Review of Donanemab and Lecanemab in Mild Dementia Stage of Alzheimer's Disease: Progress and Challenges.

Aducanumab: Appropriate use recommendations

The foundation for using intravenous immunoglobulin (IVIg) to treat Alzheimer's disease (AD) can be traced back to the discovery, in the early 1990s, of naturally occurring anti-amyloid antibodies in human blood. A decade later, a number of independent investigators reported reduced levels of naturally occurring anti-amyloid antibodies in the spinal fluid and blood of AD patients relative to age-matched controls 1–3. Dodel subsequently reported that IVIg contained elevated levels of antibodies against amyloid-β (Aβ) monomers and proposed its use as a potential treatment for AD 4.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder pathologically characterized by the accumulation of amyloid-beta (Aβ) and neurofibrillary tangles of hyperphosphorylated tau in the brain. Amyloid-targeting therapies (ATTs) are the first available disease-modifying treatments shown to slow cognitive and functional decline for patients with mild cognitive impairment owing to AD and early symptomatic AD. Currently two ATTs are commercially available, donanemab (Kisunla™) and lecanemab (Leqembi®). The main potential side effect and safety concern of ATT treatment is amyloid-related imaging abnormalities (ARIA). ARIA can be categorized into two types that can co-occur: ARIA-E (edema/sulcal effusion) and ARIA-H (hemorrhage/superficial siderosis). Although both are often asymptomatic and ARIA-E typically resolves radiographically over time, both forms can be radiologically and/or clinically serious. Treating clinicians should be equipped with a comprehensive understanding of ARIA. This review aims to provide advanced practice providers, who are pivotal to patient care in AD, with critical insights into ARIA to safely identify risk factors, understand treatment guidelines, and gain familiarity with appropriate management strategies. It emphasizes the importance of understanding APOE genotype and vascular factors in ARIA risk and recognizing the clinical and radiographic manifestations of ARIA. Practical recommendations are provided for monitoring and managing ARIA, including dose management strategies and education on symptom awareness. By fostering a comprehensive understanding of ARIA and its monitoring and management, this review aims to support the safe and effective implementation of ATTs, contributing to optimized patient care for those treated with ATTs.

Lecanemab for Alzheimer's disease: new hope or another false dawn?

Aducanumab and the “post-amyloid” era of Alzheimer research?

This review provides an updated overview of amyloid-related imaging abnormalities (ARIA) associated with antiamyloid monoclonal antibodies (mAbs) in Alzheimer's disease (AD). Following regulatory approvals for both lecanemab and donanemab in the United States, and pending decisions in Europe, standardized understanding of ARIA definitions, risk factors, and optimal MRI surveillance is increasingly important to guide treatment and ensure safety. ARIA, including vasogenic edema (ARIA-E) and microhemorrhages/siderosis (ARIA-H), are a frequent adverse event in patients receiving antiamyloid mAbs, particularly among APOE ε4 homozygotes. Incidence varies by agent and trial design. While often asymptomatic and self-limiting, ARIA can occasionally present with symptoms or recur. MRI, especially FLAIR and susceptibility-sensitive imaging, is essential for baseline risk stratification and monitoring. Key imaging biomarkers include microbleeds and superficial siderosis. Recent guidelines support genotyping and risk-adapted MRI protocols before and during therapy. ARIA reflect vascular vulnerability during amyloid clearance in AD. Their management requires close collaboration between neurologists and neuroradiologists, with harmonized MRI protocols and risk mitigation strategies critical for safe and effective use of disease-modifying therapies.

The purpose of this review is to examine the potential role of donanemab-azbt in the treatment and management of early-stage Alzheimer's disease (AD), with a focus on its efficacy, safety, and clinical relevance based on data from key clinical trials. A comprehensive literature search of PubMed was conducted using relevant keywords such as "donanemab", "Alzheimer's disease", "Kisunla", "TRAILBLAZER clinical trials", and "amyloid-related imaging abnormalities (ARIA)". Additional data were extracted from clinical trial records (clinicaltrials.gov), conference abstracts, and product monographs. Only English-language studies conducted in human populations were included. Clinical trials and peer-reviewed studies detailing the efficacy, safety, and mechanistic insights of donanemab-azbt were prioritized. Key findings from the TRAILBLAZER series of clinical trials highlighted the potential of donanemab-azbt in slowing cognitive and functional decline in early-stage AD: (1) TRAILBLAZER-ALZ (Phase 2): This trial focused on participants with intermediate levels of tau protein. Results demonstrated a statistically significant slowing of cognitive and functional decline. (2) TRAILBLAZER-ALZ 2 (Phase 3): A large-scale, randomized, double-blind, placebo-controlled study confirmed the efficacy of donanemab-azbt in reducing amyloid plaque accumulation and cognitive decline. Key results included a 35% slowing of decline on the Integrated Alzheimer's Disease Rating Scale (iADRS) and a 36% slowing on the Clinical Dementia Rating-Sum of Boxes (CDR-SB). Additional secondary outcomes showed improvements in activities of daily living and reduced risk of disease progression. (3) TRAILBLAZER-ALZ 3: This ongoing trial is evaluating donanemab's potential in delaying or preventing Alois Alzheimer in cognitively normal individuals with amyloid plaques, broadening the scope of early intervention strategies. (4) TRAILBLAZER-ALZ 4: A head-to-head comparison with aducanumab revealed superior amyloid plaque clearance with donanemab. (5) TRAILBLAZER-ALZ 5: Currently recruiting, this trial aims to evaluate safety and efficacy across diverse populations with varying tau levels and comorbidities. (6) TRAILBLAZER-ALZ 6 (Phase 3b): This trial investigates modified dosing regimens to reduce ARIA while maintaining efficacy, particularly in populations with genetic risk factors like ApoE ε4 homozygotes. Donanemab-azbt represents a promising treatment option for patients with early-stage AD. It specifically targets and reduces amyloid beta plaques, a hallmark of the disease, potentially slowing progression and preserving cognitive function. However, its administration requires careful patient selection, including genetic testing for ApoE ε4 status, to mitigate risks of ARIA. Furthermore, the findings emphasize the importance of close monitoring during treatment. Donanemab-azbt offers a new avenue for managing early-stage AD, showing promise in reducing amyloid burden and slowing cognitive decline. While its efficacy and safety have been demonstrated in clinical trials, further research is essential to validate long-term outcomes, assess effectiveness across diverse populations, and refine dosing strategies to minimize side effects. With continued investigation, donanemab-azbt could significantly impact the clinical landscape of AD treatment.

BackgroundLecanemab, a monoclonal antibody targeting amyloid beta, has recently been approved for treatment of early-stage Alzheimer’s disease (AD), demonstrating amyloid plaque reduction and slowing of cognitive decline in clinical trials. However, real-world data on its efficacy and safety remain limited. The Cognitive Neurology Unit at Tel Aviv Medical Center (TLVMC) established an infrastructure to facilitate advanced treatments for AD, utilising a multidisciplinary approach to patient screening, diagnosis, treatment initiation and follow up.MethodsLecanemab administration at the TLVMC commenced in November 2023. Patients with biomarker-confirmed early-stage AD were screened via a structured referral system, including neurological evaluations, MRI, lumbar puncture or Amyloid-PET, genetic testing, and multidisciplinary team (MDT) consensus discussions. Cognitive function was assessed using the Mini-Mental State Examination (MMSE) at baseline, six months, and twelve months. Safety monitoring included routine MRI scans for amyloid-related imaging abnormalities (ARIA).ResultsBetween July 2023 and January 2025, 169 patients were screened and 86 initiated lecanemab treatment. By January 2025, 53 patients had reached the 6-month follow-up date. In the intention-to-treat (ITT) population, MMSE scores declined significantly over 6 months (F(1, 45.13) = 7.41, p =.009). Subgroup analysis revealed a significant decline in younger patients (n = 31; F(1, 24.67) = 8.06, p =.009), but not in older patients (n = 22; F(1, 19.25) = 0.67, p =.424). At 12 months, 31 patients had reached follow-up, with no significant change in MMSE scores observed (F(1, 17.18) = 2.49, p =.133). Age subgroup analysis was not performed at 12 months due to limited sample size. No significant correlations were found between baseline biomarkers and cognitive change. ARIA occurred in 18.6% of patients, mostly asymptomatic. One patient experienced symptomatic ARIA, required hospitalization with intravenous treatment, and discontinued therapy. A mixed-effects model showed no significant effect of ARIA on MMSE change (p =.264) and no interaction with time (p =.433). Infusion-related reactions occurred in 22.1%, all mild and transient. Treatment was discontinued in 19.8% of patients due to ARIA, financial barriers, comorbidities, or personal preference.ConclusionsThis real-world analysis demonstrates the feasibility and safety of Lecanemab administration for early-stage AD within a tertiary hospital setting. Establishing dedicated infrastructure enabled streamlined patient evaluations and treatment. The findings suggest a differential response across age groups, consistent with clinical trial data. Continued longitudinal follow-up is needed to assess long-term efficacy and safety.

Anti-amyloid monoclonal antibodies have emerged as disease-modifying therapies for Alzheimer's disease. However, their broader clinical adoption is limited by amyloid-related imaging abnormalities, a key safety concern. Traditionally viewed as an unavoidable and dose-dependent adverse effect, amyloid-related imaging abnormalities often lead to treatment interruption or the exclusion of high-risk patients from therapy. Emerging evidence now suggests that amyloid-related imaging abnormalities may instead reflect a transient modifiable cerebrovascular response, primarily influenced by the kinetics of amyloid clearance rather than the absolute magnitude of amyloid removal. Recent data from titration-based dosing strategies demonstrate that gradual amyloid mobilization can significantly reduce the incidence of amyloid-related imaging abnormalities without compromising amyloid positron emission tomography responses or downstream biomarkers. This kinetic perspective may support a more nuanced re-evaluation of patient groups previously deemed unsuitable for therapy, including APOE ε4 carriers, individuals with cerebral microbleeds, and patients on antithrombotic treatment. In this Current Opinion, we propose a pragmatic clinical framework that integrates amyloid clearance kinetics, magnetic resonance imaging-based risk stratification, and individualized protocols for treatment interruption and re-challenge. By reframing amyloid-related imaging abnormalities as a modifiable clinical decision-making challenge rather than an inherent toxicity, anti-amyloid therapies may be optimized for safer use; however, whether such approaches can enable broader and more inclusive treatment strategies remains to be established in prospective studies, particularly in high-risk populations.

Lecanemab (Leqembi®) has been approved for the treatment of early Alzheimer’s disease (AD) patients. However, the safety and efficacy of lecanemab in clinical practice in Asia population remain unclear. This prospective cohort study was conducted in a single center in Eastern China, including 76 early-stage AD participants treated with lecanemab. All participants underwent at least 1 lecanemab infusion. The mean age was 66 years (65.53 ± 9.31), and 51 (67.1%) participants being female. A total of 49 (64.5%) participants were ApoE-ε4 carriers, including 34 (44.7%) heterozygotes and 15 (19.7%) homozygotes. Infusion-related side effects (IRSE), primarily occurred after the first infusion, were observed in 14 participants (18.4%). The most common IRSE were fever and fatigue. Until 9 Aug 2025, 58 participants had received treatment for more than 3 months, 44 for more than 6 months and 12 for more than 12 months. Amyloid-related imaging abnormalities (ARIA) were observed in 11 participants. Specifically, solitary ARIA-H (hemorrhage) was detected in 7 participants, while ARIA-E (edema) with or without cerebral micro-hemorrhage was identified in 4. Notably, all the 11 participants with ARIA were asymptomatic. Participants with isolated ARIA-H exhibited higher baseline Fazekas scores of PVWMHs (p = 0.008). Participants with a Clinical Dementia Rating Scale Global Score (CDR-GS) of 1 had a more rapid decline in Mini-Mental State Global Score (MMSE) scores as compared to those with a CDR-GS of 0.5. Following 12 months of lecanemab therapy, amyloid PET exhibited a significant reduction in brain amyloid burden. These data support that lecanemab appears to be generally tolerated in Asian population. The IRSE and ARIA-E events were less common than the Clarity AD study.

Amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with bapineuzumab: a retrospective analysis

Anti‐amyloid immunotherapy holds great promise for our patients and their families as the first disease‐modifying therapy for the treatment of Alzheimer’s disease (AD) to be approved. Positive clinical trials for lecanamab and donanemab showed significant and rapid lowering of brain amyloid burden and a significant slowing of cognitive decline. Amyloid‐related imaging abnormalities (ARIA) in the form of vasogenic edema (ARIA‐E) and micro ‐ and macro‐ hemorrhages (ARIA‐H) remain the major obstacle to broad use of these agents. Significant cerebrovascular pathology precludes treatment due to enhanced risk of ARIA. In addition, it is known that ApoE4 carriers are at a significantly increased risk of ARIA incidence, with 25‐40% of homozygotes developing ARIA. Understanding the mechanisms underlying ARIA is of critical importance to increase safety and broaden the use of anti‐amyloid immunotherapy.Using mouse models of amyloid deposition, we have performed systemic and intracranial anti‐beta‐amyloid antibody administration to study the potential mechanisms of both amyloid clearance and cerebrovascular disruptions that lead to ARIA. We have found that microglial activation is present along the vessels that are laden with cerebral amyloid angiopathy (CAA). Furthermore, coincident with microhemorrhage occurrence is increased expression and activity of matrix metalloproteinases (MMPs) MMP9 and MMP3. MMPs are known to degrade basement membranes and tight junction proteins that could lead to disruption of the blood‐brain barrier and, ultimately, edema and hemorrhage. in fact, it has long been understood that MMP9 plays a critical role in the hemorrhagic transformation of ischemic stroke. We have performed single‐cell transcriptomic analysis to examine the glial responses following a single anti‐amyloid immunotherapy and we find significant microglial population shifts and also enhanced signaling from microglia to perivascular macrophages, potentially implicating these cells as a key player in the development of ARIA.Ultimately, discovering the mechanisms of ARIA will result in the development of safer, next‐generation antibody therapy that has reduced ARIA risk, and also could lead to the identification of adjunct treatments that can be co‐administered with the anti‐amyloid immunotherapy to prevent the occurrence of ARIA in those at risk.

WHAT IS THIS SUMMARY ABOUT? This is a plain language summary of an article published in the journal Brain. People with Alzheimer's disease may receive treatments that target amyloid-β – a protein in the brain that is one of the key characteristics of Alzheimer's disease when it is present in higher levels than normal. This article is about amyloid-related imaging abnormalities (ARIA), which can be adverse events for people with Alzheimer's disease receiving antibody treatments targeting amyloid-β (known as anti–amyloid-β antibody treatments). This article also discusses ways to identify and manage ARIA. ARIA are adverse events that happen due to amyloid-β buildup in the brain or following treatments targeting amyloid-β. ARIA are identified on MRI scans as swelling or bleeding in the brain, and people with ARIA do not typically have symptoms. In rare cases, ARIA can cause serious symptoms or lead to disability. WHAT ARE THE KEY TAKEAWAYS? There are two types of ARIA: ARIA-E (swelling in the brain) and ARIA-H (bleeding in the brain). Presence of an APOE ε4 gene variant and exposure to anti–amyloid-β antibody treatments are major risk factors for ARIA. With the recent availability in the clinic of antibody treatments targeting amyloid-β, increased awareness is needed to identify, monitor and manage ARIA effectively. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS? Uniform detection, monitoring and management of ARIA are essential in patients receiving antibody treatments targeting amyloid-β. To increase ARIA detection in clinical trials and clinical practice, the authors recommend the implementation of uniform imaging protocols and rigorous reporting standards.

BackgroundLecanemab, a monoclonal antibody targeting amyloid‐β protofibrils, has demonstrated efficacy in reducing amyloid plaque burden and slowing cognitive decline in early Alzheimer’s disease (AD). However, treatment is associated with amyloid‐related imaging abnormalities (ARIA), including vasogenic edema (ARIA‐E) and cerebral microhemorrhages or superficial siderosis (ARIA‐H). The cognitive consequences of ARIA remain insufficiently characterized in real‐world settings.MethodThis retrospective cohort study included 92 individuals with mild cognitive impairment or mild AD who received Lecanemab between 2023 and 2025 at a single community memory clinic. All patients had biomarker‐confirmed amyloid pathology via plasma pTau217 or amyloid PET imaging. Clinical data extracted included demographics, vascular risk factors, APOE4 carrier status, antithrombotic use, infusion number, ARIA subtype and severity, and serial MRI findings. Cognitive performance was assessed longitudinally using the Mini‐Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). The primary objective was to evaluate associations between ARIA characteristics and cognitive trajectories.ResultThe majority of patients (n = 58, 63%) did not develop ARIA. Among ARIA‐positive patients (n = 34, 37%), isolated ARIA‐H and combined ARIA‐H with ARIA‐E were the most prevalent subtypes. ARIA‐E resolved in 63% of cases on follow‐up imaging, whereas ARIA‐H persisted in 60%. Most ARIA events (71%) were asymptomatic and mild to moderate in severity. There was no significant difference in cognitive outcomes between patients with asymptomatic ARIA and those without ARIA (mean MMSE 28.1 vs. 28.5, p = 0.34). However, patients with symptomatic ARIA demonstrated significantly lower follow‐up MMSE scores compared to both asymptomatic ARIA and ARIA‐negative individuals (mean MMSE 25.0, p = 0.004 and p = 0.02, respectively). A non‐significant trend toward lower cognitive scores was observed in those with higher ARIA‐H burden.ConclusionIn this real‐world cohort, symptomatic ARIA—particularly ARIA‐H—was associated with measurable cognitive decline. While most ARIA cases were asymptomatic and did not impact cognition, these findings highlight the need for routine neuroimaging surveillance and individualized treatment strategies to optimize safety and cognitive outcomes during Lecanemab therapy. This highlights the need for ongoing assessment of ARIA in clinical practice to enhance the safety and efficacy of amyloid‐targeting therapies in early AD.

BackgroundDonanemab (Kisunla ®), an IgG1 monoclonal antibody targeting the pyroglutamate‐modified form of amyloid‐β, is approved in the United States and other countries for treatment of early‐stage Alzheimer’s disease (AD). The Appropriate Use Recommendations (AUR) were developed to guide the implementation of donanemab in real‐world practice, prioritizing safety considerations and opportunity for effectiveness.MethodsThe AUR were developed by the AD and Related Disorders Therapeutic Workgroup, integrating available data and expert opinion. Workgroup members reviewed all publicly available data regarding the drug’s efficacy and safety profile, safety data pertaining to other Aβ‐targeting antibodies, as well as expert opinion. Group deliberations took place between October 2023 and November 2024 via video conferences and written exchanges, with reiterative refinement until consensus was achieved.ResultsAppropriate candidates for donanemab include persons with mild cognitive impairment or mild dementia due to AD (Clinical Stages 3‐4, MMSE 20‐30) who show biomarker support for AD by PET or CSF. Tau PET is not required for eligibility, though, if available, can be considered to individualize estimates of likely clinical response. Apolipoprotein E genotyping is required prior to treatment to inform an individual’s risk of developing Amyloid Related Imaging Abnormalities (ARIA). Pre‐treatment MRI should be obtained ≤ 12 months prior to treatment, and patients with findings of significant cerebral amyloid angiopathy or a major vascular contribution to cognitive impairment should be excluded. The decision to initiate therapy should be grounded in a shared decision‐making process that emphasizes the patient’s values and goals of care. Donanemab is administered as a monthly intravenous infusion. MRI scans to evaluate for ARIA should be performed prior to the 2nd, 3rd, 4th and 7th infusions, and at any time ARIA is suspected clinically. Clinicians may consider discontinuing treatment if amyloid clearance is demonstrated by amyloid PET 12‐18 months after initiating treatment.ConclusionsThe AUR adapt the donanemab clinical trial criteria and protocol into clinical practice, in order to maximize the safe and efficacious translation of this novel therapy into patient care. The AUR are expected to evolve as more real‐world data accumulate from ALZNET and other patient registries in the U.S. and globally.