Serum proteomics reveals APOE dependent and independent protein signatures in Alzheimer’s disease DOI Creative Commons
Valborg Guðmundsdóttir, Elisabet A. Frick, Valur Emilsson

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 9, 2024

Abstract The current demand for early intervention, prevention, and treatment of late onset Alzheimer’s disease (LOAD) warrants deeper understanding the underlying molecular processes which could contribute to biomarker drug target discovery. Utilizing high-throughput proteomic measurements in serum from a prospective population-based cohort older adults (n = 5,294), we identified 303 unique proteins associated with incident LOAD (median follow-up 12.8 years). Over 40% these were independently APOE-ε4 carrier status. These implicated neuronal overlapped protein signatures brain cerebrospinal fluid. We found 17 LOAD-association was strongly dependent on Most them showed consistent associations fluid third had brain-specific gene expression. Remarkably, four this group (TBCA, ARL2, S100A13 IRF6) downregulated by yet upregulated as consequence determined bi-directional Mendelian randomization analysis, reflecting potential response onset. Accordingly, direct association reversed upon genotype adjustment, finding replicate an external 719). Our findings provide insight into dysregulated pathways that may lead development detection LOAD, including those both independent dependent APOE-ε4. Importantly, many LOAD-associated find circulation have been be expressed - link AD tissue. Thus, here, their upstream modulating pathways, new source circulating therapeutic candidates LOAD.

Language: Английский

Report of the APOE4 National Institute on Aging/Alzheimer Disease Sequencing Project Consortium Working Group: Reducing APOE4 in Carriers is a Therapeutic Goal for Alzheimer's Disease DOI Creative Commons
Jeffery M. Vance, Lindsay A. Farrer, Yadong Huang

et al.

Annals of Neurology, Journal Year: 2024, Volume and Issue: 95(4), P. 625 - 634

Published: Jan. 5, 2024

Alzheimer's disease (AD) is the most common neurodegenerative disorder and one of leading causes disability worldwide. The apolipoprotein E4 gene (APOE4) strongest genetic risk factor for AD. In 2023, APOE4 National Institute on Aging/Alzheimer's Disease Sequencing Project working group came together to gather data discuss question whether reduce or increase as a therapeutic intervention It was unanimous consensus that cumulative from multiple studies in humans animal models support lowering should be target approaches carriers. ANN NEUROL 2024;95:625-634.

Language: Английский

Citations

17
Proteomic analysis of Alzheimer’s disease cerebrospinal fluid reveals alterations associated with APOE ε4 and atomoxetine treatment DOI Open Access
Eric B. Dammer, Anantharaman Shantaraman, Lingyan Ping

et al.

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(753)

Published: June 26, 2024

Alzheimer’s disease (AD) is currently defined by the aggregation of amyloid-β (Aβ) and tau proteins in brain. Although biofluid biomarkers are available to measure Aβ pathology, few markers complex pathophysiology that associated with these two cardinal neuropathologies. Here, we characterized proteomic landscape cerebrospinal fluid (CSF) changes pathology 300 individuals using different technologies—tandem mass tag spectrometry SomaScan. Integration both data types allowed for generation a robust protein coexpression network consisting 34 modules derived from 5242 measurements, including disease-relevant autophagy, ubiquitination, endocytosis, glycolysis. Three strongly apolipoprotein E ε4 ( APOE ε4) AD risk genotype mapped oxidant detoxification, mitogen-associated kinase signaling, neddylation, mitochondrial biology overlapped previously described lipoprotein module serum. Alterations all three blood were dementia more than 20 years before diagnosis. Analysis CSF samples an phase 2 clinical trial atomoxetine (ATX) demonstrated abnormal elevations glycolysis module—the most correlated cognitive function—were reduced ATX treatment. Clustering based on their profiles revealed heterogeneity pathological not fully reflected tau.

Language: Английский

Citations

16
Apolipoprotein E in Alzheimer’s disease trajectories and the next-generation clinical care pathway DOI
Sneha Narasimhan, David M. Holtzman, Liana G. Apostolova

et al.

Nature Neuroscience, Journal Year: 2024, Volume and Issue: 27(7), P. 1236 - 1252

Published: June 19, 2024

Language: Английский

Citations

15
Promises and Challenges of populational Proteomics in Health and Disease DOI Creative Commons
Benjamin B. Sun, Karsten Suhre, Bradford W. Gibson

et al.

Molecular & Cellular Proteomics, Journal Year: 2024, Volume and Issue: 23(7), P. 100786 - 100786

Published: May 17, 2024

Language: Английский

Citations

12
Serum proteomics reveal APOE-ε4-dependent and APOE-ε4-independent protein signatures in Alzheimer’s disease DOI Creative Commons
Elisabet A. Frick, Valur Emilsson, Þórarinn Jónmundsson

et al.

Nature Aging, Journal Year: 2024, Volume and Issue: 4(10), P. 1446 - 1464

Published: Aug. 21, 2024

A deeper understanding of the molecular processes underlying late-onset Alzheimer's disease (LOAD) could aid in biomarker and drug target discovery. Using high-throughput serum proteomics prospective population-based Age, Gene/Environment Susceptibility-Reykjavik Study (AGES) cohort 5,127 older Icelandic adults (mean age, 76.6 ± 5.6 years), we identified 303 proteins associated with incident LOAD over a median follow-up 12.8 years. Over 40% these were independently APOE-ε4 carrier status, implicated neuronal overlapped protein signatures brain cerebrospinal fluid. We 17 whose associations strongly dependent on mostly consistent Remarkably, four (TBCA, ARL2, S100A13 IRF6) downregulated by yet upregulated due to LOAD, finding replicated external cohorts possibly reflecting response onset. These findings highlight dysregulated pathways at preclinical stages including those both independent status.

Language: Английский

Citations

11
Multi-cohort cerebrospinal fluid proteomics identifies robust molecular signatures for asymptomatic and symptomatic Alzheimer’s disease. DOI Creative Commons
Carlos Cruchaga, Muhammad Ali, Yuanyuan Shen

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 16, 2024

Abstract Changes in Amyloid-β (A), hyperphosphorylated Tau (T) brain and cerebrospinal fluid (CSF) precedes AD symptoms, making CSF proteome a potential avenue to understand the pathophysiology facilitate reliable diagnostics therapies. Using AT framework three-stage study design (discovery, replication, meta-analysis), we identified 2,173 proteins dysregulated AD, that were further validated third totally independent cohort. Machine learning was implemented create validate highly accurate replicable (AUC>0.90) models predict biomarker positivity clinical status. These can also identify people will convert those cases with faster progression. The associated cluster four different protein pseudo-trajectories groups spanning continuum enrichment specific pathways including neuronal death, apoptosis tau phosphorylation (early stages), microglia dysregulation endolysosomal dysfuncton(mid-stages), plasticity longevity (mid-stages) late microglia-neuron crosstalk (late stages).

Language: Английский

Citations

6
CSF biomarkers of immune activation and Alzheimer’s disease for predicting cognitive impairment risk in the elderly DOI Creative Commons
Francis Shue, Launia J. White, Rachel Hendrix

et al.

Science Advances, Journal Year: 2024, Volume and Issue: 10(14)

Published: April 3, 2024

The immune system substantially influences age-related cognitive decline and Alzheimer's disease (AD) progression, affected by genetic environmental factors. In a Mayo Clinic Study of Aging cohort, we examined how risk factors like APOE genotype, age, sex affect inflammatory molecules AD biomarkers in cerebrospinal fluid (CSF). Among cognitively unimpaired individuals over 65 (

Language: Английский

Citations

6
Genetic and multi-omic resources for Alzheimer disease and related dementia from the Knight Alzheimer Disease Research Center DOI Creative Commons
María Victoria Fernández, Menghan Liu, Aleksandra Beric

et al.

Scientific Data, Journal Year: 2024, Volume and Issue: 11(1)

Published: July 12, 2024

Abstract The Knight-Alzheimer Disease Research Center (Knight-ADRC) at Washington University in St. Louis has pioneered and led worldwide seminal studies that have expanded our clinical, social, pathological, molecular understanding of Alzheimer Disease. Over more than 40 years, research volunteers been recruited to participate cognitive, neuropsychologic, imaging, fluid biomarkers, genomic multi-omic studies. Tissue longitudinal data collected foster, facilitate, support on dementia aging. Genetics high throughput - omics core (GHTO) 26,000 biological samples from 6,625 Knight-ADRC participants. Samples available include DNA, RNA, non-fasted plasma, cerebrospinal pellets, peripheral blood mononuclear cells. GHTO performed deep profiling (genomic, transcriptomic, epigenomic, proteomic, metabolomic) large number brain (n = 2,117), CSF 2,012) blood/plasma 8,265) with the goal identifying novel risk protective variants, identify biomarkers causal druggable targets. Overall, resources increase

Language: Английский

Citations

6
Identifying novel proteins for migraine by integrating proteomes from blood and CSF with genome‐wide association data DOI Creative Commons
Peng‐Peng Niu, Rui Zhang, Chan Zhang

et al.

CNS Neuroscience & Therapeutics, Journal Year: 2024, Volume and Issue: 30(6)

Published: June 1, 2024

Abstract Background Proteome‐wide Mendelian randomization studies have been increasingly utilized to identify potential drug targets for diseases. We aimed therapeutic migraine and its subtypes through the application of co‐localization analysis methods. Methods cis‐ protein quantitative trait loci data 1378 plasma proteins available from two with 7213 individuals 35,559 individuals, respectively. Summary were obtained a genetic study involving up 1,339,303 individuals. Proteins that passed both discovery validation analysis, sensitivity heterogeneity test, pleiotropy associated ≥2 outcomes, received strong support (PP.H4.abf ≥0.80) classified as tier 1 proteins. Results identified three (LRP11, ITIH1, ADGRF5), whose genes not previously causal in studies. LRP11 was significantly risk any (OR [odds ratio] = 0.968, 95% CI [confidence interval] 0.955–0.981, p 1.27 × 10 −6 ) significantly/suggestively subtypes. ITIH1 1.044, 1.024–1.065, 1.08 −5 visual disturbances. ADGRF5 0.964, 0.946–0.982, 8.74 suggestively aura. The effects further replicated using cerebrospinal fluid data. Apart ADGRF5, there no evidence adverse consequences when modulating levels. also another four (PLCG1, ARHGAP25, CHGA, MANBA) levels, their reported by previous Conclusions found compelling suggestive could be promising treatment without significant consequences. corresponding Future are needed confirm role these explore underlying mechanisms.

Language: Английский

Citations

5
Proteomic Network Analysis of Alzheimer’s Disease Cerebrospinal Fluid Reveals Alterations Associated withAPOEε4 Genotype and Atomoxetine Treatment DOI
Eric B. Dammer, Anantharaman Shantaraman, Lingyan Ping

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 30, 2023

Abstract Alzheimer’s disease (AD) is currently defined at the research level by aggregation of amyloid-β (Aβ) and tau proteins in brain. While biofluid biomarkers are available to measure Aβ pathology, few complex pathophysiology that associated with these two cardinal neuropathologies. Here we describe proteomic landscape cerebrospinal fluid (CSF) changes pathology 300 individuals as assessed different technologies—tandem mass tag (TMT) spectrometry SomaScan. Harmonization integration both data types allowed for generation a robust protein co-expression network consisting 34 modules derived from 5242 measurements, including disease-relevant autophagy, ubiquitination, endocytosis, glycolysis. Three strongly apolipoprotein E ε4 ( APOE ε4) AD risk genotype mapped oxidant detoxification, mitogen kinase (MAPK) signaling, neddylation, mitochondrial biology, overlapped previously described lipoprotein module serum. Neddylation detoxification/MAPK signaling had negative association whereas mitochondrion positive ε4. The directions were consistent between CSF blood independent longitudinal cohorts, altered levels all three dementia over 20 years prior diagnosis. Dual-proteomic platform analysis samples an phase 2 clinical trial atomoxetine (ATX) demonstrated abnormal elevations glycolysis module—the most correlated cognitive function—were reduced ATX treatment. Individuals who more severe glycolytic baseline responded better ATX. Clustering based on their profiles revealed ten groups did not cleanly stratify status, underscoring heterogeneity pathological fully reflected tau. proteomics holds promise development reflect diverse pathologies use trials precision medicine.

Language: Английский

Citations

11