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It is vital to assess which central nervous system structures are most affected and which inflammatory processes are responsible in humans. The inflammatory transcriptome was characterized in the cervical spinal cord and motor cortex in post\u2010mortem frozen and formalin\u2010fixed paraffin\u2010embedded specimens from human sporadic ALS\/MND and control cases using the nCounter\u00ae Neuroinflammation Panel. Archival data were reanalyzed and compared with the nCounter data. Immunohistochemistry was used to examine the inflammatory response in the spinal cord and motor cortex and validate changes found during transcriptomic analyses. In the spinal cord, marked inflammation was observed, while less inflammation was detected in the motor cortex. Examination of differentially expressed genes in the spinal cord highlighted\n                    <jats:italic>TREM2<\/jats:italic>\n                    ,\n                    <jats:italic>TYROBP<\/jats:italic>\n                    ,\n                    <jats:italic>APOE<\/jats:italic>\n                    , and\n                    <jats:italic>CD163<\/jats:italic>\n                    , as well as phagocytic pathways. In sporadic ALS\/MND spinal cord, significant microglial reactivity and involvement of TREM2, ApoE (encoded by\n                    <jats:italic>APOE<\/jats:italic>\n                    ), and TYROBP were confirmed, suggesting the involvement of the disease\u2010associated microglial (DAM) phenotype. The corticospinal tracts showed greater inflammation than the ventral horns. The precentral gyrus of ALS\/MND again showed less immune reactivity to disease when compared to controls. Finally, in the largest cohort assessed to date, we demonstrate an association between the\n                    <jats:italic>APOE<\/jats:italic>\n                    variant and ALS\/MND risk, age of onset, and survival. We find confirmed associations between\n                    <jats:italic>APOE<\/jats:italic>\n                    \u03b53\/\u03b53 and disease and between \u03b52\/\u03b52 and absence of disease. Further, \u03b54\/\u03b54 appears to be associated with earlier disease onset and a more aggressive course. We conclude that while there is widespread inflammation in the CNS in sporadic ALS\/MND, this is more marked in the spinal cord, especially the corticospinal tract. The specific markers stress the DAM phenotype as having a key role together with a possible influx of somatic macrophages. In addition,\n                    <jats:italic>APOE<\/jats:italic>\n                    function and genotype may be relevant in ALS\/MND.\n                  <\/jats:p>","DOI":"10.1111\/bpa.70019","type":"journal-article","created":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T00:15:59Z","timestamp":1749773759000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Human amyotrophic lateral sclerosis\/motor neuron disease: The disease\u2010associated microglial pathway is upregulated while\n                    <i>APOE<\/i>\n                    genotype governs risk and survival"],"prefix":"10.1111","volume":"35","author":[{"given":"Bridget A.","family":"Ashford","sequence":"first","affiliation":[{"name":"SITraN University of Sheffield  Sheffield UK"},{"name":"Neuroscience Institute University of Sheffield  Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie E.","family":"Simpson","sequence":"additional","affiliation":[{"name":"SITraN University of Sheffield  Sheffield UK"},{"name":"Neuroscience Institute University of Sheffield  Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Dawson","sequence":"additional","affiliation":[{"name":"SITraN University of Sheffield  Sheffield UK"},{"name":"Neuroscience Institute University of Sheffield  Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5884-130X","authenticated-orcid":false,"given":"Delphine","family":"Boche","sequence":"additional","affiliation":[{"name":"Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine University of Southampton  Southampton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0873-8689","authenticated-orcid":false,"given":"Johnathan","family":"Cooper\u2010Knock","sequence":"additional","affiliation":[{"name":"SITraN University of Sheffield  Sheffield UK"},{"name":"Neuroscience Institute University of Sheffield  Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul R.","family":"Heath","sequence":"additional","affiliation":[{"name":"SITraN University of Sheffield  Sheffield UK"},{"name":"Neuroscience Institute University of Sheffield  Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Fillingham","sequence":"additional","affiliation":[{"name":"SITraN University of Sheffield  Sheffield UK"},{"name":"Neuroscience Institute University of Sheffield  Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlie","family":"Appleby\u2010Mallinder","sequence":"additional","affiliation":[{"name":"Advanced Manufacturing Research Centre University of Sheffield  Rotherham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbin","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Biosciences University of Durham  Durham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Dunning","sequence":"additional","affiliation":[{"name":"Bioinformatics Core, School of Medicine and Population Health University of Sheffield  Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4969-6526","authenticated-orcid":false,"given":"J. 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