Biology subjects

Shvetcov, A.

Publications and source records attributed to Shvetcov, A..

9 recordsLinked to original sources

bioRxiv2026

Proteomic signatures of APOE ε4 across human tissues and cell types in Alzheimers disease

The apolipoprotein E {varepsilon}4 (APOE {varepsilon}4) allele is the strongest genetic risk factor for late-onset Alzheimers disease (AD). However, the underlying molecular mechanisms remain unclear. This study included 1691 participants from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP), 1226 participants from the Accelerating Medicines Partnership - Alzheimers Disease (AMP-AD) Diverse Cohorts Study, and 735 participants from the Alzheimers Disease Neuroimaging Initiative (ADNI). To characterise APOE {varepsilon}4 molecular effects, we analysed proteomic data from plasma, cerebrospinal fluid (CSF), and induced pluripotent stem cell (iPSC)-derived astrocytes and neurons, as well as transcriptomic and proteomic data from multiple brain regions. The association of APOE {varepsilon}4 with AD neuropathology was also examined. APOE {varepsilon}4 carriers shared a plasma proteomic signature enriched for immune processes, irrespective of AD diagnosis. A machine learning classifier trained on this signature discriminated APOE {varepsilon}4 carriers from non-carriers in an independent cohort using CSF proteomics. APOE {varepsilon}4 carriage was associated with higher Braak stages and Consortium to Establish a Registry for Alzheimers Disease (CERAD) score. However, only limited APOE {varepsilon}4-associated transcriptomic and proteomic changes were observed in bulk brain tissue, with poor cross-layer concordance. Proteomic analyses of iPSC-derived astrocytes and neurons further revealed cell-type-specific APOE {varepsilon}4-associated changes. APOE {varepsilon}4 is associated with a consistent proteomic signature across plasma and CSF. Its molecular effects in the brain differ across cell types, brain regions and molecular layers. These findings support the need for cell-type-resolved multi-omic studies to elucidate how APOE {varepsilon}4 confers AD risk.

neuroscience↗

bioRxiv2026

An integrated atlas of RNA to protein concordance across human tissues and cell types

Differential expression studies, single-cell atlases, and target discovery pipelines measure RNA as a proxy for protein. Across human tissues, RNA explains only 40 to 60% of the variance in protein, and no framework resolves which genes reliably translate RNA into protein. We present an integrated atlas that matches single-cell transcriptomics from Tabula Sapiens and the Human Brain Cell Atlas to cell type-resolved immunohistochemistry from the Human Protein Atlas, comprising 488,190 observations across 11,154 genes, 24 tissues, and 53 cell types. For each gene we defined a suppression rate and separated genes into concordant, variable, and suppressed classes. The pooled correlation of {rho} {approx} 0.4 reflects the mixing of these classes, and concordance depends on the interaction between gene and tissue. Suppression is predictable from gene sequence alone and traces to reduced translational efficiency and assembly-dependent degradation rather than to mRNA decay. The suppressed class is enriched for drug targets nominated on clinical evidence but not those validated by compound activity. We implement these classifications in an R package, concordR, and audit proteins nominated as brain-derived targets in neurodegeneration, where almost none survive at the protein level. Our atlas establishes RNA to protein concordance as a measurable property of the individual gene.

molecular biology↗

bioRxiv2026

Patient cerebral organoids capture Alzheimers disease proteomic biomarkers and drug targets

Patient iPSC-derived cerebral organoids are a leading human model of Alzheimers disease, yet their proteome has never been benchmarked against human disease. Clinical cohorts now nominate thousands of biomarkers and drug targets across three proteomic platforms, and whether patient organoids capture these candidates is unknown. Here, we profile AD and control cerebral organoids containing neurons, astrocytes, and microglia on the three platforms driving clinical discovery, mass spectrometry, SomaScan, and Olink, in both conditioned media and lysate. Benchmarked against 121 studies and clinical cohorts of over 17,000 plasma, CSF, and cortex samples, patient organoids detect almost every nominated candidate and reproduce the disease-associated change in roughly one in four of the most reproducible. This convergence spans plasma, CSF, and cortex, and extends to synaptic, mitochondrial, and proteostatic biology. We provide the first multi-platform reference proteome of a patient-derived AD model, establishing it as a translationally relevant system for studying AD.

neuroscience↗

bioRxiv2026

Adding iPSC donor lines does not adequately control for genetic heterogeneity

Human induced pluripotent stem cell (iPSC)-based disease modelling studies are widely expected to include three to five independent donor lines to control for the contribution of donor genetic background to phenotypic variance. This convention has been formalized into major guidelines, yet no power analysis has evaluated whether these sample sizes can detect, estimate, or control for donor-level genetic effects. Here, we provide that evaluation. Using Monte Carlo simulation, closed-form confidence intervals, population genetics, and empirical resampling of transcriptomic data from iPSC lines, we show that studies with three to five donors cannot reliably detect donor-level variance, cannot estimate its magnitude with useful precision, and cannot determine whether a treatment effect generalizes across genetic backgrounds. The sample sizes required to reliably detect, estimate, or control for donor-level variance exceed 20 donors and, for many phenotypes, exceed 50, well beyond what any standard disease modelling experiment can deliver. Adding two or three donor lines to a study does not meaningfully increase statistical power, narrow confidence intervals, or establish whether a treatment effect generalizes across genetic backgrounds. The inability to control for genetic background is not a limitation of individual study design but a structural property of iPSC-based modelling. We propose that the field adopt isogenic controls for variant-specific questions and orthogonal validation against clinical datasets for generalizability, rather than treating donor number as a proxy for rigour.

bioengineering↗

bioRxiv2026

APOE ε4 defines a systemic immune endophenotype independent of clinical trajectory in amyotrophic lateral sclerosis

BackgroundAmyotrophic lateral sclerosis (ALS) is clinically heterogeneous, and genetic modifiers may drive molecular endophenotypes without obvious clinical stratification. The apolipoprotein E {varepsilon}4 (APOE {varepsilon}4) allele is a major Alzheimers disease risk allele, but its biological impact in ALS remains unclear. MethodsUsing the Answer ALS cohort, longitudinal motor, cognitive, and neuropsychiatric measures were modelled using mixed-effects approaches. Patient induced pluripotent stem cell-derived motor neuron multiomics (chromatin accessibility, transcriptomics, and proteomics) were analysed using supervised machine learning. Plasma SomaScan profiling was used to derive an APOE {varepsilon}4-associated protein signature and to test its stability across serial visits, biological pathway enrichment, and associations with clinical progression. ResultsAPOE {varepsilon}4 carriage was not associated with baseline severity or rate of functional decline and showed no consistent effects on cognitive or neuropsychiatric trajectories. Motor neuron multiomic profiles similarly demonstrated no reproducible APOE {varepsilon}4 signal and did not reliably classify genotype. In contrast, plasma proteomics identified an APOE {varepsilon}4 protein signature that classified {varepsilon}4 status with high accuracy in ALS (AUC 0.98) and non-ALS motor neuron disease (AUC 0.86) and was enriched for immune and inflammatory biology. This systemic signature was highly stable across repeated sampling, indicating a persistent genotype-associated state. Within this plasma endophenotype, a small set of proteins tracked functional decline and a composite score stratified fast versus slow progression. Baseline composite scores were elevated in APOE {varepsilon}4 carriers in both ALS and neurologically unimpaired controls, consistent with a stable systemic shift detectable beyond overt disease status. ConclusionsAPOE {varepsilon}4 defines a persistent, immune-enriched systemic proteomic endophenotype in ALS that is not captured by clinical trajectories or motor neuron-only profiling yet relates to disease progression. Plasma-based, genotype-informed endophenotyping offers a translational pathway for biomarker stratification and therapeutic prioritisation in ALS and potentially other heterogeneous neurodegenerative disorders.

neuroscience↗

bioRxiv2025

Mapping the circulating proteome across neurodegeneration: A harmonized, consortium-scale framework for uncovering molecular pathophysiology

Large-scale plasma proteomics offers unprecedented opportunities to investigate the systemic biology of neurodegeneration, yet technical heterogeneity, site-specific artifacts, and clinical confounding remain major barriers to reproducible discovery. Leveraging data from 13,733 individuals with Alzheimers disease (AD), Parkinsons disease (PD), frontotemporal dementia (FTD), Parkinsons disease dementia (PDD), amyotrophic lateral sclerosis (ALS), and non-impaired controls in the Global Neurodegeneration Proteomics Consortium (GNPC), we present a scalable and generalizable analytical framework for harmonizing and interpreting consortium-scale proteomic datasets. Using a high-dimensional perturbation framework, we systematically benchmark five commonly used batch correction methods across a range of realistic confounding structures, including site-disease imbalance, nonlinear effects, and heteroskedasticity. Empirical Bayes modelling via limma consistently emerged as the most robust method, optimally balancing removal of site-related technical variance with retention of disease-relevant biological signal. On this harmonized foundation, we resolve neurodegenerative disease plasma signatures, including a shared immune-metabolic axis in AD and PD, neuromuscular disruption in ALS, and proteostatic imbalance in PD. Tissue and cell-type enrichment highlight widespread immune-endocrine involvement in AD and hematopoietic activation in PD. Demographically matched analyses nominate distinct, candidate biomarkers across diseases, including lipid, redox, and complement factors in AD, lysosomal and cytoskeletal proteins in PD, and muscle-derived markers in ALS. This study establishes a scalable analytical framework for integrating real-world proteomic data and provides a disease-resolved catalogue of circulating signatures to inform biomarker development and targeted intervention across neurodegenerative diseases.

neuroscience↗

bioRxiv2024

Cerebrospinal fluid proteome profiling using machine learning shows a unique protein signature associated with APOE4 genotype

INTRODUCTIONProteome changes associated with APOE4 variant carriage that are independent of Alzheimers disease (AD) pathology and diagnosis are unknown. This study investigated APOE4 proteome changes in people with AD, mild cognitive impairment, and no impairment. METHODSClinical, APOE genotype, and cerebrospinal fluid (CSF) proteome and AD biomarker data was sourced from the Alzheimers Disease Neuroimaging Initiative (ADNI) database. Proteome profiling was done using supervised machine learning. RESULTSWe found an APOE4-specific proteome signature that was independent of cognitive diagnosis and AD pathological biomarkers, and increased risk of progression to cognitive impairment. Proteins were enriched in brain regions including the caudate and cortex and cells including endothelial cells, oligodendrocytes, and astrocytes. Enriched peripheral immune cells included T cells, macrophages, and B cells. DISCUSSIONAPOE4 carriers have a unique CSF proteome signature associated with a strong brain and peripheral immune and inflammatory phenotype that likely underlies APOE4 carriers vulnerability to cognitive decline and AD.

neuroscience↗

bioRxiv2022

The neuroprotective effects of estrogen and estrogenic compounds in spinal cord injury

Spinal cord injury (SCI) occurs when the spinal cord is damaged from either a traumatic event or disease. SCI is characterised by multiple injury phases that affect the transmission of sensory and motor signals and lead to temporary or long-term functional deficits. There are few treatments for SCI. Estrogens and estrogenic compounds, however, may effectively mitigate the effects of SCI and therefore represent viable treatment options. This review systematically examines the pre-clinical literature on estrogen and estrogenic compound neuroprotection after SCI. Several estrogens were examined by the included studies: estrogen, estradiol benzoate, Premarin, isopsoralen, genistein, and selective estrogen receptor modulators. Across these pharmacotherapies, we find significant evidence that estrogens indeed offer protection against myriad pathophysiological effects of SCI and lead to improvements in functional outcomes, including locomotion. A STRING functional network analysis of proteins modulated by estrogen after SCI demonstrated that estrogen simultaneously upregulates known neuroprotective pathways, such as HIF-1, and downregulates pro-inflammatory pathways, including IL-17. These findings highlight the strong therapeutic potential of estrogen and estrogenic compounds after SCI.

neuroscience↗

bioRxiv2020

The selective estrogen receptor modulator tamoxifen protects against subtle cognitive decline and early markers of injury twenty-four hours after hippocampal silent infarct

Silent infarcts (SI) are subcortical cerebral infarcts that occur in the absence of typical symptoms associated with ischemia but are linked to cognitive decline and the development of dementia. There are no approved treatments for SI, but one potential treatment is tamoxifen, a selective estrogen receptor modulator. While SI can have long-term consequences, it is critical to establish whether treatments are able to selectively target its early consequences, to avoid progression to complete injury. We induced SI in the dorsal hippocampal CA1 of rats and assessed whether tamoxifen is protective 24 hours later against cognitive deficits and injury responses to SI including gliosis, apoptosis, inflammation and changes in estrogen receptors (ERs). Hippocampal SI led to subtle cognitive impairment on the object place recognition task, an effect ameliorated by tamoxifen administration. SI did not lead to detectable hippocampal cell loss but did increase apoptosis, astrogliosis, microgliosis and inflammation. Tamoxifen protected against the effects of SI on all measures except microgliosis. SI also increased ER and decreased ER{beta} in the hippocampus, which was again mitigated by tamoxifen. Exploratory data analyses using scatterplot matrices and principal component analysis indicated that the SI rats given tamoxifen were indistinguishable from sham controls. Further, SI rats were significantly different from all other groups, an effect produced by low levels of ER and increased apoptosis, gliosis, inflammation, ER{beta}, and time spent with the unmoved object. The results demonstrate that tamoxifen is protective against the early cellular and cognitive consequences of hippocampal SI as early as 24 hours after injury. This effect is driven by mitigation of apoptosis, gliosis, and inflammation and normalization of ER levels in the CA1, leading to improved cognitive outcomes after hippocampal SI.

neuroscience↗