Proteo-genomics of soluble TREM2 in cerebrospinal fluid provides novel insights and identifies novel modulators for Alzheimer’s disease

Molecular Neurodegeneration, Journal Year: 2024, Volume and Issue: 19(1)

Published: Jan. 3, 2024

Abstract Triggering receptor expressed on myeloid cells 2 (TREM2) plays a critical role in microglial activation, survival, and apoptosis, as well Alzheimer’s disease (AD) pathogenesis. We previously reported the MS4A locus key modulator for soluble TREM2 (sTREM2) cerebrospinal fluid (CSF). To identify additional novel genetic modifiers of sTREM2, we performed largest genome-wide association study (GWAS) identified four loci CSF sTREM2 3,350 individuals European ancestry. Through multi-ethnic fine mapping, two independent missense variants (p.M178V MS4A4A p.A112T MS4A6A ) that drive showed an epistatic effect levels AD risk. The chr 6 contains rare (rs75932628 p.R47H, P =7.16×10 -19 ; rs142232675 p.D87N, =2.71×10 -10 associated with third TGFBR2 RBMS3 gene region (rs73823326, =3.86×10 -9 included regulatory variant microglia-specific chromatin loop promoter . Using cell-based assays demonstrate overexpression knock-down TGFBR2, but not RBMS3, leads to significant changes sTREM2. last is located APOE (rs11666329, =2.52×10 -8 ), demonstrated this signal was genotype. This colocalized cis-eQTL NECTIN2 brain cortex cis-pQTL CSF. Overexpression led increase supporting findings. our knowledge, date aimed at identifying provided insights into loci, well-known risk genes, modulators involved biology.

Language: Английский

---

Developing blood-brain barrier arterial spin labelling as a non-invasive early biomarker of Alzheimer’s disease (DEBBIE-AD): a prospective observational multicohort study protocol

BMJ Open, Journal Year: 2024, Volume and Issue: 14(3), P. e081635 - e081635

Published: March 1, 2024

Introduction Loss of blood-brain barrier (BBB) integrity is hypothesised to be one the earliest microvascular signs Alzheimer’s disease (AD). Existing BBB imaging methods involve contrast agents or ionising radiation, and pose limitations in terms cost logistics. Arterial spin labelling (ASL) perfusion MRI has been recently adapted map permeability non-invasively. The DEveloping BBB-ASL as a non-Invasive Early biomarker (DEBBIE) consortium aims develop this modified ASL-MRI technique for patient-specific robust assessments. This article outlines study design DEBBIE cohorts focused on investigating potential an early AD (DEBBIE-AD). Methods analysis DEBBIE-AD consists multicohort enrolling participants with subjective cognitive decline, mild impairment AD, well age-matched healthy controls, from 13 cohorts. precision accuracy will evaluated participants. clinical value by comparing results both established novel biomarkers. provide evidence ability measure demonstrate its utility AD-related pathologies. Ethics dissemination approval was obtained 10 cohorts, pending 3 main trial each secondary endpoints submitted publication peer-reviewed journal.

Language: Английский

---

CSF proteomics identifies early changes in autosomal dominant Alzheimer’s disease

Cell, Journal Year: 2024, Volume and Issue: 187(22), P. 6309 - 6326.e15

Published: Sept. 26, 2024

In this high-throughput proteomic study of autosomal dominant Alzheimer's disease (ADAD), we sought to identify early biomarkers in cerebrospinal fluid (CSF) for monitoring and treatment strategies. We examined CSF proteins 286 mutation carriers (MCs) 177 non-carriers (NCs). The developed multi-layer regression model distinguished with different pseudo-trajectories between these groups. validated our findings independent ADAD as well sporadic AD datasets employed machine learning develop validate predictive models. Our identified 137 distinct trajectories MCs NCs, including eight that changed before traditional biomarkers. These are grouped into three stages: stage (stress response, glutamate metabolism, neuron mitochondrial damage), middle (neuronal death, apoptosis), late presymptomatic (microglial changes, cell communication). revealed a six-protein subset more effectively differentiated from compared conventional

Language: Английский

---

Benchmarking of a multi-biomarker low-volume panel for Alzheimer’s Disease and related dementia research

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

Published: June 14, 2024

Alzheimer's Disease (AD) biomarker measurement is key to aid in the diagnosis and prognosis of disease. In research setting, participant recruitment retention optimization sample use, one main challenges that observational studies face. Thus, obtaining accurate established measurements for stratification maximizing use precious samples key. Accurate technologies are currently available biomarkers, mainly immunoassays immunoprecipitation liquid chromatography-mass spectrometry (IP-MS), some them already being used clinical settings. Although immunoassays- IP-MS based platforms provide multiplexing several different coding proteins there not a current platform can measure all stablished emerging biomarkers run. The NUcleic acid Linked Immuno-Sandwich Assay (NULISA

Language: Английский

---

Genetic and multi-omic resources for Alzheimer disease and related dementia from the Knight Alzheimer Disease Research Center

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

---

Benchmarking of a multi‐biomarker low‐volume panel for Alzheimer's disease and related dementia research

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 22, 2024

Abstract INTRODUCTION In the research setting, obtaining accurate established biomarker measurements and maximizing use of precious samples is key. Accurate technologies are available for Alzheimer's disease (AD), but no platform can measure all emerging biomarkers in one run. The NUcleic acid Linked Immuno‐Sandwich Assay (NULISA) a technology that requires 15 µL sample to more than 100 analytes. METHODS We compared AD‐relevant included NULISA against validated assays cerebrospinal fluid (CSF) plasma. RESULTS CSF measures amyloid beta 42/40, phosphorylated tau (p‐tau)217 highly correlated when measured by immunoassay, mass spectrometry, or NULISA. plasma, p‐tau217 performance similar reported with other predicting amyloidosis. Other show wide range correlation values depending on platform. DISCUSSION multiplexed produces reliable results useful settings, advantage measuring additional using minimal volume. Highlights tested novel dementia setting. Cerebrospinal

Language: Английский

---

CSF proteomic profiling with amyloid/tau positivity identifies distinctive sex-different alteration of multiple proteins involved in Alzheimer’s disease

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

Published: March 16, 2024

Abstract In Alzheimer’s disease (AD), the most common cause of dementia, females have higher prevalence and faster progression, but sex-specific molecular findings in AD are limited. Here, we comprehensively examined validated 7,006 aptamers targeting 6,162 proteins cerebral spinal fluid (CSF) from 2,077 amyloid/tau positive cases controls to identify proteomic signatures AD. discovery (N=1,766), identified 330 male-specific 121 female-specific alternations CSF (FDR <0.05). These strongly predicted positivity (AUC=0.98 males; 0.99 females), significantly than those with age, sex, APOE-ε4 (AUC=0.85). The were well (r≥0.5) Stanford study (N=108) Emory (N=148). Biological follow-up these led sex differences cell-type specificity, pathways, interaction networks, drug targets. Male-specific proteins, enriched astrocytes oligodendrocytes, involved postsynaptic axon-genesis. male network exhibited direct connections among 152 highlighted PTEN, NOTCH1, FYN, MAPK8 as hubs. Drug target suggested melatonin (used for sleep-wake cycle regulation), nabumetone pain), daunorubicin, verteporfin treating males. contrast, neurons, phosphoserine residue binding including cytokine activities. female exhibits strong 51 JUN 14-3-3 (YWHAG YWHAZ) biperiden (for muscle control Parkinson’s disease), nimodipine vasospasm), quinostatin ethaverine females. Together, our provide mechanistic understanding risk insights into clinically translatable interventions.

Language: Английский

---

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

International Journal of Current Pharmaceutical Research, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 10

Published: Jan. 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.

Language: Английский

---

Sex Differences in Apolipoprotein E and Alzheimer Disease Pathology Across Ancestries

JAMA Network Open, Journal Year: 2025, Volume and Issue: 8(3), P. e250562 - e250562

Published: March 11, 2025

Importance Age, sex, and apolipoprotein E ( APOE ) are the strongest risk factors for late-onset Alzheimer disease (AD). The role of in AD varies with sex ancestry. While association biomarkers also across ancestry, no study has systematically investigated both sex-specific ancestry differences on cerebrospinal fluid (CSF) together, resulting limited insights generalizability. Objective To investigate -ε4 3 core CSF ancestries. Design, Setting, Participants This cohort examined (amyloid β1-42 [Aβ42], phosphorylated tau 181 [p-tau], total tau, participants from 20 cohorts July 1, 1985, to March 31, 2020. These individuals were grouped into African, Asian, European ancestries based genetic data. Data analyses conducted June 2023, November 10, 2024. Exposure Sex (male or female) -ε4. Main Outcomes Measures associations biomarker levels assessed within each group, adjusting age. Meta-analyses performed identify these Sensitivity exclude potential influence -ε2 allele. Results included 4592 (mean [SD] age, 70.8 [10.2] years; 2425 [52.8%] female; 119 [2.6%] 52 [1.1%] 4421 [96.3%] European). Higher dosage scores associated lower Aβ42 values (β [SE], −0.58 [0.02], P &amp;lt; .001), indicating more severe pathology; seen men women separately jointly. was statistically greater −0.63 [0.03]; .001) vs −0.52 = .01 interaction). Women had higher p-tau, neurofibrillary pathology. between p-tau expected direction (higher values) sexes, but difference sexes significant only those African 0.10 [0.18]; .57 men; β 0.66 [0.17]; .001 women; .03 neuronal damage. stronger than 0.20 [0.22]; .36 0.65 [0.22], .004 [ .16 interaction]) 0.36 0.27 [0.03], .053 interaction]); found Asian cohort. analysis excluding APOE- ε2 carriers yielded similar results. Conclusions Relevance In this study, allele accumulation men. findings underscore importance considering -ε4’s pathology mechanisms AD. Although provides robust evidence complex interplay further research is needed fully understand other differences.

Language: Английский

---

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

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: March 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.

Language: Английский

---