The Amyloid-β Pathway in Alzheimer’s Disease

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

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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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Longitudinal Associations of Blood Phosphorylated Tau181 and Neurofilament Light Chain With Neurodegeneration in Alzheimer Disease

JAMA Neurology, Journal Year: 2021, Volume and Issue: 78(4), P. 396 - 396

Published: Jan. 14, 2021

Plasma phosphorylated tau at threonine 181 (p-tau181) has been proposed as an easily accessible biomarker for the detection of Alzheimer disease (AD) pathology, but its ability to monitor progression in AD remains unclear.To study potential longitudinal plasma p-tau181 measures assessing neurodegeneration and cognitive decline comparison neurofilament light chain (NfL), a disease-nonspecific marker neuronal injury.This cohort included data from Alzheimer's Disease Neuroimaging Initiative February 1, 2007, June 6, 2016. Follow-up blood sampling was performed up 8 years. measurements were 2020. This multicentric observational 1113 participants, including cognitively unimpaired participants well patients with impairment (mild dementia). Participants eligible inclusion if they had available NfL least 1 fluorine-18-labeled fluorodeoxyglucose (FDG) positron emission tomography (PET) or structural magnetic resonance imaging scan same visit. Exclusion criteria any significant neurologic disorder other than suspected AD; presence infection, infarction, multiple lacunes detected by imaging; systemic condition that could lead difficulty complying protocol.Plasma measured single-molecule array technology.Longitudinal markers (FDG PET imaging) test scores (Preclinical Cognitive Composite Assessment Scale-Cognitive Subscale 13 tasks). Data analyzed 20 August 15, 2020.Of (mean [SD] age, 74.0 [7.6] years; 600 men [53.9%]; 992 non-Hispanic White [89.1%]), total 378 individuals (34.0%) (CU) 735 (66.0%) impaired (CImp). Of CImp group, 537 (73.1%) mild impairment, 198 (26.9%) dementia. Longitudinal changes associated (CU: r = -0.24, P < .001; CImp: 0.34, .001) prospective decrease glucose metabolism -0.05, .48; -0.27, gray matter volume -0.19, -0.31, highly AD-characteristic brain regions. These associations restricted amyloid-β-positive individuals. Both independently cognition regions typically affected AD. However, also exceeding this AD-typical spatial pattern amyloid-β-negative participants. Mediation analyses found approximately 25% 45% outcomes on mediated neuroimaging-derived neurodegeneration, suggesting links between independent these measures.Study findings suggest scalable predicting monitoring was, unlike NfL, specific. The implications use biomarkers clinical practice treatment trials.

Language: Английский

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Combination of plasma amyloid beta(1-42/1-40) and glial fibrillary acidic protein strongly associates with cerebral amyloid pathology

Alzheimer s Research & Therapy, Journal Year: 2020, Volume and Issue: 12(1)

Published: Sept. 28, 2020

Abstract Background Blood-based biomarkers for Alzheimer’s disease (AD) might facilitate identification of participants clinical trials targeting amyloid beta (Abeta) accumulation, and aid in AD diagnostics. We examined the potential plasma markers Abeta (1-42/1-40) , glial fibrillary acidic protein (GFAP) neurofilament light (NfL) to identify cerebral amyloidosis and/or severity. Methods included individuals with a positive ( n = 176: 63 ± 7 years, 87 (49%) females) or negative 76: 61 9 27 (36%) PET status, syndrome diagnosis subjective cognitive decline (18 PET+, 25 PET−), mild impairment (26 24 AD-dementia (132 PET+). Plasma GFAP, NfL were measured by Simoa. applied two-way ANOVA adjusted age sex investigate associations status diagnosis; logistic regression analysis Wald’s backward selection an optimal panel that identifies positivity; age, sex, education-adjusted linear between neuropsychological test performance; Spearman’s correlation medial temporal lobe atrophy (MTA). Results GFAP independently associated p 0.009 < 0.001 respectively), 0.048 respectively). The identifying alongside APOE (AUC 88% (95% CI 83–93%), 82% sensitivity, 86% specificity), while excluding sex. robustly performance on global cognition all major domains (GFAP: range standardized β (sβ) − 0.40 0.26; NfL: sβ 0.35 0.18; all: 0.002), whereas cognition, memory, attention, executive functioning (range 0.22 – 0.11; 0.05) but not language. showed moderate correlations MTA (both: rho> 0.33, 0.001). (Spearman’s rho 0.24, Discussion conclusions Combination provides valuable tool status. Furthermore, associate various severity measures suggesting monitoring.

Language: Английский

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Time course of phosphorylated-tau181 in blood across the Alzheimer’s disease spectrum

Brain, Journal Year: 2020, Volume and Issue: 144(1), P. 325 - 339

Published: Oct. 26, 2020

Abstract Tau phosphorylated at threonine 181 (p-tau181) measured in blood plasma has recently been proposed as an accessible, scalable, and highly specific biomarker for Alzheimer’s disease. Longitudinal studies, however, investigating the temporal dynamics of this novel are lacking. It is therefore unclear when disease process p-tau181 increases above physiological levels how it relates to spatiotemporal progression characteristic pathologies. We aimed establish natural time course across sporadic spectrum comparison those established imaging fluid-derived biomarkers examined longitudinal data from a large prospective cohort elderly individuals enrolled Disease Neuroimaging Initiative (ADNI) (n = 1067) covering wide clinical normal cognition dementia, with measures 18F-florbetapir amyloid-β PET scan baseline. A subset participants 864) also had amyloid-β1–42 CSF, another 298) undergone 18F-flortaucipir tau 6 years later. performed brain-wide analyses investigate associations baseline change regional pathology burden later, estimated changes other using previously developed method construction long-term trajectories shorter-term data. Smoothing splines demonstrated that earliest occurred even before markers reached abnormal levels, greater rates correlating increased pathology. Voxel-wise yielded relatively weak, yet significant, early accumulating brain regions cognitively healthy individuals, while strongest were observed late patients mild cognitive impairment. Cross-sectional particularly associated widespread cortical aggregation temporoparietal typical neurofibrillary tangle distribution Finally, we reaches ∼6.5 5.7 after CSF amyloid-β, respectively, following similar p-tau181. Our findings suggest presence aggregation, providing clear implications use diagnostic screening tool

Language: Английский

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Associations of amyloid and neurodegeneration plasma biomarkers with comorbidities

Alzheimer s & Dementia, Journal Year: 2021, Volume and Issue: 18(6), P. 1128 - 1140

Published: Sept. 27, 2021

Blood-based biomarkers of amyloid pathology and neurodegeneration are entering clinical use. It is critical to understand what factors affect the levels these markers.

Language: Английский

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Neuroprotective Natural Products for Alzheimer’s Disease

Cells, Journal Year: 2021, Volume and Issue: 10(6), P. 1309 - 1309

Published: May 25, 2021

Alzheimer's disease (AD) is the number one neurovegetative disease, but its treatment options are relatively few and ineffective. In efforts to discover new strategies for AD therapy, natural products have aroused interest in research community pharmaceutical industry their neuroprotective activity, targeting different pathological mechanisms associated with AD. A wide variety of from origins been evaluated preclinically clinically preventing attenuating multifactorial pathologies This review mainly focuses on possible that may be beneficial product mixtures or extracts sources demonstrated activity preclinical and/or clinical studies. It believed containing multiple bioactive compounds can work additively synergistically exhibit might an effective approach drug discovery.

Language: Английский

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Detecting amyloid positivity in early Alzheimer's disease using combinations of plasma Aβ42/Aβ40 and p‐tau

Alzheimer s & Dementia, Journal Year: 2021, Volume and Issue: 18(2), P. 283 - 293

Published: June 20, 2021

We studied usefulness of combining blood amyloid beta (Aβ)42/Aβ40, phosphorylated tau (p-tau)217, and neurofilament light (NfL) to detect abnormal brain Aβ deposition in different stages early Alzheimer's disease (AD).Plasma biomarkers were measured using mass spectrometry (Aβ42/Aβ40) immunoassays (p-tau217 NfL) cognitively unimpaired individuals (CU, N = 591) patients with mild cognitive impairment (MCI, 304) from two independent cohorts (BioFINDER-1, BioFINDER-2).In CU, a combination plasma Aβ42/Aβ40 p-tau217 detected status area under the curve (AUC) 0.83 0.86. In MCI, models including alone or had similar AUCs (0.86-0.88); however, latter showed improved model fit. The implemented an online application providing individualized risk assessments (https://brainapps.shinyapps.io/PredictABplasma/).A discriminated relatively high accuracy, whereas strongest associations pathology MCI but not CU.

Language: Английский

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Omics sciences for systems biology in Alzheimer’s disease: State-of-the-art of the evidence

Ageing Research Reviews, Journal Year: 2021, Volume and Issue: 69, P. 101346 - 101346

Published: April 27, 2021

Language: Английский

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Consideration of sex and gender in Alzheimer's disease and related disorders from a global perspective

Alzheimer s & Dementia, Journal Year: 2022, Volume and Issue: 18(12), P. 2707 - 2724

Published: April 8, 2022

Abstract Sex or gender differences in the risk of Alzheimer's disease and related dementias (ADRD) differ by world region, suggesting that there are potentially modifiable factors for intervention. However, few epidemiological clinical ADRD studies examine sex differences; even fewer evaluate context risk. The goals this perspective to: (1) provide definitions gender, biologic sex, sexual orientation. limitations examining these as binary variables; (2) an overview what is known with regard to risk, prevention, diagnosis ADRD; (3) discuss from a global, worldwide perspective. Identifying drivers throughout first step developing interventions unique each geographical sociocultural area reduce inequities ultimately global Highlights burden dementia unevenly distributed geographically gender. Scientific advances genetics biomarkers challenge beliefs binary. Discrimination against women minority (SGM) populations contributes cognitive decline. Sociocultural lead worldwide.

Language: Английский

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