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Genetic polymorphisms reducing expression of the functionally related protein CD33 are protective. Here we have contrasted cellular pathology in human post-mortem brain with and without AD to test mechanisms associated with the differential genetic risks conferred by\n                    <jats:italic>R47H<\/jats:italic>\n                    and\n                    <jats:italic>R62H TREM2<\/jats:italic>\n                    variants (\n                    <jats:italic>TREM2var<\/jats:italic>\n                    ) with and without heterozygosity for the protective rs3865444\n                    <jats:italic>CD33<\/jats:italic>\n                    polymorphism. Epistasis between\n                    <jats:italic>CD33<\/jats:italic>\n                    and\n                    <jats:italic>TREM2<\/jats:italic>\n                    was demonstrated by relative normalisation of differences in \u03b2-amyloid load in\n                    <jats:italic>TREM2var<\/jats:italic>\n                    carriers of the protective\n                    <jats:italic>CD33<\/jats:italic>\n                    allele. These functional differences were mirrored by differential microglial transcriptomic responses to \u03b2-amyloid. Controlling for\n                    <jats:italic>CD33<\/jats:italic>\n                    genotype, microglial transcriptional responses to increasing \u03b2-amyloid were lower for\n                    <jats:italic>TREM2var<\/jats:italic>\n                    , particularly for\n                    <jats:italic>R47H<\/jats:italic>\n                    compared to\n                    <jats:italic>CV<\/jats:italic>\n                    , and there was a reduction in expression of neuroplasticity pathways in\n                    <jats:italic>TREM2var. R62H<\/jats:italic>\n                    microglial signatures were distinguished from those of\n                    <jats:italic>R47H<\/jats:italic>\n                    by upregulation of genes associated with phagocytosis and from\n                    <jats:italic>CV<\/jats:italic>\n                    by differences in inflammatory gene expression including those involved in NF-kappaB signalling. Differential gene expression with increasing \u03b2-amyloid also suggested upregulation of \u03b2-amyloid production and binding pathways in excitatory neurons in\n                    <jats:italic>TREM2var<\/jats:italic>\n                    heterozygotes. There was lower enrichment for pathways positively adaptive to pathology and expressed in inhibitory neurons from\n                    <jats:italic>CV<\/jats:italic>\n                    samples for both\n                    <jats:italic>TREM2var.<\/jats:italic>\n                    Exploratory bulk tissue proteomics support these observations with evidence for adaptive plasticity in response to \u03b2-amyloid pathology in\n                    <jats:italic>CV<\/jats:italic>\n                    tissue not found for the\n                    <jats:italic>TREM2var,<\/jats:italic>\n                    which showed evidence of increased \u03b2-amyloid formation and neuroplasticity changes. Together, these results highlight differences in molecular pathology between\n                    <jats:italic>CV<\/jats:italic>\n                    and\n                    <jats:italic>TREM2var<\/jats:italic>\n                    and between the\n                    <jats:italic>TREM2var<\/jats:italic>\n                    risk variants. They highlight mechanisms of AD risk mediated by secondary effects on astroglial and neuronal functions. Demonstration of strong epistasis between\n                    <jats:italic>TREM2<\/jats:italic>\n                    and\n                    <jats:italic>CD33<\/jats:italic>\n                    with AD supports the therapeutic potential of modulators of\n                    <jats:italic>CD33<\/jats:italic>\n                    inhibition or expression.\n                  <\/jats:p>","DOI":"10.1007\/s00401-026-03036-z","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T16:06:17Z","timestamp":1781539577000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Mechanisms of increased Alzheimer\u2019s disease pathology with R47H and R62H TREM2 variants"],"prefix":"10.1007","volume":"151","author":[{"given":"Nurun N.","family":"Fancy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nanet","family":"Willumsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicky M. 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