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The AD-associated\n                  <jats:italic>\n                    rs3865444\n                    <jats:sup>CC<\/jats:sup>\n                  <\/jats:italic>\n                  risk variant reduces splicing of the sialic acid-binding domain and increases expression of the full-length (sialic acid-binding) CD33 isoform seven-fold compared to the\n                  <jats:italic>\n                    rs3865444\n                    <jats:sup>AA<\/jats:sup>\n                  <\/jats:italic>\n                  protective genotype. Here we identify CD45 as an immune cell-specific sialic acid-dependent\n                  <jats:italic>cis<\/jats:italic>\n                  CD33 binding partner, whose phosphatase activity is inhibited by CD33. Overexpression of CD33 or loss of CD45 contributes to impaired microglial clearance of amyloid beta and amyloid beta-induced loss of dendritic spines in microglial-neuronal co-cultures, aligning with a detrimental effect of CD33-mediated inhibition of CD45. CD33-CD45 interaction frequency was increased in monocytes from individuals with the\n                  <jats:italic>\n                    rs3865444\n                    <jats:sup>CC<\/jats:sup>\n                  <\/jats:italic>\n                  risk variant compared to\n                  <jats:italic>\n                    rs3865444\n                    <jats:sup>AA<\/jats:sup>\n                  <\/jats:italic>\n                  , as well as in AD compared to controls, independent of genotype. Furthermore, an interaction between\n                  <jats:italic>CD33<\/jats:italic>\n                  and\n                  <jats:italic>PTPRC<\/jats:italic>\n                  (encoding CD45) gene expression in human brain tissue was associated with a pathological diagnosis of AD and global burden of AD pathology. Our findings thus establish a functional interaction between CD33 and CD45 relevant to AD susceptibility and systemic myeloid dysfunction in this disease.\n                <\/jats:p>","DOI":"10.1101\/2025.07.28.667311","type":"posted-content","created":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T20:15:16Z","timestamp":1753992916000},"source":"Crossref","is-referenced-by-count":5,"title":["CD33-CD45 Interaction Reveals a Mechanistic Link to Alzheimer\u2019s Disease Susceptibility"],"prefix":"10.64898","author":[{"given":"Nicole","family":"Vo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cory D.","family":"Rillahan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4383-6305","authenticated-orcid":false,"given":"Zena 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