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CMV is linked with several diseases of aging, but associations with cognitive performance are not consistent. Here we address whether this may reflect a dependence on putative genetic determinants, Apolipoprotein E (<jats:italic>APOE<\/jats:italic>) \u03b54 and Tumour Necrosis Factor (<jats:italic>TNF<\/jats:italic>), and\/or the age of the subjects tested. CMV-reactive antibodies were quantitated in 419 individuals aged 71.7 [53.2\u201489.1] years, drawn from the Australian Imaging, Biomarker &amp; Lifestyle (AIBL) study. Cognitive composite scores, covering five domains, a global score of cognitive performance, brain amyloid-\u03b2 (A\u03b2) burden and demographic data were available. <jats:italic>APOE<\/jats:italic> and <jats:italic>TNF<\/jats:italic>-308 (rs1800629) genotypes were extracted from genome-wide array data. Bivariate and multivariate analyses were applied. CMV antibody levels were negatively correlated with A\u03b2 burden and correlated directly with cognition in participants carrying the minor allele of <jats:italic>TNF<\/jats:italic>-308, notably in those lacking the <jats:italic>APOE<\/jats:italic> \u03b54 allele. Cognitive performance exhibited a decrease with age, but CMV antibody levels were maintained. Regression analyses revealed significant interactions between <jats:italic>TNF-308<\/jats:italic> genotype and CMV antibody levels in the overall cohort and in participants younger than 71.1\u00a0years (median split). No such interaction was observed in those older than 71.1\u00a0years. Overall, CMV antibodies may play a protective role in carriers of the minor allele of <jats:italic>TNF<\/jats:italic>-308. This was significant in younger individuals and could be eclipsed by advanced age or carriage of the <jats:italic>APOE<\/jats:italic> \u03b54. The interactions described may explain disagreements in the literature regarding the effects of CMV and <jats:italic>TNF<\/jats:italic>-308.<\/jats:p>","DOI":"10.1186\/s12883-025-04279-1","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T09:05:03Z","timestamp":1751360703000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Relationship between cytomegalovirus antibody levels and cognitive performance is dependent on age and genetic risk"],"prefix":"10.1186","volume":"25","author":[{"given":"Michael","family":"Vacher","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Price","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phuongnhi","family":"Ha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shelley","family":"Waters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon M.","family":"Laws","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,1]]},"reference":[{"key":"4279_CR1","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.2337\/db05-1276","volume":"55","author":"TA Aly","year":"2006","unstructured":"Aly TA, Eller E, Ide A, Gowan K, Babu SR, Erlich HA, et al. 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