Biology subjects

Koychev, I.

Publications and source records attributed to Koychev, I..

8 recordsLinked to original sources

bioRxiv2026

Proteomic Signatures of Neuropathological Alterations in Alzheimer's Disease: Insights from the Bio-Hermes Study

Large-scale plasma proteomics can capture molecular changes across the Alzheimers disease (AD) continuum and provide insight into biological mechanisms associated with AD pathology. We analysed the Bio-Hermes cohort (n = 961), with participants enrolled across 17 sites in the United States from April 2021 to November 2022. Participants were stratified by clinical status and amyloid PET scan-based Core1 biomarker status (CN Core1-, CN Core1+, MCI Core1+, and AD dementia Core1+). We performed differential abundance analyses across biologically defined contrasts, clustered proteins into co-expression networks, and evaluated protein panels to distinguish participants with biologically defined AD from amyloid-negative cognitively normal controls. We also used Mendelian randomization (MR) to assess genetic evidence for potential causal relationships with AD risk. The biologically defined contrast, Core1+ vs. CN Core1-, identified 69 differentially abundant proteins. Across AD stages, eight core proteins were consistently dysregulated from preclinical through prodromal and dementia phases, and three additional proteins emerged at MCI Core1+ and remained altered in AD dementia Core1+. We identified 29 co-expression modules, six of which varied significantly across the AD continuum. Among differential abundance proteins, ACHE ranked highest for distinguishing biologically defined AD from CN Core1-. Stage-specific protein panels improved the discriminatory performance for MCI Core1+ (AUC = 0.850) and AD dementia Core1+ (AUC = 0.856). MR provided genetic evidence consistent with an association between plasma ACHE abundance and AD risk. Plasma proteomics delineated a stage-spanning core signature across the AD continuum. These findings nominate co-expression modules and candidate proteins for further validation in early detection and AD screening.

neuroscience↗

bioRxiv2025

Human whole epigenome modelling for clinical applications with Pleiades

Gene regulation in humans extends beyond the four-letter genetic code. DNA methylation, in particular, functions as a critical epigenetic regulator, dynamically programming cellular identity, adapting gene expression in response to environmental cues, and underpinning the onset and progression of numerous diseases. Here we present Pleiades, a series of whole-genome epigenetic foundation models spanning three sizes: 90M, 600M, and 7B parameters. Pleiades is trained upon an extensive proprietary corpus of human methylation and genomic data, totalling 1.9T tokens. We introduce alignment embeddings and stacked hierarchical attention techniques to provide precise epigenetic modelling without the need for extended context lengths. Collectively, these advances enable Pleiades to perform a diverse range of down-stream biological and clinical tasks, including genomic regulatory prediction, realistic generation of cell-free DNA fragments and fragment-level cell-type-of-origin classification, within a unified and scalable computational framework. We specifically apply Pleiades to the early detection of clinical Alzheimers disease and Parkinsons disease from plasma cell-free DNA, achieving high-accuracy detection (AUROC 0.89 for AD and 0.84 for PD) using a minimally invasive blood test. Combined with plasma pTau-217, Pleiades reaches an AUROC of 0.97 for AD, underscoring the promise of multimodal epigenomic and proteomic approaches. Using mechanistic interpretability, we ground Pleiades latent features in interpretable biological signals, relating its Alzheimers predictions to fragmentomic and epigenomic properties of cfDNA. These findings demonstrate the potential of genome-wide epigenomic modelling as a clinically translatable paradigm for diagnostics and precision medicine, though prospective validation in larger, more diverse cohorts will be required to confirm clinical utility.

genomics↗

bioRxiv2024

Neurodegenerative fluid biomarkers are enriched in human cervical lymph nodes

In animal models, brain neurodegeneration biomarkers drain into cervical lymph nodes (CLNs). If this occurred in humans, CLNs may provide a readily accessible source of these biomarkers, draining the site of primary pathology. We tested this hypothesis in discovery and validation cohorts using ultrasound-guided fine needle aspiration (FNA). We measured amyloid-beta 40 and 42, phospho-Tau-181, glial-fibrillary-acidic-protein, and neurofilament-light using single molecule array in CLN aspirates and plasma from: i) a discovery cohort of 25 autoimmune patients, and from ii) plasma, CLNs and capillary blood in four healthy volunteers, an optimisation-validation cohort. FNA was well-tolerated by all participants. In both cohorts, all biomarkers were detected in all plasmas and CLNs, other than neurofilament-light (8/17 of discovery cohort). CLN biomarker concentrations were significantly greater than plasma concentrations for all except neurofilament-light, most markedly for phospho-Tau-181 (266 fold; P<0.02), whose CLN concentrations decreased with age (Spearman r=-0.66, P=0.001). This study presents the first evidence that neurodegenerative biomarkers are detectable in human CLNs. Raised CLN:plasma biomarker ratios suggest their concentration in CLNs, which may offer a sensitive compartment for minimally-invasive sampling in clinical trials. Further, age-associated phospho-Tau-181 reduction with age suggests FNA of CLNs may measure the integrity of brain lymphatic drainage in vivo.

neuroscience↗

bioRxiv2023

iPSC-Astrocyte morphology reflects patient clinical markers

Human iPSCs provide powerful cellular models of Alzheimers disease (AD) and offer many advantages over non-human models, including the potential to reflect variation in individual-specific pathophysiology and clinical symptoms Previous studies have demonstrated that iPSC-neurons from individuals with Alzheimers disease (AD) reflect clinical markers, including {beta}-amyloid (A{beta}) levels and synaptic vulnerability. However, despite neuronal loss being a key hallmark of AD pathology, many risk genes are predominantly expressed in glia, highlighting them as potential therapeutic targets. In this work iPSC-derived astrocytes were generated from a cohort of individuals with high versus low levels of the inflammatory marker YKL-40, in their cerebrospinal fluid (CSF). iPSC-derived astrocytes were treated with exogenous A{beta} oligomers and high content imaging demonstrated a correlation between astrocytes that underwent the greatest morphology change from patients with low levels of CSF-YKL-40 and more protective APOE genotypes. This finding was subsequently verified using similarity learning as an unbiased approach. This study shows that iPSC-derived astrocytes from AD patients reflect key aspects of the pathophysiological phenotype of those same patients, thereby offering a novel means of modelling AD, stratifying AD patients and conducting therapeutic screens. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/548687v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1df3486org.highwire.dtl.DTLVardef@f184d8org.highwire.dtl.DTLVardef@48a33dorg.highwire.dtl.DTLVardef@d53a90_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Path integration selectively predicts midlife risk of Alzheimer's disease

The entorhinal cortex (EC) is the first cortical region to exhibit neurodegeneration in Alzheimers disease (AD), associated with EC grid cell dysfunction. Given the role of grid cells in path integration, we predicted that path integration impairment would represent the first behavioural change in adults at-risk of AD. Using immersive virtual reality, we found that midlife path integration impairments predicted both hereditary and physiological AD risk, with no corresponding impairment on tests of episodic memory or other spatial behaviours. Impairments related to poorer angular estimation and were associated with hexadirectional grid-like fMRI signal in the posterior-medial EC. These results indicate that altered path integration may represent the transition point from at-risk state to disease onset in AD, prior to impairment in other cognitive domains.

neuroscience↗

bioRxiv2021

Neurons derived from individual early Alzheimer's disease patients reflect clinical vulnerability

Establishing preclinical models of Alzheimers disease that predict clinical outcomes remains a critically important, yet to date not fully realised, goal. Models derived from human cells offer considerable advantages over non-human models, including the potential to reflect some of the inter-individual differences that are apparent in patients. Here we report an approach using induced pluripotent stem cell-derived cortical neurons from people with early symptomatic Alzheimers disease where we sought a match between individual disease characteristics in cells with analogous characteristics in the people from whom they were derived. We show that the response to amyloid-{beta} burden in life, as measured by cognitive decline and brain activity levels, varies between individuals and this vulnerability rating correlates with the individual cellular vulnerability to extrinsic amyloid-{beta} in vitro as measured by synapse loss and function. Our findings indicate that patient induced pluripotent stem cell-derived cortical neurons not only present key aspects of Alzheimers disease pathology, but also reflect key aspects of the clinical phenotypes of the same patients. Cellular models that reflect an individuals in-life clinical vulnerability thus represent a tractable method of Alzheimers disease modelling using clinical data in combination with cellular phenotypes.

neuroscience↗

bioRxiv2019

Gallery Game: Smartphone-based Assessment of Long-Term Memory in Adults at Risk of Alzheimer’s Disease

Gallery Game, deployed within the Mezurio smartphone app, targets the processes of episodic memory first vulnerable to neurofibrillary tau-related degeneration in Alzheimers Disease, prioritising both perirhinal and entorhinal cortex/hippocampal demands. Thirty-five healthy adults (aged 40-59 years), biased towards those at elevated familial risk of dementia, completed daily Gallery Game tasks for a month. Assessments consisted of cross-modal paired-associate learning, with subsequent tests of recognition and recall following delays ranging from one to 13 days. There was a non-linear decline in memory retention with increasing delays between learning and test, with significant forgetting first reported following delays of three and five days for paired-associate recall and recognition respectively, supporting the need for ecologically valid measures of longer-term memory. Gallery Game outcomes correlated as expected with established neuropsychological memory assessments, confirming the validity of this digital assessment of episodic memory. In addition, there was preliminary support for utilising the perirhinal-dependent pattern of semantic errors during object recognition as a marker of early impairment, justifying ongoing validation against traditional biomarkers of Alzheimers disease.

neuroscience↗

bioRxiv2019

Data Resource Profile:The Dementias Platform UK (DPUK) Data Portal

The Dementias Platform UK (DPUK) Data Portal is a data repository facilitating access to data for 3 370 929 individuals in 42 cohorts. The Data Portal is an end-to-end data management solution providing a secure, fully auditable, remote access environment for the analysis of cohort data. All projects utilising the data are by default collaborations with the cohort research teams generating the data. The Data Portal uses UK Secure eResearch Platform (UKSeRP) infrastructure to provide three core utilities: data discovery, access, and analysis. These are delivered using a 7 layered architecture comprising: data ingestion, data curation, platform interoperability, data discovery, access brokerage, data analysis and knowledge preservation. Automated, streamlined, and standardised procedures reduce the administrative burden for all stakeholders, particularly for requests involving multiple independent datasets, where a single request may be forwarded to multiple data controllers. Researchers are provided with their own secure lab using VMware which is accessed using two factor authentication. Over the last 2 years, 160 project proposals involving 579 individual cohort data access requests were received. These were received from 268 applicants spanning 72 institutions (56 academic, 13 commercial, 3 government) in 16 countries with 84 requests involving multiple cohorts. Project are varied including multi-modal, machine learning, and Mendelian randomisation analyses. Data access is usually free at point of use although a small number of cohorts require a data access fee.

neuroscience↗