 with the FDA’s accelerated approval of aducanumab, the first disease-modifying therapy for AD (Tampi et al., 2021). This monoclonal antibody selectively targets and removes aggregated Aβ from the brain, representing a paradigm shift in AD treatment (Ali et al., 2022). The approval, while controversial, opened a new era in AD therapeutics and provided hope for millions of patients and their families.

However, the introduction of aducanumab into clinical practice has raised important safety considerations. The drug’s mechanism of action, involving the clearance of cerebral amyloid, can lead to Amyloid-Related Imaging Abnormalities (ARIA) and other potential adverse effects (Agarwal et al., 2023; Hampel et al., 2023). As real-world use expands, comprehensive understanding of its safety profile becomes increasingly crucial for optimal patient care (Knopman et al., 2021).

Clinical trials of aducanumab provide crucial foundational safety data through rigorous scientific protocols, even with the natural constraints of sample size, study duration and population representation (Padala and Yarns, 2022). The progression from controlled trials to real-world practice represents a natural evolution in drug development, bringing distinct challenges in how we gather and analyze clinical data (Galvin et al., 2024). Real-world evidence is essential for understanding the full spectrum of adverse events and identifying potential risk factors across different patient populations. Recent initiatives, such as the International Collaboration for Alzheimer’s Research and Evaluation in Alzheimer’s Disease (ICARE AD) study, demonstrate the ongoing efforts to gather real-world safety data, despite the inherent complexities of post-marketing surveillance (Heidebrink and Paulson, 2024). Current pharmacovigilance studies, while establishing preliminary insights, need continuous updating as new data become available (Ameen et al., 2024). The evolution of safety monitoring systems, supported by advancing analytical capabilities (Silva et al., 2024), will gradually enhance our understanding of aducanumab’s safety profile in routine clinical practice.

Our study addresses these knowledge gaps through a comprehensive analysis of the FDA Adverse Event Reporting System (FAERS) database, employing multiple complementary analytical approaches. While preclinical animal studies provided initial safety insights, their translational value has inherent limitations, highlighting the critical need for real-world safety assessments (Marshall et al., 2023). This investigation aims to characterize the safety profile of aducanumab in real-world settings, identify potential risk factors, and provide evidence-based guidance for clinical monitoring.

This comprehensive pharmacovigilance analysis of the Food Drug Administration Adverse Event Reporting System (FAERS) database has provided crucial insights into the safety profile of aducanumab in real-world clinical practice. As the first anti-amyloid β monoclonal antibody to receive FDA accelerated approval for Alzheimer’s disease treatment (Cummings et al., 2021), understanding aducanumab’s safety characteristics is paramount for optimal clinical implementation and patient care management.

The adverse events identified in our analysis demonstrate a clear correlation with the drug’s mechanism of action. Aducanumab functions by selectively binding to and facilitating the clearance of amyloid β plaques in the mice brain, representing a significant advancement in disease-modifying therapies for Alzheimer’s disease (Sevigny et al., 2016). The most prominent safety signals observed were Amyloid-Related Imaging Abnormalities (ARIA), specifically ARIA-E (edema) and Amyloid related imaging abnormality-microhaemorrhages and haemosiderin deposits (ARIA-H), which are mechanistically linked to the drug’s effects on cerebral vasculature during amyloid protein clearance (Hampel et al., 2023; Doran and Sawyer, 2024). While these findings align with earlier clinical trial data, our study provides robust confirmation through larger-scale real-world evidence, offering clinicians valuable insights into the practical aspects of aducanumab administration.

A particularly noteworthy finding is the sex-neutral distribution of adverse events, suggesting that aducanumab’s safety profile remains consistent across sex (Schneider, 2020; Choi et al., 2023). This observation contrasts with some previous studies of neurological therapeutics where sex-specific differences were noted, potentially simplifying clinical decision-making processes. Higher adverse event rates were observed in patients ≥75 years, consistent with the typical age distribution of dementia, necessitating closer monitoring in this population (Liew, 2020). The temporal analysis demonstrated that most adverse events manifested within 360 days of treatment initiation, with a median onset time of 146 days, establishing a critical monitoring window for clinical surveillance. This temporal pattern provides clinicians with a clear framework for patient monitoring and risk management strategies.

Our study’s methodological strength lies in its novel application of four complementary disproportionality analysis methods, substantially enhancing the reliability of signal detection. This multi-modal analytical approach, unprecedented in previous aducanumab safety studies, provides a more comprehensive understanding of the drug’s safety profile (Wang et al., 2024). Recent evidence suggests that aducanumab, as a disease-modifying therapeutic agent, may offer enhanced efficacy when administered early in the disease course (Cummings et al., 2023; Ameen et al., 2024). This observation underscores the importance of carefully balancing therapeutic benefits against potential risks, particularly in early-stage Alzheimer’s disease patients. Despite ongoing debates surrounding the amyloid hypothesis, compelling evidence from human genetics, biochemical analyses, histopathological examinations, and animal models strongly supports the pivotal role of β-amyloid in Alzheimer’s disease pathogenesis (Musiek et al., 2021). Notably, extensive studies in transgenic mouse models have demonstrated that aducanumab penetrates the blood-brain barrier, selectively binds to parenchymal Aβ, and substantially reduces both soluble and insoluble Aβ levels in a dose-dependent manner (Sevigny et al., 2016). These preclinical findings align remarkably well with clinical observations, lending further credence to the therapeutic potential of this agent. Proteomic analyses have revealed significant modulation of several key proteins associated with mitochondrial function and metabolism in aducanumab-treated mice (Bastrup et al., 2021), offering fresh insights into the mechanism of action. Furthermore, three clinical studies have confirmed that aducanumab (3–10 mg/kg) significantly reduced amyloid plaque deposition as measured by PET imaging over a 1-year period compared to placebo (Day et al., 2022). This multilayered experimental evidence, particularly the marked effects observed in animal models, provides a robust scientific foundation for the clinical application of aducanumab.

The geographic distribution of adverse event reports, predominantly from the United States, reflects the drug’s current approval status and usage patterns. This concentration of data from a single healthcare system provides consistency in reporting standards but also highlights the need for broader international safety surveillance as global adoption increases (Fang et al., 2014). Our large sample size and rigorous statistical methodology provide compelling safety signal evidence, despite the inherent limitations of FAERS data, including reporting bias and challenges in establishing causality.

Future research directions should focus on collecting long-term safety data and examining treatment experiences across diverse populations (Dickson et al., 2023). Particular attention should be paid to understanding the impact of genetic factors, such as APOE ε4 carrier status, on safety outcomes (Raulin et al., 2022; Arafah et al., 2023; Tripathi et al., 2024). This could be implemented through routine APOE genotyping using established cost-effective methods, such as PCR-based techniques or mass spectrometry (Calero et al., 2018), which can be integrated into standard clinical workflows. While current insurance coverage for APOE testing varies among payers (Arias et al., 2021), emerging evidence supporting its role in treatment decision-making may justify broader coverage policies (Blasco and Roberts, 2023). Additionally, investigation of potential drug interactions and the effects of concurrent medications commonly prescribed to elderly patients warrants further study.

The safety signals identified through our analysis, particularly ARIA-related events, warrant careful consideration but should be viewed within the context of the drug’s potential therapeutic benefits (Vaz et al., 2022). Our findings suggest that with appropriate patient selection and monitoring protocols, aducanumab maintains a manageable safety profile. This research provides valuable insights for risk management in clinical practice and supports the optimization of personalized treatment strategies.

In conclusion, while ARIA and other adverse events require vigilant monitoring, aducanumab emerges as a viable therapeutic option when accompanied by appropriate patient screening and monitoring protocols. The establishment of clear safety patterns and risk factors through this analysis contributes significantly to the evolving landscape of Alzheimer’s disease treatment, providing clinicians with essential data for informed decision-making and patient care optimization. As our understanding of the drug’s long-term safety profile continues to evolve, ongoing pharmacovigilance efforts will remain crucial in ensuring optimal therapeutic outcomes for patients with Alzheimer’s disease.