Plasma amyloid β 40/42 ratio predicts cerebral amyloidosis in cognitively normal individuals at risk for Alzheimer's disease DOI Open Access
Andrea Vergallo, Lucile Mégret, Simone Lista

et al.

Alzheimer s & Dementia, Journal Year: 2019, Volume and Issue: 15(6), P. 764 - 775

Published: May 18, 2019

Abstract Introduction Blood‐based biomarkers of pathophysiological brain amyloid β (Aβ) accumulation, particularly for preclinical target and large‐scale interventions, are warranted to effectively enrich Alzheimer's disease clinical trials management. Methods We investigated whether plasma concentrations the Aβ 1–40 /Aβ 1–42 ratio, assessed using single‐molecule array (Simoa) immunoassay, may predict positron emission tomography status in a longitudinal monocentric cohort (N = 276) older individuals with subjective memory complaints. performed hypothesis‐driven investigation followed by no‐a‐priori hypothesis study machine learning. Results The receiver operating characteristic curve learning showed balanced accuracy 76.5% 81%, respectively, ratio. is not affected apolipoprotein E ( APOE ) ε4 allele, sex, or age. Discussion Our results encourage an independent validation confirm indication that via Simoa, improve future standard care trial design.

Language: Английский

Alzheimer disease DOI
David S. Knopman, Hélène Amieva, Ronald C. Petersen

et al.

Nature Reviews Disease Primers, Journal Year: 2021, Volume and Issue: 7(1)

Published: May 13, 2021

Language: Английский

Citations

1503
The Amyloid-β Pathway in Alzheimer’s Disease DOI Creative Commons
Harald Hampel, John Hardy, Kaj Blennow

et al.

Molecular Psychiatry, Journal Year: 2021, Volume and Issue: 26(10), P. 5481 - 5503

Published: Aug. 30, 2021

Abstract Breakthroughs in molecular medicine have positioned the amyloid-β (Aβ) pathway at center of Alzheimer’s disease (AD) pathophysiology. While detailed mechanisms and spatial-temporal dynamics leading to synaptic failure, neurodegeneration, clinical onset are still under intense investigation, established biochemical alterations Aβ cycle remain core biological hallmark AD promising targets for development disease-modifying therapies. Here, we systematically review update vast state-of-the-art literature science with evidence from basic research studies human genetic multi-modal biomarker investigations, which supports a crucial role dyshomeostasis pathophysiological dynamics. We discuss highlighting differentiated interaction distinct species other AD-related mechanisms, such as tau-mediated, neuroimmune inflammatory changes, well neurochemical imbalance. Through lens latest multimodal vivo biomarkers AD, this cross-disciplinary examines compelling hypothesis- data-driven rationale Aβ-targeting therapeutic strategies early treatment AD.

Language: Английский

Citations

1033
Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts DOI
Thomas K. Karikari, Tharick A. Pascoal, Nicholas J. Ashton

et al.

The Lancet Neurology, Journal Year: 2020, Volume and Issue: 19(5), P. 422 - 433

Published: April 22, 2020

Language: Английский

Citations

997
Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease DOI
Yingyue Zhou, Wilbur M. Song,

Prabhakar S. Andhey

et al.

Nature Medicine, Journal Year: 2020, Volume and Issue: 26(1), P. 131 - 142

Published: Jan. 1, 2020

Language: Английский

Citations

892
Alzheimer's disease drug development pipeline: 2019 DOI Creative Commons
Jeffrey L. Cummings, Garam Lee,

Aaron Ritter

et al.

Alzheimer s & Dementia Translational Research & Clinical Interventions, Journal Year: 2019, Volume and Issue: 5(1), P. 272 - 293

Published: Jan. 1, 2019

Abstract Introduction Alzheimer's disease (AD) has few available treatments, and there is a high rate of failure in AD drug development programs. Study the pipeline can provide insight into evolution how best to optimize practices. Methods We reviewed clinicaltrials.gov identified all pharmacologic trials agents currently being developed for treatment AD. Results There are 132 clinical Twenty‐eight 42 phase 3 trials; 74 83 2 30 31 1 trials. an increase number each compared with that 2018 pipeline. Nineteen target cognitive enhancement, 14 intended treat neuropsychiatric behavioral symptoms. 96 modification these, 38 (40%) have amyloid as primary or one several effects. Eighteen antiamyloid small molecules, 20 monoclonal antibodies biological therapies. Seven molecules ten biologics tau combination (18%). Amyloid most common specific Novel biomarkers (e.g., neurofilament light), new outcomes Composite Score [ADCOMS]), enrollment earlier populations, innovative trial designs Bayesian adaptive designs) features recent Discussion Drug continues robustly at phases despite setbacks programs past. Continuing unmet needs require commitment growing accelerating

Language: Английский

Citations

632
A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody DOI Creative Commons

Chad J. Swanson,

Yong Zhang,

Shobha Dhadda

et al.

Alzheimer s Research & Therapy, Journal Year: 2021, Volume and Issue: 13(1)

Published: April 17, 2021

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 Bayesian design response-adaptive randomization to assess 3 doses 2 regimens of lecanemab versus placebo in early Alzheimer's disease, mild cognitive impairment due disease (AD) AD dementia.

Language: Английский

Citations

596
The β-Secretase BACE1 in Alzheimer’s Disease DOI Creative Commons
Harald Hampel, Robert Vassar, Bart De Strooper

et al.

Biological Psychiatry, Journal Year: 2020, Volume and Issue: 89(8), P. 745 - 756

Published: Feb. 13, 2020

BACE1 (beta-site amyloid precursor protein cleaving enzyme 1) was initially cloned and characterized in 1999. It is required for the generation of all monomeric forms amyloid-β (Aβ), including Aβ

Language: Английский

Citations

494
Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology DOI Creative Commons
Nicholas J. Ashton, Tharick A. Pascoal, Thomas K. Karikari

et al.

Acta Neuropathologica, Journal Year: 2021, Volume and Issue: 141(5), P. 709 - 724

Published: Feb. 14, 2021

Abstract The quantification of phosphorylated tau in biofluids, either cerebrospinal fluid (CSF) or plasma, has shown great promise detecting Alzheimer’s disease (AD) pathophysiology. Tau at threonine 231 (p-tau231) is one such biomarker CSF but its usefulness as a blood currently unknown. Here, we developed an ultrasensitive Single molecule array (Simoa) for the plasma p-tau231 which was validated four independent cohorts ( n = 588) different settings, including full AD continuum and non-AD neurodegenerative disorders. Plasma able to identify patients with differentiate them from amyloid-β negative cognitively unimpaired (CU) older adults high accuracy (AUC 0.92–0.94). also distinguished disorders 0.93), well MCI 0.89). In neuropathology cohort, samples taken on avergae 4.2 years prior post-mortem very accurately identified comparison 0.99), this despite all being given dementia diagnosis during life. highly correlated p-tau231, pathology assessed by [ 18 F]MK-6240 positron emission tomography (PET), brain amyloidosis F]AZD469 PET. Remarkably, inflection point increasing function continuous PET standardized uptake value ratio, be earlier than standard thresholds positivity increase p-tau181. Furthermore, significantly increased quartiles 2–4, whereas p-tau217 p-tau181 only 3–4 4, respectively. Finally, differentiated individuals across entire Braak stage spectrum, staging 0 through I–II, not observed To conclude, novel assay identifies clinical stages equally p-tau181, increases earlier, already subtle deposition, threshold been attained, response early deposition. Thus, promising emerging potential facilitate trials vulnerable populations below apparent entorhinal

Language: Английский

Citations

467
Amyloid-PET and 18F-FDG-PET in the diagnostic investigation of Alzheimer's disease and other dementias DOI Creative Commons
Gaël Chételat, Javier Arbizu, Henryk Barthel

et al.

The Lancet Neurology, Journal Year: 2020, Volume and Issue: 19(11), P. 951 - 962

Published: Oct. 21, 2020

Language: Английский

Citations

398
Discovery and validation of biomarkers to aid the development of safe and effective pain therapeutics: challenges and opportunities DOI Creative Commons
Karen D. Davis, Nima Aghaeepour, Andrew H. Ahn

et al.

Nature Reviews Neurology, Journal Year: 2020, Volume and Issue: 16(7), P. 381 - 400

Published: June 15, 2020

Pain medication plays an important role in the treatment of acute and chronic pain conditions, but some drugs, opioids particular, have been overprescribed or prescribed without adequate safeguards, leading to alarming rise medication-related overdose deaths. The NIH Helping End Addiction Long-term (HEAL) Initiative is a trans-agency effort provide scientific solutions stem opioid crisis. One component initiative support biomarker discovery rigorous validation collaboration with industry leaders accelerate high-quality clinical research into neurotherapeutics pain. use objective biomarkers trial end points throughout drug development process crucial help define pathophysiological subsets pain, evaluate target engagement new drugs predict analgesic efficacy drugs. In 2018, NIH-led Discovery Validation Biomarkers Develop Non-Addictive Therapeutics for workshop convened from academia, industry, government patient advocacy groups discuss progress, challenges, gaps ideas facilitate outcomes this are outlined Consensus Statement. strategies

Language: Английский

Citations

357