Biology subjects

Thompson, T. G.

Publications and source records attributed to Thompson, T. G..

2 recordsLinked to original sources

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↗

bioRxiv2020

An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients

Neurodegenerative diseases present a challenge for systems biology, due to the lack of reliable animal models and the difficulties in obtaining samples from patients at early stages of disease, when interventions might be most effective. Studying induced pluripotent stem cell (iPSC)-derived neurons could overcome these challenges and dramatically accelerate and broaden therapeutic strategies. Here we undertook a network-based multi-omic characterization of iPSC-derived motor neurons from ALS patients carrying genetically dominant hexanucleotide expansions in C9orf72 to gain a deeper understanding of the relationship between DNA, RNA, epigenetics and protein in the same pool of tissue. ALS motor neurons showed the expected C9orf72-related alterations to specific nucleoporins and production of dipeptide repeats. RNA-seq, ATAC-seq and data-independent acquisition mass-spectrometry (DIA-MS) proteomics were then performed on the same motor neuron cultures. Using integrative computational methods that combined all of the omics, we discovered a number of novel dysregulated pathways including biological adhesion and extracellular matrix organization and disruption in other expected pathways such as RNA splicing and nuclear transport. We tested the relevance of these pathways in vivo in a C9orf72 Drosophila model, analyzing the data to determine which pathways were causing disease phenotypes and which were compensatory. We also confirmed that some pathways are altered in late-stage neurodegeneration by analyzing human postmortem C9 cervical spine data. To validate that these key pathways were integral to the C9 signature, we prepared a separate set of C9orf72 and control motor neuron cultures using a different differentiation protocol and applied the same methods. As expected, there were major overall differences between the differentiation protocols, especially at the level of in individual omics data. However, a number of the core dysregulated pathways remained significant using the integrated multiomic analysis. This new method of analyzing patient specific neural cultures allows the generation of disease-related hypotheses with a small number of patient lines which can be tested in larger cohorts of patients.

neuroscience↗