Fluid biomarkers for Alzheimer's disease have advanced rapidly during the past several years driven by breakthroughs including development of ultrasensitive and multiplexing technologies and high specificity antibodies. Blood-based biomarkers, such as neurofilament light for frontotemporal dementia and amyotrophic lateral sclerosis, and phosphorylated tau 217 for the diagnosis of Alzheimer's disease, are now being implemented in clinical practice, which is particularly timely because of the increasing clinical availability of amyloid-targeting treatments in Alzheimer's disease. Multiple fluid biomarkers are needed to capture the complexity of disease mechanisms for precise diagnosis and to measure the diverse pathologies that lead to dementia, such as vascular, alpha-synuclein, and TDP-43 pathologies. Moreover, fluid biomarkers can aid in capturing heterogeneity in treatment course between patients, probably due to copathologies or key intermediates, including microglia and astrocyte dysregulation. Increased focus on biomarker-pathology relationships in experimental models will likely accelerate biomarker development and further the understanding of their precise substrates. Future clinical implementation of biomarkers to capture the full complexity of pathologies will likely be facilitated by the expansion of diagnostic methods, development of point of care technologies, and remote sampling approaches.
Disease-modifying therapies and biomarker-based diagnostic frameworks will fundamentally altered the clinical diagnosis and management of Alzheimer's disease. Diagnosis is increasingly anchored in the biological evidence of pathology rather than clinical presentation alone, with implications for treatment eligibility, prognosis, and monitoring. In clinical practice, patients with memory complaints can present with complex mixed pathologies that develop across the lifespan. Brain imaging, particularly MRI and PET, plays a crucial role in visualising these cumulative abnormalities. With Alzheimer's disease-specific therapies now available in many regions of the world, amyloid PET plays a central role in establishing Alzheimer's disease diagnosis, determining eligibility for amyloidtargeting therapies, and quantifying treatment-related amyloid clearance. In settings where available, tau PET informs biological stage, prognosis, and clinical heterogeneity. MRI remains indispensable for differential diagnosis, the assessment of comorbid and vascular pathology, and monitoring for complications, particularly amyloid-related imaging abnormalities. Technological advances-including quantitative imaging, artificial intelligence, accelerated acquisition, and workflow optimisation-are improving reliability, efficiency, and access to these tools. Neuroimaging is now a cornerstone of Alzheimer's disease care and a crucial discriminator tool for characterising brain injury across the lifespan. With emerging fluid biomarkers, neuroimaging supports accurate diagnosis, prognosis, and treatment monitoring.
Background There are no approved exon skipping therapies to treat Duchenne muscular dystrophy due to DMD variants amenable to exon 44 skipping (DMD44). Delpacibart zotadirsen (del-zota, also known as AOC 1044) is a first-in-class antibody-oligonucleotide conjugate designed to deliver an exon 44-skipping phosphorodiamidate morpholino oligomer to muscle to restore dystrophin expression for individuals with DMD44. EXPLORE44 was a first-in-human trial to evaluate del-zota's safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy. Methods EXPLORE44 was a two-part randomised, double-blind, placebo-controlled, phase 1/2 study in healthy adult men (aged 18-55 years; part A) and ambulatory and non-ambulatory male participants with DMD44 (aged 7-27 years; part B) at ten clinical research sites in the USA. Dosing in part B was informed by safety, pharmacokinetic, and pharmacodynamic data from part A. In part B, participants with DMD44 were randomised (3:1 del-zota:placebo) within two dose cohorts to receive three intravenous doses of del-zota (5 mg/kg every 6 weeks, or 10 mg/kg every 8 weeks) or matching placebo. A computer-generated permuted-block randomisation schedule was prepared by an independent statistician with no further role in the study. Infusions were prepared by an unmasked pharmacist under supervision of the masked investigator; other site staff, participants, and sponsor team members were masked to allocation. The primary objective was safety and tolerability measured by the incidence of treatment-emergent adverse events. Secondary endpoints assessing target engagement were change from baseline in exon skipping (ie, defined as the percentage of dystrophin mRNA transcripts in which exon 44 is excluded from the mature mRNA relative to total dystrophin mRNA transcripts) and dystrophin level to month 4 (5 mg/kg cohort) or month 5 (10 mg/kg cohort). The trial was registered with ClinicalTrials.gov (NCT05670730) and is complete. Findings Between Dec 5, 2022, and June 27, 2024, we enrolled and randomly assigned 45 healthy volunteers and 26 men and boys with DMD44. In part A, three (30%) often healthy volunteers who received placebo and 21 (62%) of 34 who received del-zota reported at least one adverse event, none of which were severe or serious. In part B, nine participants with DMD44 received del-zota at 5 mg/kg, ten at 10 mg/kg, and seven received placebo; mean age 13 & centerdot;3 years (SD 4 & centerdot;2). 16 (84%) participants with DMD44 treated with del-zota and six (86%) treated with placebo reported at least one adverse event, most of which were mild or moderate; two participants, both in the 5 mg/kg del-zota group, discontinued due to adverse events (anaphylactic reaction and infusion-related reaction). Mean increases from baseline in exon 44 skipping were 36 & centerdot;6% (95% CI 20 & centerdot;8 to 52 & centerdot;4, SD 17 & centerdot;1, nominal p=0 & centerdot;0013) at 5 mg/kg, 43 & centerdot;4% (32 & centerdot;8 to 54 & centerdot;0, 14 & centerdot;9, nominal p<0 & centerdot;0001) at 10 mg/kg, and 1 & centerdot;6% (-3 & centerdot;4 to 6 & centerdot;7, 4 & centerdot;8, nominal p=0 & centerdot;44) with placebo. Mean increases from baseline in dystrophin levels were 25 & centerdot;0% (9 & centerdot;2 to 40 & centerdot;7, 17 & centerdot;0, nominal p=0 & centerdot;0082) at 5 mg/kg, 25 & centerdot;6% (13 & centerdot;0 to 38 & centerdot;3, 17 & centerdot;7, nominal p=0 & centerdot;0013) at 10 mg/kg, and-0 & centerdot;7% (-4 & centerdot;8 to 3 & centerdot;3, 3 & centerdot;9, nominal p=0 & centerdot;66) w Interpretation Del-zota had an acceptable safety profile, produced increases in exon 44 skipping and dystrophin expression, and decreased biomarkers of muscle damage in participants with DMD44. Findings from this study support further investigation of del-zota in a phase 3 study to assess efficacy and long-term safety. Funding Avidity Biosciences, A Novartis Company. Copyright (c) 2026 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.
The discovery of antibody-mediated glial and neuronal disorders has transformed the diagnosis and treatment of neurological diseases previously considered idiopathic or not recognised as immune-mediated. Antibody-mediated disorders targeting glial aquaporin-4 and myelin oligodendrocyte glycoprotein are distinct nosological entities, defined by specific targets, mechanisms, syndromes, and therapeutic implications. By contrast, antibody-mediated disorders targeting neuronal antigens (ie, autoimmune encephalitides) are still frequently analysed collectively, with data from different disorders pooled as if they represent a single disease rather than distinct entities. Evidence from anti-NMDA receptor encephalitis, anti-LGI1 encephalitis, and anti-IgLON5 disease (used here as exemplars of autoimmune encephalitides) indicates that individual autoimmune encephalitides differ in demographics, triggers, mechanisms, clinical manifestations, post-acute trajectories, and treatment requirements. The broad, heterogeneous presentations of autoimmune encephalitides require coordinated multidisciplinary care within and beyond neurology, involving specialists in paediatrics, infectious diseases, epilepsy, movement disorders, sleep medicine, intensive care, cognitive rehabilitation, and other relevant disciplines. Such interdisciplinary collaboration facilitates the recognition of new diseases and elucidation of the causes of previously unclassified disorders. Improving patient care requires not only aetiological and mechanistic insight to enable development of targeted therapies but also strengthened cross-specialty expertise to optimise diagnosis and management.
