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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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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Differential roles of Aβ42/40, p-tau231 and p-tau217 for Alzheimer’s trial selection and disease monitoring

Nature Medicine, Journal Year: 2022, Volume and Issue: 28(12), P. 2555 - 2562

Published: Dec. 1, 2022

Abstract Blood biomarkers indicative of Alzheimer’s disease (AD) pathology are altered in both preclinical and symptomatic stages the disease. Distinctive may be optimal for identification AD or monitoring progression. that correlate with changes cognition atrophy during course could used clinical trials to identify successful interventions thereby accelerate development efficient therapies. When disease-modifying treatments become approved use, blood-based might also inform on treatment implementation management practice. In BioFINDER-1 cohort, plasma phosphorylated (p)-tau231 amyloid-β42/40 ratio were more changed at lower thresholds amyloid pathology. Longitudinally, however, only p-tau217 demonstrated marked amyloid-dependent over 4–6 years disease, no such observed p-tau231, p-tau181, amyloid-β42/40, glial acidic fibrillary protein neurofilament light. Only longitudinal increases associated deterioration brain AD. The selective increase its associations cognitive decline was confirmed an independent cohort (Wisconsin Registry Prevention). These findings support differential association strongly highlight as a surrogate marker progression prodromal AD, impact new treatments.

Language: Английский

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

Nature Aging, Journal Year: 2023, Volume and Issue: 3(5), P. 506 - 519

Published: May 18, 2023

Language: Английский

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

Nature Medicine, Journal Year: 2024, Volume and Issue: 30(4), P. 1085 - 1095

Published: Feb. 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

Language: Английский

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Prediction of Longitudinal Cognitive Decline in Preclinical Alzheimer Disease Using Plasma Biomarkers

JAMA Neurology, Journal Year: 2023, Volume and Issue: 80(4), P. 360 - 360

Published: Feb. 6, 2023

Importance Alzheimer disease (AD) pathology starts with a prolonged phase of β-amyloid (Aβ) accumulation without symptoms. The duration this differs greatly among individuals. While has high relevance for clinical trial designs, it is currently unclear how to best predict the onset progression. Objective To evaluate combinations different plasma biomarkers predicting cognitive decline in Aβ-positive cognitively unimpaired (CU) Design, Setting, and Participants This prospective population-based prognostic study evaluated data from 2 longitudinal cohort studies (the Swedish BioFINDER-1 Wisconsin Registry Prevention [WRAP]), collected February 8, 2010, October 21, 2020, August 11, 2011, June 27, 2021, WRAP cohort. were CU individuals recruited memory clinics who had brain Aβ defined by cerebrospinal fluid (CSF) Aβ42/40 Pittsburgh Compound B (PiB) positron emission tomography (PET) study. A total 564 eligible Aβ-negative participants available relevant cohorts included study; those, 171 main analyses. Exposures Baseline P-tau181, P-tau217, P-tau231, glial fibrillary filament protein, neurofilament light measured plasma; CSF cohort, PiB PET uptake Main Outcomes Measures primary outcome was measures cognition (using Mini-Mental State Examination [MMSE] modified Preclinical Cognitive Composite [mPACC]) over median 6 years (range, 2-10 years). secondary conversion AD dementia. used linear regression models rates change (calculated separately). Models adjusted age, sex, education, apolipoprotein E ε4 allele status, baseline cognition. Multivariable compared based on model R coefficients corrected Akaike information criterion. Results Among analyses, 119 (mean [SD] 73.0 [5.4] years; 60.5% female) study, 52 64.4 [4.6] 65.4% In P-tau217 marker mPACC (model = 0.41) MMSE 0.34) superior covariates-only (mPACC: 0.23; MMSE: 0.04; P &amp;lt; .001 both comparisons). validated cohort; example, associated slopes ( 0.13 vs 0.01 model; .01) 0.29 0.24 .046). Sparse identified as predictor decline. Power calculations enrichment hypothetical trials revealed large relative reductions sample sizes when using enrich likely experience time. Conclusions Relevance predicted patients preclinical AD. These findings suggest that may be complement or participant selection novel disease-modifying treatments.

Language: Английский

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Confounding factors of Alzheimer's disease plasma biomarkers and their impact on clinical performance

Alzheimer s & Dementia, Journal Year: 2022, Volume and Issue: 19(4), P. 1403 - 1414

Published: Sept. 24, 2022

Abstract Introduction Plasma biomarkers will likely revolutionize the diagnostic work‐up of Alzheimer's disease (AD) globally. Before widespread use, we need to determine if confounding factors affect levels these biomarkers, and their clinical utility. Methods Participants with plasma CSF creatinine, body mass index (BMI), medical history data were included (BioFINDER‐1: n = 748, BioFINDER‐2: 421). We measured beta‐amyloid (Aβ42, Aβ40), phosphorylated tau (p‐tau217, p‐tau181), neurofilament light (NfL), glial fibrillary acidic protein (GFAP). Results In both cohorts, creatinine BMI main associated NfL, GFAP, a lesser extent p‐tau. However, adjustment for had only minor effects in models predicting either corresponding or subsequent development dementia. Discussion Creatinine are related certain levels, but they do not have clinically relevant vast majority individuals. Highlights (BMI) biomarker levels. Adjusting has influence on plasma‐cerebrospinal fluid (CSF) associations. prediction dementia using biomarkers.

Language: Английский

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Blood-based biomarkers for Alzheimer’s disease: Current state and future use in a transformed global healthcare landscape

Neuron, Journal Year: 2023, Volume and Issue: 111(18), P. 2781 - 2799

Published: June 8, 2023

Language: 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, Journal Year: 2023, Volume and Issue: 3(9), P. 1079 - 1090

Published: Aug. 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.

Language: Английский

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

EMBO Molecular Medicine, Journal Year: 2023, Volume and Issue: 15(5)

Published: March 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.

Language: Английский

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