{"topic":"neurodegeneration","sort":"top","limit":25,"offset":0,"count":25,"papers":[{"id":"doi:10.1056/nejmoa2212948","kind":"article","title":"Lecanemab in Early Alzheimer’s Disease","authors":["Christopher H. van Dyck","Chad J. Swanson","Paul S. S. Aisen","Randall John Bateman","Christopher Chen","Michelle Gee","Michio Kanekiyo","David Li","Larisa Reyderman","Sharon Cohen","Lutz Froelich","Sadao Katayama","Marwan Sabbagh","Bruno J. Vellas","David Watson","Shobha Dhadda","Michael C. Irizarry","Lynn Darden Kramer","Takeshi Iwatsubo"],"author_count":19,"year":2022,"published":"2022-11-30","venue":"New England Journal of Medicine","cited_by":5673,"doi":"10.1056/nejmoa2212948","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1056/nejmoa2212948","archive_url":"https://space-kitty.com/papers/doi:10.1056/nejmoa2212948","updated":null,"pmid":"36449413","pmcid":null,"openalex_id":"W4310461604","pdf_url":"https://www.nejm.org/doi/pdf/10.1056/NEJMoa2212948?articleTools=true","abstract":null,"abstract_license":null,"license":null,"is_open_access":true,"peer_reviewed":null,"categories":["Alzheimer's disease research and treatments"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.1038/s41392-024-01911-3","kind":"review","title":"Recent advances in Alzheimer’s disease: mechanisms, clinical trials and new drug development strategies","authors":["Jifa Zhang","Yinglu Zhang","Jiaxing Wang","Yilin Xia","Jiaxian Zhang","Lei Chen"],"author_count":6,"year":2024,"published":"2024-08-23","venue":"Signal Transduction and Targeted Therapy","cited_by":1176,"doi":"10.1038/s41392-024-01911-3","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41392-024-01911-3","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41392-024-01911-3","updated":null,"pmid":"39174535","pmcid":"PMC11344989","openalex_id":"W4401806028","pdf_url":"https://www.nature.com/articles/s41392-024-01911-3.pdf","abstract":"Alzheimer's disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate and diverse, stemming from a combination of factors such as aging, genetics, and environment. Our current understanding of AD pathologies involves various hypotheses, such as the cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, and abnormal autophagy. Nonetheless, unraveling the interplay among these pathological aspects and pinpointing the primary initiators of AD require further elucidation and validation. In the past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available drugs primarily offer symptomatic relief and often accompanied by undesirable side effects. However, recent approvals of aducanumab (1) and lecanemab (2) by the Food and Drug Administration (FDA) present the potential in disrease-modifying effects. Nevertheless, the long-term efficacy and safety of these drugs need further validation. Consequently, the quest for safer and more effective AD drugs persists as a formidable and pressing task. This review discusses the current understanding of AD pathogenesis, advances in diagnostic biomarkers, the latest updates of clinical trials, and emerging technologies for AD drug development. We highlight recent progress in the discovery of selective inhibitors, dual-target inhibitors, allosteric modulators, covalent inhibitors, proteolysis-targeting chimeras (PROTACs), and protein-protein interaction (PPI) modulators. Our goal is to provide insights into the prospective development and clinical application of novel AD drugs.","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"peer_reviewed":null,"categories":["Alzheimer's disease research and treatments"],"details":null,"provenance":"openalex+europepmc","attribution":"Abstract of \"Recent advances in Alzheimer’s disease: mechanisms, clinical trials and new drug development strategies\" by Jifa Zhang, Yinglu Zhang, Jiaxing Wang et al., https://doi.org/10.1038/s41392-024-01911-3, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1001/jamaneurol.2023.5319","kind":"article","title":"Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology","authors":["Ashton NJ","Brum WS","Di Molfetta G","Benedet AL","Arslan B","Jonaitis E","Langhough RE","Cody K","Wilson R","Carlsson CM","Vanmechelen E","Montoliu-Gaya L","Lantero-Rodriguez J","Rahmouni N","Tissot C","Stevenson J","Servaes S","Therriault J","Pascoal T","Lleó A","Alcolea D","Fortea J","Rosa-Neto P","Johnson S","Jeromin A"],"author_count":27,"year":2024,"published":"2024-03-01","venue":"JAMA neurology","cited_by":770,"doi":"10.1001/jamaneurol.2023.5319","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1001/jamaneurol.2023.5319","archive_url":"https://space-kitty.com/papers/doi:10.1001/jamaneurol.2023.5319","updated":null,"pmid":"38252443","pmcid":"PMC10804282","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC10804282/pdf","abstract":"Importance Phosphorylated tau (p-tau) is a specific blood biomarker for Alzheimer disease (AD) pathology, with p-tau217 considered to have the most utility. However, availability of p-tau217 tests for research and clinical use has been limited. Expanding access to this highly accurate AD biomarker is crucial for wider evaluation and implementation of AD blood tests. Objective To determine the utility of a novel and commercially available immunoassay for plasma p-tau217 to detect AD pathology and evaluate reference ranges for abnormal amyloid β (Aβ) and longitudinal change across 3 selected cohorts. Design, setting, and participants This cohort study examined data from 3 single-center observational cohorts: cross-sectional and longitudinal data from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort (visits October 2017-August 2021) and Wisconsin Registry for Alzheimer's Prevention (WRAP) cohort (visits February 2007-November 2020) and cross-sectional data from the Sant Pau Initiative on Neurodegeneration (SPIN) cohort (baseline visits March 2009-November 2021). Participants included individuals with and without cognitive impairment grouped by amyloid and tau (AT) status using PET or CSF biomarkers. Data were analyzed from February to June 2023. Exposures Magnetic resonance imaging, Aβ positron emission tomography (PET), tau PET, cerebrospinal fluid (CSF) biomarkers (Aβ42/40 and p-tau immunoassays), and plasma p-tau217 (ALZpath pTau217 assay). Main outcomes and measures Accuracy of plasma p-tau217 in detecting abnormal amyloid and tau pathology, longitudinal p-tau217 change according to baseline pathology status. Results The study included 786 participants (mean [SD] age, 66.3 [9.7] years; 504 females [64.1%] and 282 males [35.9%]). High accuracy was observed in identifying elevated Aβ (area under the curve [AUC], 0.92-0.96; 95% CI, 0.89-0.99) and tau pathology (AUC, 0.93-0.97; 95% CI, 0.84-0.99) across all cohorts. These accuracies were comparable with CSF biomarkers in determining abnormal PET signal. The detection of abnormal Aβ pathology using a 3-range reference yielded reproducible results and reduced confirmatory testing by approximately 80%. Longitudinally, plasma p-tau217 values showed an annual increase only in Aβ-positive individuals, with the highest increase observed in those with tau positivity. Conclusions and relevance This study found that a commercially available plasma p-tau217 immunoassay accurately identified biological AD, comparable with results using CSF biomarkers, with reproducible cut-offs across cohorts. It detected longitudinal changes, including at the preclinical stage.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology\" by Ashton NJ, Brum WS, Di Molfetta G et al., https://doi.org/10.1001/jamaneurol.2023.5319, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.14283/jpad.2023.30","kind":"article","title":"Lecanemab: Appropriate Use Recommendations","authors":["Jeffrey L. Cummings","Liana G. Apostolova","Gil Dan Rabinovici","A Atri","Pau Aisen","Steven Mark Greenberg","S Hendrix","D Selkoe","Michael Walter Weiner","Ronald Carl Petersen","Stephen Salloway"],"author_count":11,"year":2023,"published":"2023-03-22","venue":"The Journal of Prevention of Alzheimer s Disease","cited_by":960,"doi":"10.14283/jpad.2023.30","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.14283/jpad.2023.30","archive_url":"https://space-kitty.com/papers/doi:10.14283/jpad.2023.30","updated":null,"pmid":"37357276","pmcid":"PMC10313141","openalex_id":"W4360591479","pdf_url":"https://europepmc.org/articles/PMC10313141/pdf","abstract":"Lecanemab (Leqembi®) is approved in the United States for the treatment of Alzheimer's disease (AD) to be initiated in early AD (mild cognitive impairment [MCI] due to AD or mild AD dementia) with confirmed brain amyloid pathology. Appropriate Use Recommendations (AURs) are intended to help guide the introduction of new therapies into real-world clinical practice. Community dwelling patients with AD differ from those participating in clinical trials. Administration of lecanemab at clinical trial sites by individuals experienced with monoclonal antibody therapy also differs from the community clinic-based administration of lecanemab. These AURs use clinical trial data as well as research and care information regarding AD to help clinicians administer lecanemab with optimal safety and opportunity for effectiveness. Safety and efficacy of lecanemab are known only for patients like those participating in the phase 2 and phase 3 lecanemab trials, and these AURs adhere closely to the inclusion and exclusion criteria of the trials. Adverse events may occur with lecanemab including amyloid related imaging abnormalities (ARIA) and infusion reactions. Monitoring guidelines for these events are detailed in this AUR. Most ARIA with lecanemab is asymptomatic, but a few cases are serious or, very rarely, fatal. Microhemorrhages and rare macrohemorrhages may occur in patients receiving lecanemab. Anticoagulation increases the risk of hemorrhage, and the AUR recommends that patients requiring anticoagulants not receive lecanemab until more data regarding this interaction are available. Patients who are apolipoprotein E ε4 (APOE4) gene carriers, especially APOE4 homozygotes, are at higher risk for ARIA, and the AUR recommends APOE genotyping to better inform risk discussions with patients who are lecanemab candidates. Clinician and institutional preparedness are mandatory for use of lecanemab, and protocols for management of serious events should be developed and implemented. Communication between clinicians and therapy candidates or those on therapy is a key element of good clinical practice for the use of lecanemab. Patients and their care partners must understand the potential benefits, the potential harms, and the monitoring requirements for treatment with this agent. Culture-specific communication and building of trust between clinicians and patients are the foundation for successful use of lecanemab.","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"peer_reviewed":null,"categories":["Alzheimer's disease research and treatments"],"details":null,"provenance":"openalex+europepmc","attribution":"Abstract of \"Lecanemab: Appropriate Use Recommendations\" by Jeffrey L. Cummings, Liana G. Apostolova, Gil Dan Rabinovici et al., https://doi.org/10.14283/jpad.2023.30, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1186/s13195-021-00813-8","kind":"article","title":"A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody","authors":["Chad J. Swanson","Yong Zhang","Shobha Dhadda","Jinping Wang","June M. Kaplow","Robert Y. K. Lai","Lars Lannfelt","Heather Bradley","Martin P. Rabe","Akihiko Koyama","Larisa Reyderman","Donald A. Berry","Scott M. Berry","Robert J. Gordon","Lynn Darden Kramer","Jeffrey L. Cummings"],"author_count":16,"year":2021,"published":"2021-04-17","venue":"Alzheimer s Research & Therapy","cited_by":844,"doi":"10.1186/s13195-021-00813-8","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1186/s13195-021-00813-8","archive_url":"https://space-kitty.com/papers/doi:10.1186/s13195-021-00813-8","updated":null,"pmid":"33865446","pmcid":"PMC8053280","openalex_id":"W3152692563","pdf_url":"https://alzres.biomedcentral.com/counter/pdf/10.1186/s13195-021-00813-8","abstract":"BACKGROUND: Lecanemab (BAN2401), an IgG1 monoclonal antibody, preferentially targets soluble aggregated amyloid beta (Aβ), with activity across oligomers, protofibrils, and insoluble fibrils. BAN2401-G000-201, a randomized double-blind clinical trial, utilized a Bayesian design with response-adaptive randomization to assess 3 doses across 2 regimens of lecanemab versus placebo in early Alzheimer's disease, mild cognitive impairment due to Alzheimer's disease (AD) and mild AD dementia. METHODS: BAN2401-G000-201 aimed to establish the effective dose 90% (ED90), defined as the simplest dose that achieves ≥90% of the maximum treatment effect. The primary endpoint was Bayesian analysis of 12-month clinical change on the Alzheimer's Disease Composite Score (ADCOMS) for the ED90 dose, which required an 80% probability of ≥25% clinical reduction in decline versus placebo. Key secondary endpoints included 18-month Bayesian and frequentist analyses of brain amyloid reduction using positron emission tomography; clinical decline on ADCOMS, Clinical Dementia Rating-Sum-of-Boxes (CDR-SB), and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14); changes in CSF core biomarkers; and total hippocampal volume (HV) using volumetric magnetic resonance imaging. RESULTS: A total of 854 randomized subjects were treated (lecanemab, 609; placebo, 245). At 12 months, the 10-mg/kg biweekly ED90 dose showed a 64% probability to be better than placebo by 25% on ADCOMS, which missed the 80% threshold for the primary outcome. At 18 months, 10-mg/kg biweekly lecanemab reduced brain amyloid (-0.306 SUVr units) while showing a drug-placebo difference in favor of active treatment by 27% and 30% on ADCOMS, 56% and 47% on ADAS-Cog14, and 33% and 26% on CDR-SB versus placebo according to Bayesian and frequentist analyses, respectively. CSF biomarkers were supportive of a treatment effect. Lecanemab was well-tolerated with 9.9% incidence of amyloid-related imaging abnormalities-edema/effusion at 10 mg/kg biweekly. CONCLUSIONS: BAN2401-G000-201 did not meet the 12-month primary endpoint. However, prespecified 18-month Bayesian and frequentist analyses demonstrated reduction in brain amyloid accompanied by a consistent reduction of clinical decline across several clinical and biomarker endpoints. A phase 3 study (Clarity AD) in early Alzheimer's disease is underway. TRIAL REGISTRATION: Clinical Trials.gov NCT01767311 .","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"peer_reviewed":null,"categories":["Alzheimer's disease research and treatments"],"details":null,"provenance":"openalex+europepmc","attribution":"Abstract of \"A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody\" by Chad J. Swanson, Yong Zhang, Shobha Dhadda et al., https://doi.org/10.1186/s13195-021-00813-8, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1038/s41591-024-02869-z","kind":"article","title":"Highly accurate blood test for Alzheimer's disease is similar or superior to clinical cerebrospinal fluid tests","authors":["Barthélemy NR","Salvadó G","Schindler SE","He Y","Janelidze S","Collij LE","Saef B","Henson RL","Chen CD","Gordon BA","Li Y","La Joie R","Benzinger TLS","Morris JC","Mattsson-Carlgren N","Palmqvist S","Ossenkoppele R","Rabinovici GD","Stomrud E","Bateman RJ","Hansson O"],"author_count":21,"year":2024,"published":"2024-02-21","venue":"Nature medicine","cited_by":449,"doi":"10.1038/s41591-024-02869-z","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41591-024-02869-z","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41591-024-02869-z","updated":null,"pmid":"38382645","pmcid":"PMC11031399","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC11031399/pdf","abstract":"With the emergence of Alzheimer's disease (AD) disease-modifying therapies, identifying patients who could benefit from these treatments becomes critical. In this study, we evaluated whether a precise blood test could perform as well as established cerebrospinal fluid (CSF) tests in detecting amyloid-β (Aβ) plaques and tau tangles. Plasma %p-tau217 (ratio of phosporylated-tau217 to non-phosphorylated tau) was analyzed by mass spectrometry in the Swedish BioFINDER-2 cohort (n = 1,422) and the US Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC) cohort (n = 337). Matched CSF samples were analyzed with clinically used and FDA-approved automated immunoassays for Aβ42/40 and p-tau181/Aβ42. The primary and secondary outcomes were detection of brain Aβ or tau pathology, respectively, using positron emission tomography (PET) imaging as the reference standard. Main analyses were focused on individuals with cognitive impairment (mild cognitive impairment and mild dementia), which is the target population for available disease-modifying treatments. Plasma %p-tau217 was clinically equivalent to FDA-approved CSF tests in classifying Aβ PET status, with an area under the curve (AUC) for both between 0.95 and 0.97. Plasma %p-tau217 was generally superior to CSF tests in classification of tau-PET with AUCs of 0.95-0.98. In cognitively impaired subcohorts (BioFINDER-2: n = 720; Knight ADRC: n = 50), plasma %p-tau217 had an accuracy, a positive predictive value and a negative predictive value of 89-90% for Aβ PET and 87-88% for tau PET status, which was clinically equivalent to CSF tests, further improving to 95% using a two-cutoffs approach. Blood plasma %p-tau217 demonstrated performance that was clinically equivalent or superior to clinically used FDA-approved CSF tests in the detection of AD pathology. Use of high-performance blood tests in clinical practice can improve access to accurate AD diagnosis and AD-specific treatments.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Highly accurate blood test for Alzheimer's disease is similar or superior to clinical cerebrospinal fluid tests\" by Barthélemy NR, Salvadó G, Schindler SE et al., https://doi.org/10.1038/s41591-024-02869-z, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1007/s00401-021-02275-6","kind":"article","title":"Plasma p-tau231: a new biomarker for incipient Alzheimer's disease pathology","authors":["Ashton NJ","Pascoal TA","Karikari TK","Benedet AL","Lantero-Rodriguez J","Brinkmalm G","Snellman A","Schöll M","Troakes C","Hye A","Gauthier S","Vanmechelen E","Zetterberg H","Rosa-Neto P","Blennow K"],"author_count":15,"year":2021,"published":"2021-02-14","venue":"Acta neuropathologica","cited_by":615,"doi":"10.1007/s00401-021-02275-6","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1007/s00401-021-02275-6","archive_url":"https://space-kitty.com/papers/doi:10.1007/s00401-021-02275-6","updated":null,"pmid":"33585983","pmcid":"PMC8043944","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC8043944/pdf","abstract":"The quantification of phosphorylated tau in biofluids, either cerebrospinal fluid (CSF) or plasma, has shown great promise in detecting Alzheimer's disease (AD) pathophysiology. Tau phosphorylated at threonine 231 (p-tau231) is one such biomarker in CSF but its usefulness as a blood biomarker is currently unknown. Here, we developed an ultrasensitive Single molecule array (Simoa) for the quantification of plasma p-tau231 which was validated in four independent cohorts (n = 588) in different settings, including the full AD continuum and non-AD neurodegenerative disorders. Plasma p-tau231 was able to identify patients with AD and differentiate them from amyloid-β negative cognitively unimpaired (CU) older adults with high accuracy (AUC = 0.92-0.94). Plasma p-tau231 also distinguished AD patients from patients with non-AD neurodegenerative disorders (AUC = 0.93), as well as from amyloid-β negative MCI patients (AUC = 0.89). In a neuropathology cohort, plasma p-tau231 in samples taken on avergae 4.2 years prior to post-mortem very accurately identified AD neuropathology in comparison to non-AD neurodegenerative disorders (AUC = 0.99), this is despite all patients being given an AD dementia diagnosis during life. Plasma p-tau231 was highly correlated with CSF p-tau231, tau pathology as assessed by [ 18 F]MK-6240 positron emission tomography (PET), and brain amyloidosis by [ 18 F]AZD469 PET. Remarkably, the inflection point of plasma p-tau231, increasing as a function of continuous [ 18 F]AZD469 amyloid-β PET standardized uptake value ratio, was shown to be earlier than standard thresholds of amyloid-β PET positivity and the increase of plasma p-tau181. Furthermore, plasma p-tau231 was significantly increased in amyloid-β PET quartiles 2-4, whereas CSF p-tau217 and plasma p-tau181 increased only at quartiles 3-4 and 4, respectively. Finally, plasma p-tau231 differentiated individuals across the entire Braak stage spectrum, including Braak staging from Braak 0 through Braak I-II, which was not observed for plasma p-tau181. To conclude, this novel plasma p-tau231 assay identifies the clinical stages of AD and neuropathology equally well as plasma p-tau181, but increases earlier, already with subtle amyloid-β deposition, prior to the threshold for amyloid-β PET positivity has been attained, and also in response to early brain tau deposition. Thus, plasma p-tau231 is a promising novel biomarker of emerging AD pathology with the potential to facilitate clinical trials to identify vulnerable populations below PET threshold of amyloid-β positivity or apparent entorhinal tau deposition.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Plasma p-tau231: a new biomarker for incipient Alzheimer's disease pathology\" by Ashton NJ, Pascoal TA, Karikari TK et al., https://doi.org/10.1007/s00401-021-02275-6, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1038/s41591-022-01925-w","kind":"article","title":"Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer's disease","authors":["Milà-Alomà M","Ashton NJ","Shekari M","Salvadó G","Ortiz-Romero P","Montoliu-Gaya L","Benedet AL","Karikari TK","Lantero-Rodriguez J","Vanmechelen E","Day TA","González-Escalante A","Sánchez-Benavides G","Minguillon C","Fauria K","Molinuevo JL","Dage JL","Zetterberg H","Gispert JD","Suárez-Calvet M","Blennow K"],"author_count":21,"year":2022,"published":"2022-08-11","venue":"Nature medicine","cited_by":534,"doi":"10.1038/s41591-022-01925-w","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41591-022-01925-w","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41591-022-01925-w","updated":null,"pmid":"35953717","pmcid":"PMC9499867","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC9499867/pdf","abstract":"Blood biomarkers indicating elevated amyloid-β (Aβ) pathology in preclinical Alzheimer's disease are needed to facilitate the initial screening process of participants in disease-modifying trials. Previous biofluid data suggest that phosphorylated tau231 (p-tau231) could indicate incipient Aβ pathology, but a comprehensive comparison with other putative blood biomarkers is lacking. In the ALFA+ cohort, all tested plasma biomarkers (p-tau181, p-tau217, p-tau231, GFAP, NfL and Aβ42/40) were significantly changed in preclinical Alzheimer's disease. However, plasma p-tau231 reached abnormal levels with the lowest Aβ burden. Plasma p-tau231 and p-tau217 had the strongest association with Aβ positron emission tomography (PET) retention in early accumulating regions and associated with longitudinal increases in Aβ PET uptake in individuals without overt Aβ pathology at baseline. In summary, plasma p-tau231 and p-tau217 better capture the earliest cerebral Aβ changes, before overt Aβ plaque pathology is present, and are promising blood biomarkers to enrich a preclinical population for Alzheimer's disease clinical trials.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer's disease\" by Milà-Alomà M, Ashton NJ, Shekari M et al., https://doi.org/10.1038/s41591-022-01925-w, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1007/s40259-023-00633-2","kind":"review","title":"Anti-Amyloid Monoclonal Antibodies for the Treatment of Alzheimer’s Disease","authors":["Jeffrey L. Cummings","Amanda M. Leisgang Osse","Davis Cammann","Jayde Powell","Jingchun Chen"],"author_count":5,"year":2023,"published":"2023-11-13","venue":"BioDrugs","cited_by":377,"doi":"10.1007/s40259-023-00633-2","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1007/s40259-023-00633-2","archive_url":"https://space-kitty.com/papers/doi:10.1007/s40259-023-00633-2","updated":null,"pmid":"37955845","pmcid":null,"openalex_id":"W4388626497","pdf_url":"https://link.springer.com/content/pdf/10.1007/s40259-023-00633-2.pdf","abstract":null,"abstract_license":null,"license":"cc-by-nc","is_open_access":true,"peer_reviewed":null,"categories":["Alzheimer's disease research and treatments"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.1007/s13311-022-01308-6","kind":"article","title":"Lecanemab, Aducanumab, and Gantenerumab — Binding Profiles to Different Forms of Amyloid-Beta Might Explain Efficacy and Side Effects in Clinical Trials for Alzheimer's Disease","authors":["Linda Söderberg","Malin Johannesson","Patrik Nygren","Hanna Laudon","Fredrik Eriksson","Gunilla Osswald","Christer Möller","Lars Lannfelt"],"author_count":8,"year":2022,"published":"2022-10-17","venue":"Neurotherapeutics","cited_by":433,"doi":"10.1007/s13311-022-01308-6","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1007/s13311-022-01308-6","archive_url":"https://space-kitty.com/papers/doi:10.1007/s13311-022-01308-6","updated":null,"pmid":"36253511","pmcid":"PMC10119362","openalex_id":"W4306644813","pdf_url":"https://link.springer.com/content/pdf/10.1007/s13311-022-01308-6.pdf","abstract":"Immunotherapy against amyloid-beta (Aβ) is a promising option for the treatment of Alzheimer's disease (AD). Aβ exists as various species, including monomers, oligomers, protofibrils, and insoluble fibrils in plaques. Oligomers and protofibrils have been shown to be toxic, and removal of these aggregates might represent an effective treatment for AD. We have characterized the binding properties of lecanemab, aducanumab, and gantenerumab to different Aβ species with inhibition ELISA, immunodepletion, and surface plasmon resonance. All three antibodies bound monomers with low affinity. However, lecanemab and aducanumab had very weak binding to monomers, and gantenerumab somewhat stronger binding. Lecanemab was distinctive as it had tenfold stronger binding to protofibrils compared to fibrils. Aducanumab and gantenerumab preferred binding to fibrils over protofibrils. Our results show different binding profiles of lecanemab, aducanumab, and gantenerumab that may explain clinical results observed for these antibodies regarding both efficacy and side effects.","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"peer_reviewed":null,"categories":["Alzheimer's disease research and treatments"],"details":null,"provenance":"openalex+europepmc","attribution":"Abstract of \"Lecanemab, Aducanumab, and Gantenerumab — Binding Profiles to Different Forms of Amyloid-Beta Might Explain Efficacy and Side Effects in Clinical Trials for Alzheimer's Disease\" by Linda Söderberg, Malin Johannesson, Patrik Nygren et al., https://doi.org/10.1007/s13311-022-01308-6, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1038/s41591-022-02074-w","kind":"article","title":"Differential roles of Aβ42/40, p-tau231 and p-tau217 for Alzheimer's trial selection and disease monitoring","authors":["Ashton NJ","Janelidze S","Mattsson-Carlgren N","Binette AP","Strandberg O","Brum WS","Karikari TK","González-Ortiz F","Di Molfetta G","Meda FJ","Jonaitis EM","Koscik RL","Cody K","Betthauser TJ","Li Y","Vanmechelen E","Palmqvist S","Stomrud E","Bateman RJ","Zetterberg H","Johnson SC","Blennow K","Hansson O"],"author_count":23,"year":2022,"published":"2022-12-01","venue":"Nature medicine","cited_by":420,"doi":"10.1038/s41591-022-02074-w","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41591-022-02074-w","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41591-022-02074-w","updated":null,"pmid":"36456833","pmcid":"PMC9800279","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC9800279/pdf","abstract":"Blood biomarkers indicative of Alzheimer's disease (AD) pathology are altered in both preclinical and symptomatic stages of the disease. Distinctive biomarkers may be optimal for the identification of AD pathology or monitoring of disease progression. Blood biomarkers that correlate with changes in cognition and atrophy during the course of the disease could be used in clinical trials to identify successful interventions and thereby accelerate the development of efficient therapies. When disease-modifying treatments become approved for use, efficient blood-based biomarkers might also inform on treatment implementation and management in clinical practice. In the BioFINDER-1 cohort, plasma phosphorylated (p)-tau231 and amyloid-β42/40 ratio were more changed at lower thresholds of amyloid pathology. Longitudinally, however, only p-tau217 demonstrated marked amyloid-dependent changes over 4-6 years in both preclinical and symptomatic stages of the disease, with no such changes observed in p-tau231, p-tau181, amyloid-β42/40, glial acidic fibrillary protein or neurofilament light. Only longitudinal increases of p-tau217 were also associated with clinical deterioration and brain atrophy in preclinical AD. The selective longitudinal increase of p-tau217 and its associations with cognitive decline and atrophy was confirmed in an independent cohort (Wisconsin Registry for Alzheimer's Prevention). These findings support the differential association of plasma biomarkers with disease development and strongly highlight p-tau217 as a surrogate marker of disease progression in preclinical and prodromal AD, with impact for the development of new disease-modifying treatments.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Differential roles of Aβ42/40, p-tau231 and p-tau217 for Alzheimer's trial selection and disease monitoring\" by Ashton NJ, Janelidze S, Mattsson-Carlgren N et al., https://doi.org/10.1038/s41591-022-02074-w, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1186/s13195-022-01124-2","kind":"article","title":"Lecanemab in patients with early Alzheimer’s disease: detailed results on biomarker, cognitive, and clinical effects from the randomized and open-label extension of the phase 2 proof-of-concept study","authors":["Eric McDade","Jeffrey L. Cummings","Shobha Dhadda","Chad J. Swanson","Larisa Reyderman","Michio Kanekiyo","Akihiko Koyama","Michael C. Irizarry","Lynn Darden Kramer","Randall John Bateman"],"author_count":10,"year":2022,"published":"2022-12-21","venue":"Alzheimer s Research & Therapy","cited_by":306,"doi":"10.1186/s13195-022-01124-2","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1186/s13195-022-01124-2","archive_url":"https://space-kitty.com/papers/doi:10.1186/s13195-022-01124-2","updated":null,"pmid":"36544184","pmcid":"PMC9768996","openalex_id":"W4312128797","pdf_url":"https://alzres.biomedcentral.com/counter/pdf/10.1186/s13195-022-01124-2","abstract":"BACKGROUND: Lecanemab, a humanized IgG1 monoclonal antibody that targets soluble aggregated Aβ species (protofibrils), has demonstrated robust brain fibrillar amyloid reduction and slowing of clinical decline in early AD. The objective of this analysis is to report results from study 201 blinded period (core), the open-label extension (OLE), and gap period (between core and OLE) supporting the effectiveness of lecanemab. METHODS: The lecanemab study 201 core was a double-blind, randomized, placebo-controlled study of 856 patients randomized to one of five dose regimens or placebo. An OLE of study 201 was initiated to allow patients to receive open-label lecanemab 10mg/kg biweekly for up to 24 months, with an intervening off-treatment period (gap period) ranging from 9 to 59 months (mean 24 months). RESULTS: At 12 and 18 months of treatment in the core, lecanemab 10 mg/kg biweekly demonstrated dose-dependent reductions of brain amyloid measured PET and corresponding changes in plasma biomarkers and slowing of cognitive decline. The rates of clinical progression during the gap were similar in lecanemab and placebo subjects, with clinical treatment differences maintained after discontinued dosing over an average of 24 months in the gap period. During the gap, plasma Aβ42/40 ratio and p-tau181 levels began to return towards pre-randomization levels more quickly than amyloid PET. At OLE baseline, treatment differences vs placebo at 18 months in the randomized period were maintained across 3 clinical assessments. In the OLE, lecanemab 10 mg/kg biweekly treatment produced dose-dependent reductions in amyloid PET SUVr, improvements in plasma Aβ42/40 ratio, and reductions in plasma p-tau181. CONCLUSIONS: Lecanemab treatment resulted in significant reduction in amyloid plaques and a slowing of clinical decline. Data indicate that rapid and pronounced amyloid reduction correlates with clinical benefit and potential disease-modifying effects, as well as the potential to use plasma biomarkers to monitor for lecanemab treatment effects. TRIAL REGISTRATION: ClinicalTrials.gov NCT01767311 .","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"peer_reviewed":null,"categories":["Alzheimer's disease research and treatments"],"details":null,"provenance":"openalex+europepmc","attribution":"Abstract of \"Lecanemab in patients with early Alzheimer’s disease: detailed results on biomarker, cognitive, and clinical effects from the randomized and open-label extension of the phase 2 proof-of-concept study\" by Eric McDade, Jeffrey L. Cummings, Shobha Dhadda et al., https://doi.org/10.1186/s13195-022-01124-2, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1002/alz.12748","kind":"article","title":"The AHEAD 3‐45 Study: Design of a prevention trial for Alzheimer's disease","authors":["Michael S. Rafii","Reisa Anne Sperling","Michael Donohue","Jin Zhou","Claire Roberts","Michael C. Irizarry","Shobha Dhadda","Gopalan Sethuraman","Lynn Darden Kramer","Chad J. Swanson","David Xinzheyang Li","Stephen Krause","Robert A. Rissman","Sarah Walter","Rema Raman","Keith A. Johnson","Paul S. S. Aisen"],"author_count":17,"year":2022,"published":"2022-08-15","venue":"Alzheimer s & Dementia","cited_by":291,"doi":"10.1002/alz.12748","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1002/alz.12748","archive_url":"https://space-kitty.com/papers/doi:10.1002/alz.12748","updated":null,"pmid":"35971310","pmcid":null,"openalex_id":"W4291824893","pdf_url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/alz.12748","abstract":null,"abstract_license":null,"license":"cc-by-nc","is_open_access":true,"peer_reviewed":null,"categories":["Alzheimer's disease research and treatments"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.1186/s12929-023-00976-6","kind":"review","title":"Clinical trials of new drugs for Alzheimer disease: a 2020–2023 update","authors":["Li‐Kai Huang","Yi‐Chun Kuan","Ho-Wei Lin","Chaur‐Jong Hu"],"author_count":4,"year":2023,"published":"2023-10-02","venue":"Journal of Biomedical Science","cited_by":252,"doi":"10.1186/s12929-023-00976-6","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1186/s12929-023-00976-6","archive_url":"https://space-kitty.com/papers/doi:10.1186/s12929-023-00976-6","updated":null,"pmid":"37784171","pmcid":"PMC10544555","openalex_id":"W4387259038","pdf_url":"https://jbiomedsci.biomedcentral.com/counter/pdf/10.1186/s12929-023-00976-6","abstract":"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.","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"peer_reviewed":null,"categories":["Alzheimer's disease research and treatments"],"details":null,"provenance":"openalex+europepmc","attribution":"Abstract of \"Clinical trials of new drugs for Alzheimer disease: a 2020–2023 update\" by Li‐Kai Huang, Yi‐Chun Kuan, Ho-Wei Lin et al., https://doi.org/10.1186/s12929-023-00976-6, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1001/jamaneurol.2022.5272","kind":"article","title":"Prediction of Longitudinal Cognitive Decline in Preclinical Alzheimer Disease Using Plasma Biomarkers","authors":["Mattsson-Carlgren N","Salvadó G","Ashton NJ","Tideman P","Stomrud E","Zetterberg H","Ossenkoppele R","Betthauser TJ","Cody KA","Jonaitis EM","Langhough R","Palmqvist S","Blennow K","Janelidze S","Johnson SC","Hansson O"],"author_count":16,"year":2023,"published":"2023-04-01","venue":"JAMA neurology","cited_by":295,"doi":"10.1001/jamaneurol.2022.5272","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1001/jamaneurol.2022.5272","archive_url":"https://space-kitty.com/papers/doi:10.1001/jamaneurol.2022.5272","updated":null,"pmid":"36745413","pmcid":"PMC10087054","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC10087054/pdf","abstract":"Importance Alzheimer disease (AD) pathology starts with a prolonged phase of β-amyloid (Aβ) accumulation without symptoms. The duration of this phase differs greatly among individuals. While this disease phase has high relevance for clinical trial designs, it is currently unclear how to best predict the onset of clinical progression. Objective To evaluate combinations of different plasma biomarkers for predicting cognitive decline in Aβ-positive cognitively unimpaired (CU) individuals. Design, setting, and participants This prospective population-based prognostic study evaluated data from 2 prospective longitudinal cohort studies (the Swedish BioFINDER-1 and the Wisconsin Registry for Alzheimer Prevention [WRAP]), with data collected from February 8, 2010, to October 21, 2020, for the BioFINDER-1 cohort and from August 11, 2011, to June 27, 2021, for the WRAP cohort. Participants were CU individuals recruited from memory clinics who had brain Aβ pathology defined by cerebrospinal fluid (CSF) Aβ42/40 in the BioFINDER-1 study and by Pittsburgh Compound B (PiB) positron emission tomography (PET) in the WRAP study. A total of 564 eligible Aβ-positive and Aβ-negative CU participants with available relevant data from the BioFINDER-1 and WRAP cohorts were included in the study; of those, 171 Aβ-positive participants were included in the main analyses. Exposures Baseline P-tau181, P-tau217, P-tau231, glial fibrillary filament protein, and neurofilament light measured in plasma; CSF biomarkers in the BioFINDER-1 cohort, and PiB PET uptake in the WRAP cohort. Main outcomes and measures The primary outcome was longitudinal measures of cognition (using the Mini-Mental State Examination [MMSE] and the modified Preclinical Alzheimer Cognitive Composite [mPACC]) over a median of 6 years (range, 2-10 years). The secondary outcome was conversion to AD dementia. Baseline biomarkers were used in linear regression models to predict rates of longitudinal cognitive change (calculated separately). Models were adjusted for age, sex, years of education, apolipoprotein E ε4 allele status, and baseline cognition. Multivariable models were compared based on model R2 coefficients and corrected Akaike information criterion. Results Among 171 Aβ-positive CU participants included in the main analyses, 119 (mean [SD] age, 73.0 [5.4] years; 60.5% female) were from the BioFINDER-1 study, and 52 (mean [SD] age, 64.4 [4.6] years; 65.4% female) were from the WRAP study. In the BioFINDER-1 cohort, plasma P-tau217 was the best marker to predict cognitive decline in the mPACC (model R2 = 0.41) and the MMSE (model R2 = 0.34) and was superior to the covariates-only models (mPACC: R2 = 0.23; MMSE: R2 = 0.04; P < .001 for both comparisons). Results were validated in the WRAP cohort; for example, plasma P-tau217 was associated with mPACC slopes (R2 = 0.13 vs 0.01 in the covariates-only model; P = .01) and MMSE slopes (R2 = 0.29 vs 0.24 in the covariates-only model; P = .046). Sparse models were identified with plasma P-tau217 as a predictor of cognitive decline. Power calculations for enrichment in hypothetical clinical trials revealed large relative reductions in sample sizes when using plasma P-tau217 to enrich for CU individuals likely to experience cognitive decline over time. Conclusions and relevance In this study, plasma P-tau217 predicted cognitive decline in patients with preclinical AD. These findings suggest that plasma P-tau217 may be used as a complement to CSF or PET for participant selection in clinical trials of novel disease-modifying treatments.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Prediction of Longitudinal Cognitive Decline in Preclinical Alzheimer Disease Using Plasma Biomarkers\" by Mattsson-Carlgren N, Salvadó G, Ashton NJ et al., https://doi.org/10.1001/jamaneurol.2022.5272, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.3389/fnagi.2022.870517","kind":"review","title":"Impact of Anti-amyloid-β Monoclonal Antibodies on the Pathology and Clinical Profile of Alzheimer’s Disease: A Focus on Aducanumab and Lecanemab","authors":["Mingchao Shi","Fengna Chu","Feiqi Zhu","Jie Zhu"],"author_count":4,"year":2022,"published":"2022-04-12","venue":"Frontiers in Aging Neuroscience","cited_by":275,"doi":"10.3389/fnagi.2022.870517","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.3389/fnagi.2022.870517","archive_url":"https://space-kitty.com/papers/doi:10.3389/fnagi.2022.870517","updated":null,"pmid":"35493943","pmcid":"PMC9039457","openalex_id":"W4223533048","pdf_url":"https://www.frontiersin.org/articles/10.3389/fnagi.2022.870517/pdf","abstract":"Alzheimer's disease (AD) is the most prevalent form of age-related dementia in the world, and its main pathological features consist of amyloid-β (Aβ) plaque deposits and neurofibrillary tangles formed by hyperphosphorylated tau protein. So far, only a few AD treatments approved have been applied in the clinic, but the effects of these drugs are limited only for partial symptomatic relief to patients with AD and are unable to alter AD progression. Later, all efforts for AD treatments with targeting the pathogenic factors were unsuccessful over the past decades, which suggested that the pathogenesis of AD is complex. Recently, disease-modifying therapies (DMTs) that can change the underlying pathophysiology of AD, with anti-Aβ monoclonal antibodies (mabs) (e.g., aducanumab, bapineuzumab, gantenerumab, solanezumab, and lecanemab) have been developed successively and conducted in clinical trials based on the theory that a systemic failure of cell-mediated Aβ clearance contributes to AD occurrence and progression. In the review, we summarized recent studies on the therapeutic effects and clinical trial results of these mabs in patients with AD. Specifically, we focused on the discussion of the impact of aducanumab and lecanemab on AD pathology and clinical profiles. The review provides a possible evidence for applying immunotherapy with anti-Aβ mabs in AD and analyzes lessons learned from these clinical trials in order to further study the therapeutic and adverse effects of these anti-Aβ mabs on AD.","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"peer_reviewed":null,"categories":["Alzheimer's disease research and treatments"],"details":null,"provenance":"openalex+europepmc","attribution":"Abstract of \"Impact of Anti-amyloid-β Monoclonal Antibodies on the Pathology and Clinical Profile of Alzheimer’s Disease: A Focus on Aducanumab and Lecanemab\" by Mingchao Shi, Fengna Chu, Feiqi Zhu et al., https://doi.org/10.3389/fnagi.2022.870517, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1186/s13195-024-01441-8","kind":"article","title":"Updated safety results from phase 3 lecanemab study in early Alzheimer’s disease","authors":["Lawrence S. Honig","Marwan Noel Sabbagh","Christopher H. van Dyck","Reisa Anne Sperling","Steven M. Hersch","André P. C. Matta","Luigi Giorgi","Michelle Gee","Michio Kanekiyo","David Li","Derk D. Purcell","Shobha Dhadda","Michael C. Irizarry","Lynn Darden Kramer"],"author_count":14,"year":2024,"published":"2024-05-10","venue":"Alzheimer s Research & Therapy","cited_by":180,"doi":"10.1186/s13195-024-01441-8","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1186/s13195-024-01441-8","archive_url":"https://space-kitty.com/papers/doi:10.1186/s13195-024-01441-8","updated":null,"pmid":"38730496","pmcid":"PMC11084061","openalex_id":"W4396804148","pdf_url":"https://europepmc.org/articles/PMC11084061/pdf","abstract":"BACKGROUND: Alzheimer disease (AD) is a major health problem of aging, with tremendous burden on healthcare systems, patients, and families globally. Lecanemab, an FDA-approved amyloid beta (Aβ)-directed antibody indicated for the treatment of early AD, binds with high affinity to soluble Aβ protofibrils, which have been shown to be more toxic to neurons than monomers or insoluble fibrils. Lecanemab has been shown to be well tolerated in multiple clinical trials, although risks include an increased rate of amyloid-related imaging abnormalities (ARIA) and infusion reactions relative to placebo. METHODS: Clarity AD was an 18-month treatment (Core study), multicenter, double-blind, placebo-controlled, parallel-group study with open-label extension (OLE) in participants with early AD. Eligible participants were randomized 1:1 across 2 treatment groups (placebo and lecanemab 10 mg/kg biweekly). Safety evaluations included monitoring of vital signs, physical examinations, adverse events, clinical laboratory parameters, and 12-lead electrocardiograms. ARIA occurrence was monitored throughout the study by magnetic resonance imaging, read both locally and centrally. RESULTS: Overall, 1795 participants from Core and 1612 participants with at least one dose of lecanemab (Core + OLE) were included. Lecanemab was generally well-tolerated in Clarity AD, with no deaths related to lecanemab in the Core study. There were 9 deaths during the OLE, with 4 deemed possibly related to study treatment. Of the 24 deaths in Core + OLE, 3 were due to intracerebral hemorrhage (ICH): 1 placebo in the Core due to ICH, and 2 lecanemab in OLE with concurrent ICH (1 on tissue plasminogen activator and 1 on anticoagulant therapy). In the Core + OLE, the most common adverse events in the lecanemab group (> 10%) were infusion-related reactions (24.5%), ARIA with hemosiderin deposits (ARIA-H) microhemorrhages (16.0%), COVID-19 (14.7%), ARIA with edema (ARIA-E; 13.6%), and headache (10.3%). ARIA-E and ARIA-H were largely radiographically mild-to-moderate. ARIA-E generally occurred within 3-6 months of treatment, was more common in ApoE e4 carriers (16.8%) and most common in ApoE ε4 homozygous participants (34.5%). CONCLUSIONS: Lecanemab was generally well-tolerated, with the most common adverse events being infusion-related reactions, ARIA-H, ARIA-E. Clinicians, participants, and caregivers should understand the incidence, monitoring, and management of these events for optimal patient care. TRIAL REGISTRATION: ClinicalTrials.gov numbers: Clarity AD NCT03887455).","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"peer_reviewed":null,"categories":["Alzheimer's disease research and treatments"],"details":null,"provenance":"openalex+europepmc","attribution":"Abstract of \"Updated safety results from phase 3 lecanemab study in early Alzheimer’s disease\" by Lawrence S. Honig, Marwan Noel Sabbagh, Christopher H. van Dyck et al., https://doi.org/10.1186/s13195-024-01441-8, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1038/s41467-020-15436-0","kind":"article","title":"Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer's disease","authors":["Janelidze S","Stomrud E","Smith R","Palmqvist S","Mattsson N","Airey DC","Proctor NK","Chai X","Shcherbinin S","Sims JR","Triana-Baltzer G","Theunis C","Slemmon R","Mercken M","Kolb H","Dage JL","Hansson O"],"author_count":17,"year":2020,"published":"2020-04-03","venue":"Nature communications","cited_by":388,"doi":"10.1038/s41467-020-15436-0","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41467-020-15436-0","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41467-020-15436-0","updated":null,"pmid":"32246036","pmcid":"PMC7125218","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC7125218/pdf","abstract":"Cerebrospinal fluid (CSF) p-tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer's disease (AD), reflecting abnormal tau metabolism in the brain. Here we investigate the performance of CSF p-tau217 as a biomarker of AD in comparison to p-tau181. In the Swedish BioFINDER cohort (n = 194), p-tau217 shows stronger correlations with the tau positron emission tomography (PET) tracer [ 18 F]flortaucipir, and more accurately identifies individuals with abnormally increased [ 18 F]flortaucipir retention. Furthermore, longitudinal increases in p-tau217 are higher compared to p-tau181 and better correlate with [ 18 F]flortaucipir uptake. P-tau217 correlates better than p-tau181 with CSF and PET measures of neocortical amyloid-β burden and more accurately distinguishes AD dementia from non-AD neurodegenerative disorders. Higher correlations between p-tau217 and [ 18 F]flortaucipir are corroborated in an independent EXPEDITION3 trial cohort (n = 32). The main results are validated using a different p-tau217 immunoassay. These findings suggest that p-tau217 might be more useful than p-tau181 in the diagnostic work up of AD.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer's disease\" by Janelidze S, Stomrud E, Smith R et al., https://doi.org/10.1038/s41467-020-15436-0, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1186/s40035-025-00465-w","kind":"review","title":"Second-generation anti-amyloid monoclonal antibodies for Alzheimer’s disease: current landscape and future perspectives","authors":["Byeong‐Hyeon Kim","Sujin Kim","Yunkwon Nam","Yong‐Ho Park","Seong Min Shin","Minho Moon"],"author_count":6,"year":2025,"published":"2025-01-26","venue":"Translational Neurodegeneration","cited_by":149,"doi":"10.1186/s40035-025-00465-w","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1186/s40035-025-00465-w","archive_url":"https://space-kitty.com/papers/doi:10.1186/s40035-025-00465-w","updated":null,"pmid":"39865265","pmcid":"PMC11771116","openalex_id":"W4406829716","pdf_url":"https://translationalneurodegeneration.biomedcentral.com/counter/pdf/10.1186/s40035-025-00465-w","abstract":"Alzheimer's disease (AD) is the most common type of dementia. Monoclonal antibodies (MABs) serve as a promising therapeutic approach for AD by selectively targeting key pathogenic factors, such as amyloid-β (Aβ) peptide, tau protein, and neuroinflammation. Specifically, based on their efficacy in removing Aβ plaques from the brains of patients with AD, the U.S. Food and Drug Administration has approved three anti-amyloid MABs, aducanumab (Aduhelm®), lecanemab (Leqembi®), and donanemab (Kisunla™). Notably, lecanemab received traditional approval after demonstrating clinical benefit, supporting the Aβ cascade hypothesis. These MABs targeting Aβ are categorized based on their affinity to diverse conformational features of Aβ, including monomer, fibril, protofibril, and plaque forms of Aβ as well as pyroglutamate Aβ. First-generation MABs targeting the non-toxic monomeric Aβ, such as solanezumab, bapineuzumab, and crenezumab, failed to demonstrate clinical benefit for AD in clinical trials. In contrast, second-generation MABs, including aducanumab, lecanemab, donanemab, and gantenerumab directed against pathogenic Aβ species and aggregates have shown that reducing Aβ deposition can be an effective strategy to slow cognitive impairment in AD. In this review, we provide a comprehensive overview of the current status, mechanisms, outcomes, and limitations of second-generation MABs for the clinical treatment of AD. Moreover, we discuss the perspectives and future directions of anti-amyloid MABs in the treatment of AD.","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"peer_reviewed":null,"categories":["Alzheimer's disease research and treatments"],"details":null,"provenance":"openalex+europepmc","attribution":"Abstract of \"Second-generation anti-amyloid monoclonal antibodies for Alzheimer’s disease: current landscape and future perspectives\" by Byeong‐Hyeon Kim, Sujin Kim, Yunkwon Nam et al., https://doi.org/10.1186/s40035-025-00465-w, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1016/j.tjpad.2025.100150","kind":"article","title":"Donanemab: Appropriate use recommendations","authors":["Rabinovici GD","Selkoe DJ","Schindler SE","Aisen P","Apostolova LG","Atri A","Greenberg SM","Hendrix SB","Petersen RC","Weiner M","Salloway S","Cummings J"],"author_count":12,"year":2025,"published":"2025-03-27","venue":"The journal of prevention of Alzheimer's disease","cited_by":205,"doi":"10.1016/j.tjpad.2025.100150","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1016/j.tjpad.2025.100150","archive_url":"https://space-kitty.com/papers/doi:10.1016/j.tjpad.2025.100150","updated":null,"pmid":"40155270","pmcid":"PMC12180672","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC12180672/pdf","abstract":"Donanemab (Kisunla®), an IgG1 monoclonal antibody targeting N-terminal pyroglutamate-modified forms of amyloid-β, is approved in the United States for treatment of early symptomatic Alzheimer's disease (AD). Appropriate Use Recommendations (AUR) were developed to guide the implementation of donanemab in real-world practice, prioritizing safety considerations and opportunity for effectiveness. The AUR were developed by the AD and Related Disorders Therapeutic Workgroup by consensus, integrating available data and expert opinion. Appropriate candidates for donanemab treatment include persons with mild cognitive impairment or mild dementia due to AD (Clinical Stages 3-4, MMSE 20-30) who have biomarker confirmation of AD pathology by PET or CSF. Tau PET is not required for eligibility. Apolipoprotein E (APOE) genotyping should be performed prior to treatment to inform an individual's risk of developing Amyloid-Related Imaging Abnormalities (ARIA). Pre-treatment MRI should be obtained no more than 12 months prior to treatment. Patients with findings of >4 cerebral microbleeds, cortical superficial siderosis or a major vascular contribution to cognitive impairment should be excluded from treatment. 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. Surveillance MRIs to evaluate for ARIA should be performed prior to the 2nd, 3rd, 4th and 7th infusions, prior to the 12th dose in higher risk individuals, and at any time ARIA is suspected clinically. Clinicians may consider discontinuing treatment if amyloid clearance is demonstrated by amyloid PET, typically obtained 12-18 months after initiating treatment.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Donanemab: Appropriate use recommendations\" by Rabinovici GD, Selkoe DJ, Schindler SE et al., https://doi.org/10.1016/j.tjpad.2025.100150, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1001/jamaneurol.2020.4201","kind":"article","title":"Associations of Plasma Phospho-Tau217 Levels With Tau Positron Emission Tomography in Early Alzheimer Disease","authors":["Janelidze S","Berron D","Smith R","Strandberg O","Proctor NK","Dage JL","Stomrud E","Palmqvist S","Mattsson-Carlgren N","Hansson O"],"author_count":10,"year":2021,"published":"2021-02-01","venue":"JAMA neurology","cited_by":344,"doi":"10.1001/jamaneurol.2020.4201","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1001/jamaneurol.2020.4201","archive_url":"https://space-kitty.com/papers/doi:10.1001/jamaneurol.2020.4201","updated":null,"pmid":"33165506","pmcid":"PMC7653537","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC7653537/pdf","abstract":"Importance There is an urgent need for inexpensive and minimally invasive blood biomarkers for Alzheimer disease (AD) that could be used to detect early disease changes. Objective To assess how early in the course of AD plasma levels of tau phosphorylated at threonine 217 (P-tau217) start to change compared with levels of established cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers of AD pathology. Design, setting, and participants This cohort study included cognitively healthy control individuals (n = 225) and participants with subjective cognitive decline (n = 89) or mild cognitive impairment (n = 176) from the BioFINDER-2 study. Participants were enrolled at 2 different hospitals in Sweden from January 2017 to October 2019. All study participants underwent plasma P-tau217 assessments and tau- and amyloid-β (Aβ)-PET imaging. A subcohort of 111 participants had 2 or 3 tau-PET scans. Main outcomes and measures Changes in plasma P-tau217 levels in preclinical and prodromal AD compared with changes in CSF P-tau217 and PET measures. Results Of 490 participants, 251 were women (51.2%) and the mean (SD) age was 65.9 (13.1) years. Plasma P-tau217 levels were increased in cognitively unimpaired participants with abnormal Aβ-PET but normal tau-PET in the entorhinal cortex (Aβ-PET+/ tau-PET- group vs Aβ-PET-/ tau-PET- group: median, 2.2 pg/mL [interquartile range (IQR), 1.5-2.9 pg/mL] vs 0.7 pg/mL [IQR, 0.3-1.4 pg/mL]). Most cognitively unimpaired participants who were discordant for plasma P-tau217 and tau-PET were positive for plasma P-tau217 and negative for tau-PET (P-tau217+/tau-PET-: 36 [94.7%]; P-tau217-/tau-PET+: 2 [5.3%]). Event-based modeling of cross-sectional data predicted that in cognitively unimpaired participants and in those with mild cognitive impairment, both plasma and CSF P-tau217 would change before the tau-PET signal in the entorhinal cortex, followed by more widespread cortical tau-PET changes. When testing the association with global Aβ load in nonlinear spline models, both plasma and CSF P-tau217 were increased at lower Aβ-PET values compared with tau-PET measures. Among participants with normal baseline tau-PET, the rates of longitudinal increase in tau-PET in the entorhinal cortex were higher in those with abnormal plasma P-tau217 at baseline (median standardized uptake value ratio, 0.029 [IQR, -0.006 to 0.041] vs -0.001 [IQR, -0.021 to 0.020]; Mann-Whitney U, P = .02). Conclusions and relevance In this cohort study, plasma P-tau217 levels were increased during the early preclinical stages of AD when insoluble tau aggregates were not yet detectable by tau-PET. Plasma P-tau217 may hold promise as a biomarker for early AD brain pathology.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Associations of Plasma Phospho-Tau217 Levels With Tau Positron Emission Tomography in Early Alzheimer Disease\" by Janelidze S, Berron D, Smith R et al., https://doi.org/10.1001/jamaneurol.2020.4201, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1001/jamaneurol.2022.4485","kind":"article","title":"Association of Phosphorylated Tau Biomarkers With Amyloid Positron Emission Tomography vs Tau Positron Emission Tomography","authors":["Therriault J","Vermeiren M","Servaes S","Tissot C","Ashton NJ","Benedet AL","Karikari TK","Lantero-Rodriguez J","Brum WS","Lussier FZ","Bezgin G","Stevenson J","Rahmouni N","Kunach P","Wang YT","Fernandez-Arias J","Socualaya KQ","Macedo AC","Ferrari-Souza JP","Ferreira PCL","Bellaver B","Leffa DT","Zimmer ER","Vitali P","Soucy JP"],"author_count":33,"year":2023,"published":"2023-02-01","venue":"JAMA neurology","cited_by":245,"doi":"10.1001/jamaneurol.2022.4485","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1001/jamaneurol.2022.4485","archive_url":"https://space-kitty.com/papers/doi:10.1001/jamaneurol.2022.4485","updated":null,"pmid":"36508198","pmcid":"PMC9856704","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC9856704/pdf","abstract":"Importance The recent proliferation of phosphorylated tau (p-tau) biomarkers has raised questions about their preferential association with the hallmark pathologies of Alzheimer disease (AD): amyloid-β plaques and tau neurofibrillary tangles. Objective To determine whether cerebrospinal fluid (CSF) and plasma p-tau biomarkers preferentially reflect cerebral β-amyloidosis or neurofibrillary tangle aggregation measured with positron emission tomography (PET). Design, setting, and participants This was a cross-sectional study of 2 observational cohorts: the Translational Biomarkers in Aging and Dementia (TRIAD) study, with data collected between October 2017 and August 2021, and the Alzheimer's Disease Neuroimaging Initiative (ADNI), with data collected between September 2015 and November 2019. TRIAD was a single-center study, and ADNI was a multicenter study. Two independent subsamples were derived from TRIAD. The first TRIAD subsample comprised individuals assessed with CSF p-tau (p-tau181, p-tau217, p-tau231, p-tau235), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. The second TRIAD subsample included individuals assessed with plasma p-tau (p-tau181, p-tau217, p-tau231), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. An independent cohort from ADNI comprised individuals assessed with CSF p-tau181, [18F]florbetapir PET, and [18F]flortaucipir PET. Participants were included based on the availability of p-tau and PET biomarker assessments collected within 9 months of each other. Exclusion criteria were a history of head trauma or magnetic resonance imaging/PET safety contraindications. No participants who met eligibility criteria were excluded. Exposures Amyloid PET, tau PET, and CSF and plasma assessments of p-tau measured with single molecule array (Simoa) assay or enzyme-linked immunosorbent assay. Main outcomes and measures Associations between p-tau biomarkers with amyloid PET and tau PET. Results A total of 609 participants (mean [SD] age, 66.9 [13.6] years; 347 female [57%]; 262 male [43%]) were included in the study. For all 4 phosphorylation sites assessed in CSF, p-tau was significantly more closely associated with amyloid-PET values than tau-PET values (p-tau181 difference, 13%; 95% CI, 3%-22%; P = .006; p-tau217 difference, 11%; 95% CI, 3%-20%; P = .003; p-tau231 difference, 15%; 95% CI, 5%-22%; P < .001; p-tau235 difference, 9%; 95% CI, 1%-19%; P = .02) . These results were replicated with plasma p-tau181 (difference, 11%; 95% CI, 1%-22%; P = .02), p-tau217 (difference, 9%; 95% CI, 1%-19%; P = .02), p-tau231 (difference, 13%; 95% CI, 3%-24%; P = .009), and CSF p-tau181 (difference, 9%; 95% CI, 1%-21%; P = .02) in independent cohorts. Conclusions and relevance Results of this cross-sectional study of 2 observational cohorts suggest that the p-tau abnormality as an early event in AD pathogenesis was associated with amyloid-β accumulation and highlights the need for careful interpretation of p-tau biomarkers in the context of the amyloid/tau/neurodegeneration, or A/T/(N), framework.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Association of Phosphorylated Tau Biomarkers With Amyloid Positron Emission Tomography vs Tau Positron Emission Tomography\" by Therriault J, Vermeiren M, Servaes S et al., https://doi.org/10.1001/jamaneurol.2022.4485, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1016/j.cell.2023.09.023","kind":"review","title":"Accelerating Alzheimer’s therapeutic development: The past and future of clinical trials","authors":["Adam L. Boxer","Reisa Anne Sperling"],"author_count":2,"year":2023,"published":"2023-10-01","venue":"Cell","cited_by":197,"doi":"10.1016/j.cell.2023.09.023","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1016/j.cell.2023.09.023","archive_url":"https://space-kitty.com/papers/doi:10.1016/j.cell.2023.09.023","updated":null,"pmid":"37848035","pmcid":null,"openalex_id":"W4387675480","pdf_url":null,"abstract":null,"abstract_license":null,"license":"cc-by-nc","is_open_access":true,"peer_reviewed":null,"categories":["Alzheimer's disease research and treatments"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.1038/s41591-025-03574-1","kind":"article","title":"Microglial mechanisms drive amyloid-β clearance in immunized patients with Alzheimer’s disease","authors":["Lynn van Olst","Brooke Simonton","Alex J. Edwards","Anne V. Forsyth","Jake Sondag Boles","Pouya Jamshidi","Thomas H. Watson","Nate Shepard","Talia Krainc","Benney MR Argue","Ziyang Zhang","Joshua Kuruvilla","Lily Camp","Mengwei Li","Hang Xu","Jeanette L. Norman","Joshua Gabriel Cahan","Robert J. Vassar","Jinmiao Chen","Rudolph J. Castellani","James A. R. Nicoll","Delphine Boche","David Gate"],"author_count":23,"year":2025,"published":"2025-03-06","venue":"Nature Medicine","cited_by":136,"doi":"10.1038/s41591-025-03574-1","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41591-025-03574-1","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41591-025-03574-1","updated":null,"pmid":"40050704","pmcid":"PMC12092304","openalex_id":"W4408201841","pdf_url":"https://europepmc.org/articles/PMC12092304/pdf","abstract":"Alzheimer's disease (AD) therapies utilizing amyloid-β (Aβ) immunization have shown potential in clinical trials. Yet, the mechanisms driving Aβ clearance in the immunized AD brain remain unclear. Here, we use spatial transcriptomics to explore the effects of both active and passive Aβ immunization in the AD brain. We compare actively immunized patients with AD with nonimmunized patients with AD and neurologically healthy controls, identifying distinct microglial states associated with Aβ clearance. Using high-resolution spatial transcriptomics alongside single-cell RNA sequencing, we delve deeper into the transcriptional pathways involved in Aβ removal after lecanemab treatment. We uncover spatially distinct microglial responses that vary by brain region. Our analysis reveals upregulation of the triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (APOE) in microglia across immunization approaches, which correlate positively with antibody responses and Aβ removal. Furthermore, we show that complement signaling in brain myeloid cells contributes to Aβ clearance after immunization. These findings provide new insights into the transcriptional mechanisms orchestrating Aβ removal and shed light on the role of microglia in immune-mediated Aβ clearance. Importantly, our work uncovers potential molecular targets that could enhance Aβ-targeted immunotherapies, offering new avenues for developing more effective therapeutic strategies to combat AD.","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"peer_reviewed":null,"categories":["Alzheimer's disease research and treatments"],"details":null,"provenance":"openalex+europepmc","attribution":"Abstract of \"Microglial mechanisms drive amyloid-β clearance in immunized patients with Alzheimer’s disease\" by Lynn van Olst, Brooke Simonton, Alex J. Edwards et al., https://doi.org/10.1038/s41591-025-03574-1, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.3390/ijms22126355","kind":"review","title":"Neurotoxic Soluble Amyloid Oligomers Drive Alzheimer’s Pathogenesis and Represent a Clinically Validated Target for Slowing Disease Progression","authors":["Martin Tolar","John Hey","Aidan Power","Susan R. Abushakra"],"author_count":4,"year":2021,"published":"2021-06-14","venue":"International Journal of Molecular Sciences","cited_by":245,"doi":"10.3390/ijms22126355","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.3390/ijms22126355","archive_url":"https://space-kitty.com/papers/doi:10.3390/ijms22126355","updated":null,"pmid":"34198582","pmcid":"PMC8231952","openalex_id":"W3166605268","pdf_url":"https://www.mdpi.com/1422-0067/22/12/6355/pdf?version=1623751084","abstract":"A large body of clinical and nonclinical evidence supports the role of neurotoxic soluble beta amyloid (amyloid, Aβ) oligomers as upstream pathogenic drivers of Alzheimer's disease (AD). Recent late-stage trials in AD that have evaluated agents targeting distinct species of Aβ provide compelling evidence that inhibition of Aβ oligomer toxicity represents an effective approach to slow or stop disease progression: (1) only agents that target soluble Aβ oligomers show clinical efficacy in AD patients; (2) clearance of amyloid plaque does not correlate with clinical improvements; (3) agents that predominantly target amyloid monomers or plaque failed to show clinical effects; and (4) in positive trials, efficacy is greater in carriers of the ε4 allele of apolipoprotein E (APOE4), who are known to have higher brain concentrations of Aβ oligomers. These trials also show that inhibiting Aβ neurotoxicity leads to a reduction in tau pathology, suggesting a pathogenic sequence of events where amyloid toxicity drives an increase in tau formation and deposition. The late-stage agents with positive clinical or biomarker data include four antibodies that engage Aβ oligomers (aducanumab, lecanemab, gantenerumab, and donanemab) and ALZ-801, an oral agent that fully blocks the formation of Aβ oligomers at the clinical dose.","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"peer_reviewed":null,"categories":["Alzheimer's disease research and treatments"],"details":null,"provenance":"openalex+europepmc","attribution":"Abstract of \"Neurotoxic Soluble Amyloid Oligomers Drive Alzheimer’s Pathogenesis and Represent a Clinically Validated Target for Slowing Disease Progression\" by Martin Tolar, John Hey, Aidan Power et al., https://doi.org/10.3390/ijms22126355, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."}],"next":"https://space-kitty.com/api/v1/topics/neurodegeneration/papers?sort=top&limit=25&offset=25"}