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AD sometimes pathologically overlaps with age-related tauopathies such as four repeat (4R)-tau predominant argyrophilic grain disease (AGD). While AGD is often detected with AD pathology, the contribution of <jats:italic>APOE4<\/jats:italic> to AGD risk is not clear despite its robust effects on AD pathogenesis. Specifically, how <jats:italic>APOE<\/jats:italic> genotype influences A\u03b2 and tau pathology in co-occurring AGD and AD has not been fully understood. Using postmortem brain samples (N\u2009=\u2009353) from a neuropathologically defined cohort comprising of cases with AD and\/or AGD pathology built to best represent different <jats:italic>APOE<\/jats:italic> genotypes, we measured the amounts of major AD-related molecules, including A\u03b240, A\u03b242, apolipoprotein E (apoE), total tau (tTau), and pTau181, in the temporal cortex. The presence of tau lesions characteristic of AD (AD-tau) was correlated with cognitive decline based on Mini-Mental State Examination (MMSE) scores, while the presence of AGD tau lesions (AGD-tau) was not. Interestingly, while <jats:italic>APOE4<\/jats:italic> increased the risk of AD-tau pathology, it did not increase the risk of AGD-tau pathology. Although <jats:italic>APOE4<\/jats:italic> was significantly associated with higher levels of insoluble A\u03b240, A\u03b242, apoE, and pTau181, the <jats:italic>APOE4<\/jats:italic> effect was no longer detected in the presence of AGD-tau. We also found that co-occurrence of AGD with AD was associated with lower insoluble A\u03b242 and pTau181 levels. Overall, our findings suggest that different patterns of A\u03b2, tau, and apoE accumulation mediate the development of AD-tau and AGD-tau pathology, which is affected by <jats:italic>APOE<\/jats:italic> genotype.<\/jats:p>","DOI":"10.1186\/s40478-024-01731-0","type":"journal-article","created":{"date-parts":[[2024,2,9]],"date-time":"2024-02-09T09:02:49Z","timestamp":1707469369000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Impact of APOE on amyloid and tau accumulation in argyrophilic grain disease and Alzheimer\u2019s disease"],"prefix":"10.1186","volume":"12","author":[{"given":"Ana-Caroline","family":"Raulin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney V.","family":"Doss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael G.","family":"Heckman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily C.","family":"Craver","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zonghua","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadafumi C.","family":"Ikezu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Sekiya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Chen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka A.","family":"Martens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cassandra L.","family":"Rosenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey A.","family":"Kuchenbecker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"DeTure","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. 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