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Here we compared <jats:italic>TREM2<\/jats:italic> cases with a variant (<jats:italic>TREM2<jats:sup>+<\/jats:sup>)<\/jats:italic> and cases without a <jats:italic>TREM2<\/jats:italic> variant (<jats:italic>TREM2<jats:sup>\u2212<\/jats:sup><\/jats:italic>), considering pathological burden, inflammatory response and altered canonical pathways and biochemical functions between the cohorts. We hypothesised that <jats:italic>TREM2<jats:sup>+<\/jats:sup><\/jats:italic> cases would have a loss of function, indicating an altered inflammatory profile compared to <jats:italic>TREM2<jats:sup>\u2212<\/jats:sup><\/jats:italic> cases. Immunohistochemistry was performed using antibodies against A\u03b2, tau and microglia markers in <jats:italic>TREM2<jats:sup>+<\/jats:sup><\/jats:italic> cases, with and without AD, which were compared to sporadic <jats:italic>TREM2<jats:sup>\u2212<\/jats:sup><\/jats:italic> AD, familial AD and neurologically normal control cases. A\u03b2 and tau load were measured along with the composition of A\u03b2 plaques, in addition to microglial load and circularity. Expression and proteomic profiles were determined from the frontal cortex of selected cases. <jats:italic>TREM2<jats:sup>+<\/jats:sup><\/jats:italic> control cases had no A\u03b2 or tau deposition. No differences in the amount of A\u03b2 or tau, or the composition of A\u03b2 plaques were observed between <jats:italic>TREM2<jats:sup>+<\/jats:sup><\/jats:italic> and <jats:italic>TREM2<jats:sup>\u2212<\/jats:sup><\/jats:italic> SAD cases. There were no differences in microglial load observed between disease groups. However, the <jats:italic>TREM2<jats:sup>+<\/jats:sup><\/jats:italic> SAD cases showed more amoeboid microglia than the <jats:italic>TREM2<jats:sup>\u2212<\/jats:sup><\/jats:italic> SAD cases, although no differences in the spatial relationship of microglia and A\u03b2 plaques were identified. Visualisation of the canonical pathways and biological functions showed differences between the disease groups and the normal controls, clearly showing a number of pathways upregulated in <jats:italic>TREM2<jats:sup>+<\/jats:sup><\/jats:italic> SAD, <jats:italic>TREM2<jats:sup>\u2212<\/jats:sup><\/jats:italic> SAD and FAD groups whilst, the <jats:italic>TREM2<jats:sup>+<\/jats:sup><\/jats:italic> controls cases showed a downregulation of the majority of the represented pathways. These findings suggest that the <jats:italic>TREM2<jats:sup>+<\/jats:sup><\/jats:italic> control group, although carrying the <jats:italic>TREM2<jats:sup>+<\/jats:sup><\/jats:italic> variant, have no pathological hallmarks of AD, have altered microglial and expression profiles compared to the <jats:italic>TREM2<jats:sup>+<\/jats:sup><\/jats:italic> SAD cases. This indicates that other unknown factors may initiate the onset of AD, with <jats:italic>TREM2<\/jats:italic> influencing the microglial involvement in disease pathogenesis.<\/jats:p>","DOI":"10.1111\/bpa.12842","type":"journal-article","created":{"date-parts":[[2020,4,8]],"date-time":"2020-04-08T10:37:20Z","timestamp":1586342240000},"page":"794-810","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Investigation of pathology, expression and proteomic profiles in human <i>TREM2<\/i> variant postmortem brains with and without Alzheimer\u2019s disease"],"prefix":"10.1111","volume":"30","author":[{"given":"Christina E.","family":"Toomey","sequence":"first","affiliation":[{"name":"The Queen Square Brain Bank for Neurological Disorders Department of Clinical and Movement Neuroscience UCL Queen Square Institute of Neurology London UK"},{"name":"Department of Neurodegenerative diseases UCL Queen Square Institute of 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