Donanemab in Early Symptomatic Alzheimer Disease

JAMA, Год журнала: 2023, Номер 330(6), С. 512 - 512

Опубликована: Июль 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

Язык: Английский

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

Alzheimer s & Dementia, Год журнала: 2024, Номер 20(8), С. 5143 - 5169

Опубликована: Июнь 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.

Язык: Английский

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

JAMA Neurology, Год журнала: 2024, Номер 81(3), С. 255 - 255

Опубликована: Янв. 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.

Язык: Английский

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Blood biomarkers for Alzheimer’s disease in clinical practice and trials

Nature Aging, Год журнала: 2023, Номер 3(5), С. 506 - 519

Опубликована: Май 18, 2023

Язык: Английский

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Highly accurate blood test for Alzheimer’s disease is similar or superior to clinical cerebrospinal fluid tests

Nature Medicine, Год журнала: 2024, Номер 30(4), С. 1085 - 1095

Опубликована: Фев. 21, 2024

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 perform as well established cerebrospinal fluid (CSF) tests in detecting amyloid-β (Aβ) plaques and tau tangles. Plasma %p-tau217 (ratio phosporylated-tau217 to non-phosphorylated tau) was analyzed by mass spectrometry Swedish BioFINDER-2 cohort (n = 1,422) US Charles F. Joanne Knight Alzheimer Disease Research Center (Knight ADRC) 337). Matched CSF samples were with clinically used FDA-approved automated immunoassays for Aβ42/40 p-tau181/Aβ42. The primary secondary outcomes detection brain Aβ or pathology, respectively, using positron emission tomography (PET) imaging reference standard. Main analyses focused on individuals cognitive impairment (mild mild dementia), which is target population available treatments. equivalent classifying PET status, an area under curve (AUC) both between 0.95 0.97. generally superior classification tau-PET AUCs 0.95-0.98. cognitively impaired subcohorts (BioFINDER-2: n 720; ADRC: 50), plasma had accuracy, positive predictive value negative 89-90% 87-88% tests, further improving 95% two-cutoffs approach. Blood demonstrated performance that AD pathology. Use high-performance clinical practice can improve access accurate diagnosis AD-specific

Язык: Английский

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Association of Phosphorylated Tau Biomarkers With Amyloid Positron Emission Tomography vs Tau Positron Emission Tomography

JAMA Neurology, Год журнала: 2022, Номер 80(2), С. 188 - 188

Опубликована: Дек. 12, 2022

Importance The recent proliferation of phosphorylated tau (p-tau) biomarkers has raised questions about their preferential association with the hallmark pathologies Alzheimer disease (AD): amyloid-β plaques and neurofibrillary tangles. Objective To determine whether cerebrospinal fluid (CSF) plasma p-tau preferentially reflect cerebral β-amyloidosis or tangle aggregation measured positron emission tomography (PET). Design, Setting, Participants This was a cross-sectional study 2 observational cohorts: Translational Biomarkers in Aging Dementia (TRIAD) study, data collected between October 2017 August 2021, Alzheimer’s Disease Neuroimaging Initiative (ADNI), September 2015 November 2019. TRIAD single-center ADNI multicenter study. Two independent subsamples were derived from TRIAD. first subsample comprised individuals assessed CSF (p-tau 181 , 217 231 235 ), [ 18 F]AZD4694 amyloid PET, F]MK6240 PET. second included An cohort F]florbetapir F]flortaucipir based on availability PET biomarker assessments within 9 months each other. Exclusion criteria history head trauma magnetic resonance imaging/PET safety contraindications. No participants who met eligibility excluded. Exposures Amyloid single molecule array (Simoa) assay enzyme-linked immunosorbent assay. Main Outcomes Measures Associations Results A total 609 (mean [SD] age, 66.9 [13.6] years; 347 female [57%]; 262 male [43%]) For all 4 phosphorylation sites CSF, significantly more closely associated amyloid-PET values than tau-PET difference, 13%; 95% CI, 3%-22%; P = .006; 11%; 3%-20%; .003; 15%; 5%-22%; < .001; 9%; 1%-19%; .02) . These results replicated (difference, 1%-22%; .02), 3%-24%; .009), 1%-21%; cohorts. Conclusions Relevance this cohorts suggest that abnormality as an early event AD pathogenesis accumulation highlights need for careful interpretation context amyloid/tau/neurodegeneration, A/T/(N), framework.

Язык: Английский

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CSF MTBR-tau243 is a specific biomarker of tau tangle pathology in Alzheimer’s disease

Nature Medicine, Год журнала: 2023, Номер 29(8), С. 1954 - 1963

Опубликована: Июль 13, 2023

Abstract Aggregated insoluble tau is one of two defining features Alzheimer’s disease. Because clinical symptoms are strongly correlated with aggregates, drug development and diagnosis need cost-effective accessible specific fluid biomarkers aggregates; however, recent studies suggest that the currently available cannot specifically track aggregates. We show microtubule-binding region (MTBR) containing residue 243 (MTBR-tau243) a new cerebrospinal (CSF) biomarker for aggregates compared it to multiple other phosphorylated measures (p-tau181, p-tau205, p-tau217 p-tau231) in independent cohorts (BioFINDER-2, n = 448; Knight Alzheimer Disease Research Center, 219). MTBR-tau243 was most associated tau-positron emission tomography (PET) cognition, whereas showing lowest association amyloid-PET. In combination explained total variance tau-PET burden (0.58 ≤ R 2 0.75) performance predicting cognitive (0.34 0.48) approached (0.44 0.52). levels longitudinally increased unlike CSF p-tau species. aggregate pathology, which may be utilized interventional trials patients. Based on these findings, we propose revise A/T/(N) criteria include as representing (‘T’).

Язык: Английский

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A two-step workflow based on plasma p-tau217 to screen for amyloid β positivity with further confirmatory testing only in uncertain cases

Nature Aging, Год журнала: 2023, Номер 3(9), С. 1079 - 1090

Опубликована: Авг. 31, 2023

Cost-effective strategies for identifying amyloid-β (Aβ) positivity in patients with cognitive impairment are urgently needed recent approvals of anti-Aβ immunotherapies Alzheimer's disease (AD). Blood biomarkers can accurately detect AD pathology, but it is unclear whether their incorporation into a full diagnostic workflow reduce the number confirmatory cerebrospinal fluid (CSF) or positron emission tomography (PET) tests while classifying patients. We evaluated two-step determining Aβ-PET status mild (MCI) from two independent memory clinic-based cohorts (n = 348). A blood-based model including plasma tau protein 217 (p-tau217), age and APOE ε4 was developed BioFINDER-1 (area under curve (AUC) 89.3%) validated BioFINDER-2 (AUC 94.3%). In step 1, used to stratify low, intermediate high risk positivity. 2, we assumed referral only intermediate-risk CSF Aβ42/Aβ40 testing, whereas 1 alone determined Aβ-status low- high-risk groups. Depending on lenient, moderate stringent thresholds were overall accuracy detecting 88.2%, 90.5% 92.0%, respectively, reducing necessary by 85.9%, 72.7% 61.2%, respectively. secondary analyses, an adapted version led successful validation different p-tau217 immunoassay TRIAD cohort 84). conclusion, using p-tau217-based stratification MCI substantially need testing patients, offering cost-effective strategy clinic settings.

Язык: Английский

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Specific associations between plasma biomarkers and postmortem amyloid plaque and tau tangle loads

EMBO Molecular Medicine, Год журнала: 2023, Номер 15(5)

Опубликована: Март 13, 2023

Several promising plasma biomarkers for Alzheimer's disease have been recently developed, but their neuropathological correlates not yet fully determined. To investigate and compare independent associations between multiple (p-tau181, p-tau217, p-tau231, Aβ42/40, GFAP, NfL) neuropathologic measures of amyloid tau, we included 105 participants from the Arizona Study Aging Neurodegenerative Disorders (AZSAND) with antemortem samples a postmortem exam, 48 whom had longitudinal p-tau217 p-tau181. When simultaneously including plaque tangle loads, Aβ42/40 ratio p-tau231 were only associated plaques (ρAβ42/40 [95%CI] = -0.53[-0.65, -0.35], ρp-tau231 0.28[0.10, 0.43]), GFAP was tangles (ρGFAP 0.39[0.17, 0.57]), p-tau181 both (ρp-tau217 0.40[0.21, 0.56], ρp-tau181 0.36[0.15, 0.50]) 0.52[0.34, 0.66]; 0.36[0.17, 0.52]). A model combining showed highest accuracy predicting presence change (ADNC, AUC[95%CI] 0.89[0.82, 0.96]) load (R2 0.55), while alone optimal 0.45). Our results suggest that high-performing assays might be an combination to assess Alzheimer's-related pathology in vivo.

Язык: Английский

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Plasma Biomarker Strategy for Selecting Patients With Alzheimer Disease for Antiamyloid Immunotherapies

JAMA Neurology, Год журнала: 2023, Номер 81(1), С. 69 - 69

Опубликована: Дек. 4, 2023

Antiamyloid immunotherapies against Alzheimer disease (AD) are emerging. Scalable, cost-effective tools will be needed to identify amyloid β (Aβ)-positive patients without an advanced stage of tau pathology who most likely benefit from these therapies. Blood-based biomarkers might reduce the need use cerebrospinal fluid (CSF) or positron emission tomography (PET) for this.

Язык: Английский

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