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Our aim is to review the most recent evidence on novel antibody therapies for Alzheimer's disease directed against amyloid‐β. This is a joint statement of the European Association of Neurology and the European Psychiatric Association. After numerous unsuccessful endeavors to create a disease‐modifying therapy for Alzheimer's disease, substantial and consistent evidence supporting the clinical effectiveness of monoclonal antibodies aimed at amyloid‐β is finally emerging. The latest trials not only achieved their primary objective of slowing the progression of the disease over several months but also demonstrated positive secondary clinical outcomes and a decrease in amyloid‐β levels as observed through positron emission tomography scans. Taken as a whole, these findings mark a significant breakthrough by substantiating that reducing amyloid‐β yields tangible clinical benefits, beyond mere changes in biomarkers. Concurrently, the regular utilization of the new generation of drugs will determine whether statistical efficacy translates into clinically meaningful improvements. This may well signify the dawning of a new era in the development of drugs for Alzheimer's disease.

INTRODUCTION Lecanemab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that preferentially targets soluble aggregated Aβ species (protofibrils) with activity at amyloid plaques. Amyloid‐related imaging abnormalities (ARIA) profiles appear to differ for various anti‐amyloid antibodies. Here, we present ARIA data from a large phase 2 lecanemab trial (Study 201) in early Alzheimer's disease. METHODS Study 201 trial was double‐blind, placebo‐controlled (core) with an open‐label extension (OLE). Observed ARIA events were summarized and modeled via Kaplan‐Meier graphs. An exposure response model was developed. RESULTS In the phase 2 core and OLE, there was a low incidence of ARIA‐E (<10%), with <3% symptomatic cases. ARIA‐E was generally asymptomatic, mild‐to‐moderate in severity, and occurred early (<3 months). ARIA‐E was correlated with maximum lecanemab serum concentration and incidence was higher in apolipoprotein E4 (ApoE4) homozygous carriers. ARIA‐H and ARIA‐E occurred with similar frequency in core and OLE. DISCUSSION Lecanemab can be administered without titration with modest incidence of ARIA.

The emergence of the United States Food and Drug Administration (FDA)‐approved amyloid‐targeting therapies for Alzheimer's disease challenges clinicians and healthcare providers with a transformative landscape. Effectively communicating the risks, benefits, burdens, costs, and available support associated with these novel disease‐modifying treatments to patients, families, and other healthcare providers is essential but complex. In response, the Alzheimer's Association's Clinical Meaningfulness Workgroup has proposed language surrounding treatment eligibility, benefits, amyloid‐related imaging abnormalities (ARIA), apolipoprotein E (APOE) genotyping, and treatment costs, serving as a resource to healthcare professionals in navigating discussions with patients and their families. As the landscape evolves with the approval of new Alzheimer's therapies, this resource stands poised for updates, ensuring its continued relevance in facilitating informed and meaningful patient‐provider dialogues. Highlights Effective communication of risks, benefits, burdens, and costs of FDA‐approved amyloid‐targeting antibodies is essential to patients, families, and healthcare providers. The Alzheimer's Association's Clinical Meaningfulness Workgroup provides language for physicians and healthcare providers around treatment eligibility, benefits, ARIA, APOE genotyping, and treatment costs. This supplementary resource may be updated as new AD therapies become approved.

Prior authorization criteria for Federal Drug Administration (FDA) approved immunotherapeutics, among the class of anti‐amyloid monoclonal antibodies (mAbs), established by state drug formulary committees, are tailored for adults with late‐onset Alzheimer's disease. This overlooks adults with Down syndrome (DS), who often experience dementia at a younger age and with different diagnostic assessment outcomes. This exclusion may deny DS adults access to potential disease‐modifying treatments. To address this issue, an international expert panel convened to establish adaptations of prescribing criteria suitable for DS patients and parameters for access to Centers for Medicare & Medicaid Services (CMS) registries. The panel proposed mitigating disparities by modifying CMS and payer criteria to account for younger onset age, using alternative language and assessment instruments validated for cognitive decline in the DS population. The panel also recommended enhancing prescribing clinicians' diagnostic capabilities for DS and initiated awareness‐raising activities within healthcare organizations. These efforts facilitated discussions with federal officials, aimed at achieving equity in access to anti‐amyloid immunotherapeutics, with implications for national authorities worldwide evaluating these and other new disease‐modifying therapeutics for Alzheimer's disease.

INTRODUCTION The societal impact of anti‐amyloid treatment (AAT) for Alzheimer's disease (AD) depends largely on patient eligibility. Estimates suggest that 1% to 18% of individuals with AD may qualify for AAT; however, data from everyday clinical practice remain limited. This study assessed AAT eligibility in patients at a tertiary memory clinic. METHODS We included 1309 new patients (63 ± 8 years, 45% women, Mini‐Mental State Examination [MMSE] 25 ± 5) who presented to the Alzheimer Center Amsterdam (2020–2022) for standardized diagnostic workup. Eligibility for AAT was based on lecanemab's approved label guidelines. RESULTS Of 1309 new patients, 514 (39% of new patients) had clinical mild cognitive impairment (MCI) or AD. Of these, 108 (8% new patients/21% clinical MCI/AD) met Clinical Dementia Rating/MMSE criteria, were amyloid positive, and had < 4 microbleeds/superficial siderosis. After further excluding apolipoprotein E ε4/ε4 homozygotes and anticoagulant users, 79 patients (6% new patients/15% clinical MCI/AD) remained eligible. DISCUSSION Findings indicate limited eligibility for AAT in tertiary memory clinics. Highlights Initial eligibility for lecanemab was 8% of all patients and 21% of those with clinical mild cognitive impairment (MCI) or Alzheimer's disease (AD) based on approved guidelines in a tertiary memory clinic population. After strict exclusions (such as apolipoprotein E ε4/ε4 homozygosity and anticoagulant use), eligibility dropped to 6% of all patients and 15% of those with clinical MCI or AD. The study highlights the limited real‐world applicability of anti‐amyloid treatment under current guidelines.

The body of evidence suggesting a causative, initiating role of beta amyloid (Aβ) in the pathogenesis of Alzheimer’s disease (AD) is substantial. Yet, only a few anti-amyloid agents have shown meaningful efficacy in clinical trials. We evaluated the unifying characteristics of anti-amyloid agents with positive clinical or biomarker effects in long-duration trials and analyzed how pharmacological characteristics determine their clinical product profiles. Four agents with the potential for near term approval fulfill these criteria: the injectable antibodies, aducanumab, gantenerumab, and BAN2401, and a small molecule oral agent, ALZ-801. Aducanumab and BAN2401 showed significant efficacy on both clinical and biomarker outcomes; gantenerumab showed significant biomarker effects, with no clinical efficacy reported to date; and ALZ-801 showed significant clinical effects in the high-risk population of patients homozygous for the ε4 allele of apolipoprotein E gene (APOE4) and a dose-dependent preservation of hippocampal volume. We explored how the pharmacological properties of these agents, namely selectivity for Aβ oligomers, plasma half-life, brain penetration, and time to peak brain exposure, determine their clinical profiles. A crucial characteristic shared by these agents is their ability to engage neurotoxic soluble Aβ oligomers, albeit to various degrees. Aducanumab and gantenerumab partially target oligomers, while mostly clearing insoluble amyloid plaques; BAN2401 preferentially targets soluble protofibrils (large oligomers) over plaques; and ALZ-801 blocks the formation of oligomers without binding to plaques. The degree of selectivity for Aβ oligomers and brain exposure drive the magnitude and onset of clinical efficacy, while the clearance of plaques is associated with vasogenic brain edema. Only the highest doses of aducanumab and BAN2401 show modest efficacy, and higher dosing is limited by increased risk of vasogenic edema, especially in APOE4 carriers. These limitations can be avoided, and efficacy improved by small molecule agents that selectively inhibit the formation or block the toxicity of Aβ oligomers without clearing amyloid plaques. The most advanced selective anti-oligomer agent is ALZ-801, an optimized oral prodrug of tramiprosate, which demonstrated efficacy in homozygous APOE4/4 AD subjects. ALZ-801 selectively and fully inhibits the formation of Aβ42 oligomers at the clinical dose, without evidence of vasogenic edema, and will be evaluated in a phase 3 trial in homozygous APOE4/4 patients with early AD. In addition to clinical measures, the phase 3 trial will include cerebrospinal fluid, plasma, and imaging biomarkers to gain further insights into the role of soluble Aβ oligomers in the pathogenesis of AD and their impact on disease progression.

INTRODUCTION We previously demonstrated that single‐domain amnestic mild cognitive impairment (SDAm‐MCI) detected through longitudinal neuropsychological testing in our research cohort is less severe than in clinically incident symptomatic individuals. This study aims to replicate and expand this work using a National Alzheimer's Coordinating Center dataset. METHODS Participants were classified into two groups: those enrolled with normal cognition (Normal Enrollees) and those enrolled with SDAm‐MCI (Amnestic Enrollees). Groups were compared at the time of diagnosis and on rates of cognitive decline post‐diagnosis. RESULTS At SDAm‐MCI diagnosis, Normal Enrollees were 17% to 39% less impaired on memory tasks, after which the slope of change over time steepened compared to their pre‐symptomatic change and was steeper than in Amnestic Enrollees. DISCUSSION Incident MCI detected through longitudinal neuropsychological testing is initially milder but may progress more steeply than in clinically established MCI. Sensitive assessment of cognitive decline is essential for capturing early changes that are more likely to be amenable to therapeutic treatment. Highlights Longitudinal cognitive evaluation detects symptomatic Alzheimer's disease earlier than mental status exams. At the time of diagnosis, converters were less impaired compared to initially symptomatic patients. Converters’ cognition declined more steeply than initially symptomatic patients. Sensitive cognitive tests are essential to capture early changes, given new disease‐modifying therapies.

Alzheimer disease (AD) accounts for 60–70% of dementia cases. Given the seriousness of the disease and continual increase in patient numbers, developing effective therapies to treat AD has become urgent. Presently, the drugs available for AD treatment, including cholinesterase inhibitors and an antagonist of the N-methyl-D-aspartate receptor, can only inhibit dementia symptoms for a limited period of time but cannot stop or reverse disease progression. On the basis of the amyloid hypothesis, many global drug companies have conducted many clinical trials on amyloid clearing therapy but without success. Thus, the amyloid hypothesis may not be completely feasible. The number of anti-amyloid trials decreased in 2019, which might be a turning point. An in-depth and comprehensive understanding of the contribution of amyloid beta and other factors of AD is crucial for developing novel pharmacotherapies. In ongoing clinical trials, researchers have developed and are testing several possible interventions aimed at various targets, including anti-amyloid and anti-tau interventions, neurotransmitter modification, anti-neuroinflammation and neuroprotection interventions, and cognitive enhancement, and interventions to relieve behavioral psychological symptoms. In this article, we present the current state of clinical trials for AD at clinicaltrials.gov . We reviewed the underlying mechanisms of these trials, tried to understand the reason why prior clinical trials failed, and analyzed the future trend of AD clinical trials.

Disease-modifying treatment strategies for Alzheimer disease (AD) are still under extensive research. Nowadays, only symptomatic treatments exist for this disease, all trying to counterbalance the neurotransmitter disturbance: 3 cholinesterase inhibitors and memantine. To block the progression of the disease, therapeutic agents are supposed to interfere with the pathogenic steps responsible for the clinical symptoms, classically including the deposition of extracellular amyloid β plaques and intracellular neurofibrillary tangle formation. Other underlying mechanisms are targeted by neuroprotective, anti-inflammatory, growth factor promotive, metabolic efficacious agents and stem cell therapies. Recent therapies have integrated multiple new features such as novel biomarkers, new neuropsychological outcomes, enrollment of earlier populations in the course of the disease, and innovative trial designs. In the near future different specific agents for every patient might be used in a “precision medicine” context, where aberrant biomarkers accompanied with a particular pattern of neuropsychological and neuroimaging findings could determine a specific treatment regimen within a customized therapeutic framework. In this review, we discuss potential disease-modifying therapies that are currently being studied and potential individualized therapeutic frameworks that can be proved beneficial for patients with AD.

Alzheimer's disease (AD) is the leading cause of dementia, presenting a significant unmet medical need worldwide. The pathogenesis of AD involves various pathophysiological events, including the accumulation of amyloid and tau, neuro-inflammation, and neuronal injury. Clinical trials focusing on new drugs for AD were documented in 2020, but subsequent developments have emerged since then. Notably, the US-FDA has approved Aducanumab and Lecanemab, both antibodies targeting amyloid, marking the end of a nearly two-decade period without new AD drugs. In this comprehensive report, we review all trials listed in clinicaltrials.gov, elucidating their underlying mechanisms and study designs. Ongoing clinical trials are investigating numerous promising new drugs for AD. The main trends in these trials involve pathophysiology-based, disease-modifying therapies and the recruitment of participants in earlier stages of the disease. These trends underscore the significance of conducting fundamental research on pathophysiology, prevention, and intervention prior to the occurrence of brain damage caused by AD.