GWAS meta-analysis of CSF Alzheimer's disease biomarkers 18,948 individuals reveal novel loci and genes regulating lipid metabolism, brain volume and autophagy

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Май 21, 2025

Cerebrospinal fluid (CSF) amyloid beta (Aβ42), total tau (t-tau), and phosphorylated (p-tau181) are well accepted markers of Alzheimer’s disease. We performed a GWAS meta-analysis including 18,948 individuals European 416 non-European ancestry. identified 12 genome-wide significant loci across all three biomarkers, eight them novel. replicated the association CSF biomarkers with APOE, CR1, GMNC/CCDC50 C16orf95/MAP1LC3B. Novel included BIN1 for Aβ42 GNA12, MS4A6A, SLCO1A2 both t-tau p-tau181, as additional on chr. 8, near ANGPT1 9 SMARCA2. also demonstrated that these variants were not only associated level but showed AD risk, disease progression and/or brain amyloidosis. The genes implicated in lipid metabolism independent autophagy volume regulation driven by p-tau181 dysregulation.

Язык: Английский

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Ubiquitin–proteasome system in the different stages of dominantly inherited Alzheimer's disease

Alzheimer s & Dementia, Год журнала: 2025, Номер 21(5)

Опубликована: Май 1, 2025

Abstract INTRODUCTION This study investigated the role of ubiquitin–proteasome system (UPS) in dominantly inherited Alzheimer's disease (DIAD) by examining cerebrospinal fluid (CSF) levels UPS proteins. METHOD The SOMAscan assay was used to detect changes proteins mutation carriers (MCs) relative progression; imaging and CSF biomarkers amyloid, tau, neurodegeneration measures; Clinical Dementia Rating scale. RESULTS Subtle increases specific ubiquitin enzymes were detected MCs up two decades before symptom onset, with more pronounced elevations UPS‐activating near onset. Significant correlations found between (AD) biomarkers, especially autophagy markers late‐stage tau microglia, axonal degeneration. DISCUSSION rise alongside tau‐related suggests involvement neurofibrillary tangles. Elevated DIAD may serve as indicators progression, support a therapeutic target AD. Highlights investigates ubiquitin‐proteasome Dominantly Inherited Disease (DIAD), highlighting early molecular linked progression. Using proteomics, we identified significant protein alterations carriers, notably 20 years clinical Correlations particularly markers, suggest strong association dysregulation pathology DIAD. Dynamic align A/T biological staging: shown increase across Aβ/tau (A/T) groups, largest A+/T+ group, reinforcing their These findings underscore potential for progression novel targets, tau‐pathology‐driven neurodegeneration. work contributes understanding AD pathogenesis, emphasizing importance quality control systems offering avenues future biomarker discovery development disease.

Язык: Английский

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ALZHEIMER'S DISEASE: COMPREHENSIVE INSIGHTS INTO RISK FACTORS, BIOMARKERS, AND ADVANCED TREATMENT APPROACHES

International Journal of Current Pharmaceutical Research, Год журнала: 2025, Номер unknown, С. 1 - 10

Опубликована: Янв. 15, 2025

Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder primarily affecting individuals over 60. It multifactorial driven by both modifiable factors, such as lifestyle, diet, and prior health conditions, well non-modifiable like age, genetics, family history. The key pathological features of AD include the buildup amyloid β plaques neurofibrillary tangles resulting from hyperphosphorylated tau proteins in brain. Biomarkers protein levels cerebrospinal fluid (CSF) blood are essential for diagnosing tracking progression. Current research focuses on developing drugs targeting multiple aspects pathology, including inflammation, oxidative stress, synaptic dysfunction, accumulation. These treatments aim to slow cognitive decline neuronal damage. Given complexity AD, multi-targeted therapeutic approaches being explored enhance treatment efficacy. This review provides an overview risk biomarkers used diagnosis, latest advances clinical drug development.

Язык: Английский

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Large-scale Plasma Proteomic Profiling Unveils Novel Diagnostic Biomarkers and Pathways for Alzheimer's Disease

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Март 18, 2025

Alzheimer disease (AD) is a complex neurodegenerative disorder. Proteomic studies have been instrumental in identifying AD-related proteins present the brain, cerebrospinal fluid, and plasma. This study comprehensively examined 6,905 plasma more than 3,300 well-characterized individuals to identify new proteins, pathways, predictive model for AD. With three-stage analysis (discovery, replication, meta-analysis) we identified 416 (294 novel) associated with clinical AD status findings were further validated two external datasets including 7,000 samples seven previous studies. Pathway revealed that these involved endothelial blood hemostatic (ACHE, SMOC1, SMOC2, VEGFA, VEGFB, SPARC), capturing brain barrier (BBB) disruption due disease. Other pathways known processes implicated AD, such as lipid dysregulation (APOE, BIN1, CLU, SMPD1, PLA2G12A, CTSF) or immune response (C5, CFB, DEFA5, FBXL4), which includes be part of causal pathway indicating some are pathogenesis. An enrichment neural (axonal guidance signaling myelination signaling) indicates that, fact, proteomics capture brain- disease-related changes, can lead identification novel biomarkers models. Machine learning was employed set highly both (AUC > 0.72) biomarker-defined 0.88), replicated multiple cohorts well orthogonal platforms. These extensive underscore potential using early detection monitoring potentially guiding treatment decisions.

Язык: Английский

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The CentiMarker project: Standardizing quantitative Alzheimer's disease fluid biomarkers for biologic interpretation

Alzheimer s & Dementia, Год журнала: 2025, Номер 21(4)

Опубликована: Апрель 1, 2025

Abstract INTRODUCTION Biomarkers play a crucial role in understanding Alzheimer's disease (AD) pathogenesis and treatment effects. However, comparing biomarker measures without standardization appreciating their magnitude relative to the can be challenging. METHODS To address this issue, we propose CentiMarker approach, similar Centiloid, which provides standardized scale between normal (0) nearly maximum abnormal AD (100) ranges. We applied cerebrospinal fluid (CSF) biomarkers dominantly inherited sporadic cohorts. RESULTS CentiMarkers facilitated interpretation of abnormality, demonstrating comparable changes distributions across stages. make effect more than original scales various biomarkers. DISCUSSION The versatility makes it valuable tool for comparison research, enabling informed cross‐study comparisons contributing accelerated therapeutic development. Adoption could enhance reporting advance our AD. Highlights Comparing metric standardize from when using scales.

Язык: Английский

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Alzheimer's polygenic risk scores are associated with cognitive phenotypes in Down syndrome

Alzheimer s & Dementia, Год журнала: 2023, Номер 20(2), С. 1038 - 1049

Опубликована: Окт. 19, 2023

Abstract INTRODUCTION This study aimed to investigate the influence of overall Alzheimer's disease (AD) genetic architecture on Down syndrome (DS) status, cognitive measures, and cerebrospinal fluid (CSF) biomarkers. METHODS AD polygenic risk scores (PRS) were tested for association with DS‐related traits. RESULTS The PRS was associated status in several cohorts sporadic late‐ early‐onset familial late‐onset AD, but not or DS. On other hand, lower DS Mental Status Examination memory higher PRS, independent intellectual disability APOE (PRS including , p = 2.84 × 10 −4 ; excluding nonAPOE 1.60 −2 ). exhibited significant associations Aβ42, tTau, pTau, Aβ42/40 ratio DISCUSSION These data indicate that influences CSF phenotypes adults, supporting common pathways decline both Highlights presented here is first its kind. aspects individuals, independently genotype . results point an overlap between genes leads those dementia population. ε4 linked decline, expanding insights adults.

Язык: Английский

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Comprehensive Systematic Computation on Alzheimer's Disease Classification

Archives of Computational Methods in Engineering, Год журнала: 2024, Номер unknown

Опубликована: Апрель 30, 2024

Язык: Английский

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The CentiMarker Project: Standardizing Quantitative Alzheimer’s disease Fluid Biomarkers for Biologic Interpretation

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 27, 2024

ABSTRACT Introduction Biomarkers have been essential to understanding Alzheimer’s disease (AD) pathogenesis, pathophysiology, progression, and treatment effects. However, each biomarker measure is a representation of the biological target, assay used it, variance assay. Thus, measures are difficult compare without standardization, units magnitude effect relative appreciate, even for experts. To facilitate quantitative comparisons AD biomarkers in context biologic effects, we propose standardization approach between normal ranges maximum abnormal ranges, which refer as CentiMarker, similar Centiloid PET. Methods We developed scale that creates percentile values ranging from 0 population 100 most across stages. applied this CSF plasma autosomal dominant AD, assessing distribution by estimated years symptom onset, biomarkers, cohorts. then validated large national sporadic cohort. Results found CentiMarker provided an easily interpretable metric abnormality. The changes, range, several fluid including amyloid-β, phospho-tau other were comparable stages both early onset late AD. Discussion offers robust versatile framework standardized comparison biomarkers. Its broader adoption could reporting, allowing more informed cross-study contributing accelerated therapeutic development.

Язык: Английский

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Polygenic proxies of age-related plasma protein levels reveal TIMP2 role in cognitive performance

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Окт. 18, 2024

Background While numerous studies have identified blood proteins that modulate brain aging in mice, the direct translation of these findings to human health remains a substantial challenge. Bridging this gap is critical for developing interventions can effectively target and associated diseases.Methods We first 12 with or rejuvenating properties murine brains through systematic review. Using protein quantitative trait loci data proteins, we developed polygenic scores predict plasma levels, which then validated two independent cohorts. employed association models explore between genetically predicted levels cognitive performance, focusing specifically on their interaction key genetic markers such as sex, APOE-ε4 Aβ42 status.Results Predicted Tissue Inhibitor Metalloproteinases 2 (TIMP2) were significantly improved global cognition memory performance humans, also when stratified by APOE-ε4, status.Conclusions This finding aligns TIMP2's brain-rejuvenating role models, suggesting it promising therapeutic age-related diseases humans.

Язык: Английский

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Polygenic proxies of age-related plasma protein levels reveal TIMP2 role in cognitive performance

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 24, 2024

Several studies have identified blood proteins that influence brain aging performance in mice, yet translating these findings to humans remains challenging. Here we found higher predicted plasma levels of Tissue Inhibitor Metalloproteinases 2 (TIMP2) were significantly associated with improved global cognition and memory humans. We first 12 or rejuvenating effects on murine brains through a systematic review. Using protein quantitative trait loci data for proteins, computed polygenic scores as proxies validated their prediction accuracy two independent cohorts. Association models between genetic cognitive highlighted the significance TIMP2, also when stratified by sex,

Язык: Английский

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