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

A 3’UTR Insertion Is a Candidate Causal Variant at theTMEM106BLocus Associated with Increased Risk for FTLD-TDP DOI Creative Commons
Augustine Chemparathy, Yann Le Guen,

Yi Zeng

et al.

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

Published: July 8, 2023

Single nucleotide variants near

Language: Английский

Citations

10
Multi-tissue proteomic signatures of Alzheimer's disease: a systematic investigation in brain, CSF, blood and an exploratory study in tears DOI
Jie Shen, Yuhui Huang,

Minyu Wu

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 15, 2025

Abstract Proteomic studies have the potential to identify etiological biomarker and interventional targets for Alzheimer’s disease (AD). However, limited systematically investigated compared proteomic profiling related AD across multiple tissues. First, we reviewed 112 of (comprising 107 case-control 16,997 individuals 5 prospective cohort 60,782 individuals) synthesized a map 902 brain bulk, 315 cerebrospinal fluid (CSF), 9 blood markers that were consistently altered in at least studies. In particular, total 55 common proteins same direction bulk CSF, whereas 33 opposite direction. Next, applied proteome-wide Mendelian randomization identified 28 brain, 32 59 plasma genetically predicted associated with (all FDR < 0.05). The comparison tissues uncovered panel 20 AD-related two human Overall, pool 1,219 multi-tissue high confidence two-phase investigation. exploratory analysis utilizing matched study among 79 community-dwelling older adults, detected 845 protein tears, which 312 severity-dependent manner normal cognition controls, mild cognitive impairment (MCI) dementia stages. Among these, levels STXBP1, UBE2V1, PALM, PYGB, ST13, GPD1 significantly different or MCI controls P our provides comprehensive roadmap biomarkers help enhance exploration underlying mechanisms, facilitate development minimally invasive screening methods, novel interventions.

Language: Английский

Citations

0
Neuroinflammatory fluid biomarkers in patients with Alzheimer’s disease: a systematic literature review DOI Creative Commons
Michael T. Heneka, Serge Gauthier,

Sagar Anil Chandekar

et al.

Molecular Psychiatry, Journal Year: 2025, Volume and Issue: unknown

Published: March 6, 2025

Neuroinflammation is associated with both early and late stages of the pathophysiology Alzheimer's disease (AD). Fluid biomarkers are gaining significance in clinical practice for diagnosis presymptomatic stages, monitoring, prognosis. This systematic literature review (SLR) aimed to identify fluid neuroinflammation related across AD continuum examined long-term outcomes changes biomarkers. The SLR was conducted per Cochrane Handbook Systematic Reviews Interventions Preferred Reporting Items Meta-Analyses (PRISMA) guidelines. We used PubMed®, Embase®, Collaboration databases search articles English (between 2012 2022) on or mild cognitive impairment due AD, using "neuroinflammation" other "immune" strings. Two independent reviewers screened titles data from full-text SLR. After initial screening, 54 studies were prioritized extraction based upon their relevance research questions. Nine YKL-40, seven sTREM2, 11 GFAP relationship between neuroinflammatory stage disease. longitudinal further explored association Cerebrospinal (CSF) levels YKL-40 elevated patients dementia, while CSF sTREM2 more strongly preclinical symptomatic AD. Plasma remained consistently dementia individuals β-amyloid pathology. Longitudinal plasma appeared be predictive decline over time. Neuroinflammatory progression. More MCI needed validate diagnosis, prognosis practice.

Language: Английский

Citations

0
Plasma protein risk scores for mild cognitive impairment and Alzheimer's disease in the Framingham heart study DOI Creative Commons
Habbiburr Rehman, Ting Fang Alvin Ang, Qiushan Tao

et al.

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: 21(3)

Published: March 1, 2025

Abstract INTRODUCTION It is unclear whether aggregated plasma protein risk scores (PPRSs) could be useful in predicting the risks of mild cognitive impairment (MCI) and Alzheimer's disease (AD). METHODS The Cox proportional hazard model with Least Absolute Shrinkage Selection Operator penalty was used to build PPRSs for MCI AD 1515 Framingham Heart Study Generation 2 1128 proteins measured at exam 5 (cognitively normal [CN] = 1258, 129, 128). RESULTS PPRS had a ratio (HR) 6.97 [5.34, 9.12], discriminating power (C‐index 82.52%). HR 5.74 [4.67, 7.05] 88.15%). Both were also significantly associated changes, brain atrophy, biomarkers. Proteins involved several pathways related leukocyte, chemotaxis, immunity, inflammation, cellular migration. DISCUSSION This study suggests that serve well predict developing as changes AD‐related pathogenesis brain. Highlights developed preclinical stage, MCI. loss volume, increasing level Leukocyte, migration enriched identified being PPRSs.

Language: Английский

Citations

0
Circadian protein expression patterns in healthy young adults DOI
A. Specht,

German Kolosov,

Katie L.J. Cederberg

et al.

Sleep Health, Journal Year: 2023, Volume and Issue: 10(1), P. S41 - S51

Published: Dec. 11, 2023

Language: Английский

Citations

8
Novel early-onset Alzheimer-associated genes influence risk through dysregulation of glutamate, immune activation, and intracell signaling pathways DOI Creative Commons
Carlos Cruchaga, Joseph Bradley, Daniel Western

et al.

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

Published: June 5, 2024

Abstract Alzheimer Disease (AD) is a highly polygenic disease that presents with relatively earlier onset (≤70yo; EOAD) in about 5% of cases. Around 90% these EOAD cases remain unexplained by pathogenic mutations. Using data from and controls, we performed genome-wide association study (GWAS) trans-ancestry meta-analysis on non-Hispanic Whites (NHW, NCase=6,282, NControl=13,386), African Americans (AA NCase=782, NControl=3,663) East Asians (NCase=375, NControl=838 CO). We identified eight novel significant loci: six the ancestry-specific analyses two analysis. By integrating gene-based analysis, eQTL, pQTL functional annotations, nominate four genes are involved microglia activation, glutamate production, signaling pathways. These results indicate EOAD, although sharing many LOAD, harbors unique pathways could be used to create better prediction models or target identification for this type AD

Language: Английский

Citations

3
A 3′UTR Insertion Is a Candidate Causal Variant at the TMEM106B Locus Associated With Increased Risk for FTLD-TDP DOI Creative Commons
Augustine Chemparathy, Yann Le Guen, Yi Zeng

et al.

Neurology Genetics, Journal Year: 2024, Volume and Issue: 10(1)

Published: Feb. 1, 2024

Single-nucleotide variants near TMEM106B associate with the risk of frontotemporal lobar dementia TDP-43 inclusions (FTLD-TDP) and Alzheimer disease (AD) in genome-wide association studies (GWASs), but causal variant at this locus remains unclear. Here, we asked whether a novel structural on is variant.

Language: Английский

Citations

2
Head-to-head comparison of aptamer- and antibody-based proteomic platforms in human cerebrospinal fluid samples from a real-world memory clinic cohort DOI
Raquel Puerta, Amanda Cano, Pablo García‐González

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 18, 2024

Abstract High-throughput proteomic platforms have a crucial role in identifying novel Alzheimer’s disease (AD) biomarkers and pathways. In this study, we evaluated the reproducibility reliability of aptamer-based (SomaScan® 7k) antibody-based (Olink® Explore 3k) cerebrospinal fluid (CSF) samples from Ace Alzheimer Center Barcelona real-world cohort. Intra- interplatform was through correlations between two independent SomaScan® assays analyzing same Olink® results. Our 12-category metric combining both correlation analyses identified 2,428 highly reproducible SomaScan CSF measures, with over 600 proteins well reproduced on another platform. The association among AD clinical phenotypes revealed that significant associations mainly involved proteins. validation these proteomics platforms, measured using scarce biomaterial, is essential for accurate analysis proper interpretation innovative This classification could enhance confidence multiplexed improve design future panels.

Language: Английский

Citations

2
Elevated serum sodium is linked to increased amyloid‐dependent tau pathology, neurodegeneration, and cognitive impairment in Alzheimer's disease DOI Creative Commons
Yuhan Chen, Zhibo Wang,

Xipeng Liu

et al.

Journal of Neurochemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 6, 2024

Abstract Vascular dysfunction is implicated in the pathophysiology of Alzheimer's disease (AD). While sodium essential for maintaining vascular function, its role AD pathology remains unclear. We included 353 participants from Disease Neuroimaging Initiative (ADNI), assessing serum levels, cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers, magnetic resonance imaging (MRI), cognitive function. An independent sample ( N = 471) with available CSF sodium‐related proteins biomarkers was also included. Associations between levels pathology, neurodegeneration, cognition were evaluated using linear regression models. Spearman's correlation analyses assessed relationships biomarkers. Higher associated increased reduced hippocampal volume, greater decline (all p < 0.05). The relationship amyloid PET evident several AD‐susceptible brain regions, including neocortex limbic system. Individuals high exhibited higher tau lower more severe per unit increase compared to those low Among 14 proteins, which inter‐correlated, six significantly correlated PET, while two volume channel subunit beta‐2 (SCN2B) beta‐3 (SCN3B) showing strongest correlations. These findings underscore crucial progression, highlighting a potential network dysregulation involved pathology. Targeting may offer novel therapeutic approach slowing particularly by impeding progression amyloid‐related downstream events. image

Language: Английский

Citations

2
A genetic and proteomic comparison of key AD biomarkers across tissues DOI Creative Commons
Thomas W. Marsh, Daniel Western, Jigyasha Timsina

et al.

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(9), P. 6423 - 6440

Published: July 30, 2024

Abstract INTRODUCTION Plasma has been proposed as an alternative to cerebrospinal fluid (CSF) for measuring Alzheimer's disease (AD) biomarkers, but no studies have analyzed in detail which biofluid is more informative genetics of AD. METHOD Eleven proteins associated with AD (α‐synuclein, apolipoprotein E [apoE], CLU, GFAP, GRN, NfL, NRGN, SNAP‐25, TREM2, VILIP‐1, YKL‐40) were assessed plasma ( n = 2317) and CSF 3107). Both genome‐wide association study (GWAS) analyses performed each protein, followed by functional annotation. Additional characterization biomarker included calculation correlations predictive power. RESULTS Eighteen protein quantitative train loci (pQTLs) 10 16 pQTLs 9 identified. shared some genetic loci, levels between tissues correlated weakly. better compared plasma. DISCUSSION The present results indicate that than Highlights identification novel trait both (CSF). neurodegeneration‐related (AD). Neurofilament light (NfL), triggering receptor expressed on myeloid cells 2 (TREM2), chitinase‐3‐like 1 (YKL‐40) tend show relatively strong inter‐tissue associations. A signal the APOE ) region was identified, eQTL APOC1 .

Language: Английский

Citations

1