Donanemab in Early Symptomatic Alzheimer Disease

JAMA, Journal Year: 2023, Volume and Issue: 330(6), P. 512 - 512

Published: July 17, 2023

Importance There are limited efficacious treatments for Alzheimer disease. Objective To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque. Design, Setting, Participants Multicenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic disease (mild cognitive impairment/mild dementia) low/medium or high tau pathology based on positron emission tomography imaging from June 2020 November 2021 (last patient visit primary outcome April 2023). Interventions were randomized a 1:1 ratio receive donanemab (n = 860) placebo 876) intravenously every 4 weeks 72 weeks. the group switched blinded manner if dose completion criteria met. Main Outcomes Measures The was change integrated Disease Rating Scale (iADRS) score baseline 76 (range, 0-144; lower scores indicate greater impairment). 24 gated outcomes (primary, secondary, exploratory), including secondary sum boxes Clinical Dementia (CDR-SB) 0-18; higher Statistical testing allocated α .04 population outcomes, remainder (.01) combined outcomes. Results Among (mean age, 73.0 years; 996 [57.4%] women; 1182 [68.1%] 552 [31.8%] pathology), 1320 (76%) completed trial. Of 23 statistically significant. least-squares mean (LSM) iADRS at −6.02 (95% CI, −7.01 −5.03) −9.27 −10.23 −8.31) (difference, 3.25 [95% 1.88-4.62]; P < .001) −10.2 −11.22 −9.16) −13.1 −14.10 −12.13) 2.92 1.51-4.33]; population. LSM CDR-SB 1.20 1.00-1.41) 1.88 1.68-2.08) −0.67 −0.95 −0.40]; 1.72 1.53-1.91) 2.42 2.24-2.60) −0.7 −0.45]; Amyloid-related abnormalities edema effusion occurred 205 (24.0%; 52 symptomatic) 18 (2.1%; 0 during study) infusion-related reactions 74 (8.7%) (0.5%) placebo. Three deaths 1 considered treatment related. Conclusions Relevance pathology, significantly slowed clinical progression those Trial Registration ClinicalTrials.gov Identifier: NCT04437511

Language: Английский

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Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer’s Disease

The Journal of Prevention of Alzheimer s Disease, Journal Year: 2022, Volume and Issue: unknown

Published: Jan. 1, 2022

Alzheimer's disease is a progressive, irreversible, and fatal for which accumulation of amyloid beta thought to play key role in pathogenesis. Aducanumab human monoclonal antibody directed against aggregated soluble insoluble forms beta.We evaluated the efficacy safety aducanumab early disease.EMERGE ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies patients with disease.These involved 348 sites 20 countries.Participants included 1638 (EMERGE) 1647 (ENGAGE) (aged 50-85 years, confirmed pathology) who met clinical criteria mild cognitive impairment due or dementia, 1812 (55.2%) completed study.Participants randomly assigned 1:1:1 receive low dose (3 6 mg/kg target dose), high (10 placebo via IV infusion once every 4 weeks over 76 weeks.The primary outcome measure was change from baseline week 78 on Clinical Dementia Rating Sum Boxes (CDR-SB), an integrated scale that assesses both function cognition. Other measures assessments; secondary tertiary outcomes assessed cognition, function, behavior; biomarker endpoints.EMERGE halted based futility analysis data pooled first approximately 50% enrolled patients; subsequent analyses larger set collected up declaration followed prespecified statistical analyses. The endpoint EMERGE (difference -0.39 high-dose vs [95% CI, -0.69 -0.09; P=.012; 22% decrease]) but not 0.03, -0.26 0.33; P=.833; 2% increase]). Results substudies engagement dose-dependent reduction markers pathophysiology. most common adverse event amyloid-related imaging abnormalities-edema.Data demonstrated statistically significant across all four endpoints. did meet its A dose- time-dependent pathophysiological observed trials.

Language: Английский

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Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(8), P. 5143 - 5169

Published: June 27, 2024

Abstract The National Institute on Aging and the Alzheimer's Association convened three separate work groups in 2011 single 2012 2018 to create recommendations for diagnosis characterization of disease (AD). present document updates research framework response several recent developments. Defining diseases biologically, rather than based syndromic presentation, has long been standard many areas medicine (e.g., oncology), is becoming a unifying concept common all neurodegenerative diseases, not just AD. consistent with this principle. Our intent objective criteria staging AD, incorporating advances biomarkers, serve as bridge between clinical care. These are intended provide step‐by‐step practice guidelines workflow or specific treatment protocols, but general principles inform AD that reflect current science. Highlights We define (AD) be biological process begins appearance neuropathologic change (ADNPC) while people asymptomatic. Progression burden leads later progression symptoms. Early‐changing Core 1 biomarkers (amyloid positron emission tomography [PET], approved cerebrospinal fluid accurate plasma [especially phosphorylated tau 217]) map onto either amyloid beta tauopathy pathway; however, these presence ADNPC more generally (i.e., both neuritic plaques tangles). An abnormal biomarker result sufficient establish decision making throughout continuum. Later‐changing 2 (biofluid PET) can prognostic information, when abnormal, will increase confidence contributing integrated scheme described accommodates fact copathologies, cognitive reserve, resistance may modify relationships stages.

Language: Английский

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The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 21(4), P. 306 - 318

Published: Feb. 17, 2022

Language: Английский

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The Alzheimer's Association appropriate use recommendations for blood biomarkers in Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2022, Volume and Issue: 18(12), P. 2669 - 2686

Published: July 31, 2022

Abstract Blood‐based markers (BBMs) have recently shown promise to revolutionize the diagnostic and prognostic work‐up of Alzheimer's disease (AD), as well improve design interventional trials. Here we discuss in detail further research needed be performed before widespread use BBMs. We already now recommend BBMs (pre‐)screeners identify individuals likely AD pathological changes for inclusion trials evaluating disease‐modifying therapies, provided status is confirmed with positron emission tomography (PET) or cerebrospinal fluid (CSF) testing. also encourage studying longitudinal BBM ongoing future However, should not yet used primary endpoints pivotal Further, cautiously start using specialized memory clinics part patients cognitive symptoms results whenever possible CSF PET. Additional data are stand‐alone markers, considering care.

Language: Английский

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Blood-based biomarkers for Alzheimer's disease: towards clinical implementation

The Lancet Neurology, Journal Year: 2021, Volume and Issue: 21(1), P. 66 - 77

Published: Nov. 25, 2021

Language: Английский

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Head-to-Head Comparison of 8 Plasma Amyloid-β 42/40 Assays in Alzheimer Disease

JAMA Neurology, Journal Year: 2021, Volume and Issue: 78(11), P. 1375 - 1375

Published: Sept. 20, 2021

Blood-based tests for brain amyloid-β (Aβ) pathology are needed widespread implementation of Alzheimer disease (AD) biomarkers in clinical care and to facilitate patient screening monitoring treatment responses trials.To compare the performance plasma Aβ42/40 measured using 8 different Aβ assays when detecting abnormal status patients with early AD.This study included 182 cognitively unimpaired participants 104 mild cognitive impairment from BioFINDER cohort who were enrolled at 3 hospitals Sweden underwent positron emission tomography (PET) imaging cerebrospinal fluid (CSF) collection 2010 2014. Plasma was an immunoprecipitation-coupled mass spectrometry developed Washington University (IP-MS-WashU), antibody-free liquid chromatography MS by Araclon (LC-MS-Arc), immunoassays Roche Diagnostics (IA-Elc); Euroimmun (IA-EI); Amsterdam Medical Center, ADx Neurosciences, Quanterix (IA-N4PE). also IP-MS-based method Shimadzu 200 (IP-MS-Shim) Gothenburg (IP-MS-UGOT) another immunoassay (IA-Quan) among 227 participants. For validation, 122 (51 normal, 51 impairment, 20 AD dementia) Disease Neuroimaging Initiative Aβ-PET assessments IP-MS-WashU, IP-MS-Shim, IP-MS-UGOT, IA-Elc, IA-N4PE, IA-Quan assays.Discriminative accuracy quantified CSF status.A total 408 this study. In cohort, mean (SD) age 71.6 (5.6) years 49.3% women. When identifying whole IP-MS-WashU showed significantly higher (area under receiver operating characteristic curve [AUC], 0.86; 95% CI, 0.81-0.90) than LC-MS-Arc Aβ42/40, IA-Elc IA-EI IA-N4PE (AUC range, 0.69-0.78; P < .05). performed better IP-MS-UGOT (AUC, 0.84 vs 0.68 0.64, respectively; .001), while there no difference AUCs between IP-MS-Shim (0.87 0.83; = .16) 2 subcohorts where these available. The results similar as outcome. IPMS-WashU IPMS-Shim highest coefficients correlations (r 0.56-0.65). replicated (mean [SD] age, 72.4 [5.4] years; 43.4% women), assay but not assay.The independent cohorts indicate that certain MS-based methods most pathology.

Language: Английский

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Head-to-head comparison of 10 plasma phospho-tau assays in prodromal Alzheimer’s disease

Brain, Journal Year: 2022, Volume and Issue: 146(4), P. 1592 - 1601

Published: Sept. 10, 2022

Plasma phospho-tau (p-tau) species have emerged as the most promising blood-based biomarkers of Alzheimer's disease. Here, we performed a head-to-head comparison p-tau181, p-tau217 and p-tau231 measured using 10 assays to detect abnormal brain amyloid-β (Aβ) status predict future progression dementia. The study included 135 patients with baseline diagnosis mild cognitive impairment (mean age 72.4 years; 60.7% women) who were followed for an average 4.9 years. Seventy-one participants had Aβ-status (i.e. CSF Aβ42/40) at baseline; 45 these Aβ-positive progressed dementia during follow-up. P-tau concentrations determined in plasma CSF. P-tau217 p-tau181 both immunoassays developed by Lilly Research Laboratories (Lilly) mass spectrometry Washington University (WashU). was also analysed Simoa immunoassay Janssen Development (Janss). P-tau181 from ADxNeurosciences (ADx), Lumipulse Fujirebio (Fuji) Splex Mesoscale Discovery (Splex). Both quantified Gothenburg (UGOT). We found that spectrometry-based (p-tau217WashU) exhibited significantly better performance than all other p-tau when detecting Aβ [area under curve (AUC) = 0.947; Pdiff < 0.015] or (AUC 0.932; 0.027). Among immunoassays, p-tau217Lilly highest AUCs (0.886-0.889), which not different p-tau217Janss, p-tau181ADx p-tau181WashU (AUCrange 0.835-0.872; > 0.09), but higher compared AUC p-tau231UGOT, p-tau181Lilly, p-tau181UGOT, p-tau181Fuji p-tau181Splex 0.642-0.813; ≤ 0.029). Correlations between values strongest p-tau217WashU (R 0.891) 0.755; 0.003 versus p-tau217WashU) weak moderate rest (Rrange 0.320-0.669). In conclusion, our findings suggest among tested assays, measures perform best identifying those will subsequently progress Several (p-tau217Lilly, p-tau181WashU) showed relatively high consistent accuracy across outcomes. results further indicate performing metrics rival gold standards Aβ-PET If validated, significant impacts diagnosis, screening treatment future.

Language: Английский

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Tau biomarkers in Alzheimer's disease: towards implementation in clinical practice and trials

The Lancet Neurology, Journal Year: 2022, Volume and Issue: 21(8), P. 726 - 734

Published: May 25, 2022

Language: Английский

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Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology

JAMA Neurology, Journal Year: 2024, Volume and Issue: 81(3), P. 255 - 255

Published: Jan. 22, 2024

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 tests research and clinical use has been limited. Expanding access this highly accurate AD crucial wider evaluation implementation tests. Objective To determine utility novel commercially available immunoassay plasma detect pathology evaluate reference ranges abnormal amyloid β (Aβ) longitudinal change across 3 selected cohorts. Design, Setting, Participants This cohort study examined data from single-center observational cohorts: cross-sectional Translational Biomarkers in Aging Dementia (TRIAD) (visits October 2017–August 2021) Wisconsin Registry Alzheimer’s Prevention (WRAP) February 2007–November 2020) Sant Pau Initiative on Neurodegeneration (SPIN) (baseline visits March 2009–November 2021). included individuals without cognitive impairment grouped by (AT) status using PET or CSF biomarkers. Data were analyzed June 2023. Exposures Magnetic resonance imaging, Aβ positron emission tomography (PET), PET, cerebrospinal fluid (CSF) biomarkers (Aβ42/40 p-tau immunoassays), (ALZpath pTau217 assay). Main Outcomes Measures Accuracy detecting according baseline status. Results The 786 participants (mean [SD] age, 66.3 [9.7] years; 504 females [64.1%] 282 males [35.9%]). High accuracy was observed identifying elevated (area under curve [AUC], 0.92-0.96; 95% CI, 0.89-0.99) (AUC, 0.93-0.97; 0.84-0.99) all These accuracies comparable determining signal. detection 3-range yielded reproducible results reduced confirmatory testing approximately 80%. Longitudinally, values showed an annual increase only Aβ-positive individuals, highest those positivity. Conclusions Relevance found that accurately identified biological AD, biomarkers, cut-offs It detected changes, including at preclinical stage.

Language: Английский

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