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Although APOE4 is strongly associated with amyloid-\u03b2 (A\u03b2), its relationship with tau accumulation is less understood. Studies evaluating the role of APOE4 on tau accumulation showed conflicting results, particularly regarding the independence of these associations from A\u03b2 load. In this study, we examined three independent longitudinal cohorts (BioFINDER-1, BioFINDER-2 and WRAP), in which participants had cross-sectional and longitudinal measures of tau tangles [tau-PET; temporal meta-region of interest (meta-ROI) and entorhinal] or soluble p-tau (p-tau217), A\u03b2-PET and APOE genotype.<\/jats:p>\n                  <jats:p>The study included a total of 1370 cognitively unimpaired subjects and 449 with mild cognitive impairment, followed longitudinally with tau-PET and p-tau217. APOE4 carriers accounted for 40.2%\u201350% of the cohorts. Different linear regressions (cross-sectional) and linear mixed-effect models (longitudinal) with tau measures as outcomes were fitted to test the effect of APOE4 both as an independent predictor and in combination with baseline A\u03b2 load (including interaction). All models included age, sex and cognitive status as covariates.<\/jats:p>\n                  <jats:p>We found no independent effects of APOE4 carriership on insoluble tau in either cohort (BioFINDER-2 or WRAP), on both cross-sectional and longitudinal tau-PET in the temporal meta-ROI, when A\u03b2 was present in the model (P = 0.531\u20130.949). A\u03b2 alone was the best predictor of insoluble tau accumulation, with no interaction between APOE4 and A\u03b2 on tau-PET. In BioFINDER-2, there was a significant interaction between APOE4 and A\u03b2 (b = 0.166, P &amp;lt; 0.001) in the entorhinal cortex at baseline. However, the interaction was not present in WRAP PET. No independent effects of the APOE4 carriership on baseline (P = 0.683\u20130.708) and longitudinal (P = 0.188\u20130.570) soluble p-tau217 were observed when A\u03b2 was included in the model in BioFINDER-1 and WRAP. Likewise, no interaction between APOE4 and A\u03b2 on soluble p-tau217 was observed. Mediation analysis revealed that A\u03b2 load fully mediated most associations between APOE4 and tau (46%\u2013112%, either cross-sectional or longitudinal tau-PET or soluble p-tau217). In the largest cohort (BioFINDER-2), looking at APOE4 groups by the number of \u03b54 alleles, we found an interaction between APOE4 homozygotes and A\u03b2 on tau-PET levels at baseline and over time in the temporal meta-ROI, whereas in the entorhinal cortex this effect was observed only at baseline.<\/jats:p>\n                  <jats:p>In conclusion, although APOE4 is strongly associated with A\u03b2 aggregation, it seems to be associated minimally with longitudinal changes in soluble or insoluble p-tau levels at a given level of A\u03b2 pathology, confirming the primacy of A\u03b2 in driving tau pathology.<\/jats:p>","DOI":"10.1093\/brain\/awaf016","type":"journal-article","created":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T06:03:36Z","timestamp":1737007416000},"page":"2373-2383","source":"Crossref","is-referenced-by-count":34,"title":["<i>APOE4<\/i>\n                    impact on soluble and insoluble tau pathology is mostly influenced by amyloid-\u03b2"],"prefix":"10.1093","volume":"148","author":[{"given":"Claudia","family":"Cicognola","sequence":"first","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Faculty of Medicine, Lund University , 22184 Lund ,","place":["Sweden"]},{"name":"Memory Clinic, Sk\u00e5ne University Hospital , 21146 Malm\u00f6 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5210-9230","authenticated-orcid":false,"given":"Gemma","family":"Salvad\u00f3","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Faculty of Medicine, Lund University , 22184 Lund ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7147-0112","authenticated-orcid":false,"given":"Ruben","family":"Smith","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Faculty of Medicine, Lund University , 22184 Lund ,","place":["Sweden"]},{"name":"Memory Clinic, Sk\u00e5ne University Hospital , 21146 Malm\u00f6 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9267-1930","authenticated-orcid":false,"given":"Sebastian","family":"Palmqvist","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Faculty of Medicine, Lund University , 22184 Lund ,","place":["Sweden"]},{"name":"Memory Clinic, Sk\u00e5ne University Hospital , 21146 Malm\u00f6 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Stomrud","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Faculty of Medicine, Lund University , 22184 Lund ,","place":["Sweden"]},{"name":"Memory Clinic, Sk\u00e5ne University Hospital , 21146 Malm\u00f6 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8856-1352","authenticated-orcid":false,"given":"Tobey J","family":"Betthauser","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer\u2019s Institute, School of Medicine and Public Health, University of Wisconsin-Madison , Madison, WI 53792 ,","place":["USA"]},{"name":"Wisconsin Alzheimer\u2019s Disease Research Center, School of Medicine and Public Health, University of Wisconsin-Madison , Madison, WI 53792 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sterling C","family":"Johnson","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer\u2019s Institute, School of Medicine and Public Health, University of Wisconsin-Madison , Madison, WI 53792 ,","place":["USA"]},{"name":"Wisconsin Alzheimer\u2019s Disease Research Center, School of Medicine and Public Health, University of Wisconsin-Madison , Madison, WI 53792 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shorena","family":"Janelidze","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Faculty of Medicine, Lund University , 22184 Lund ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8885-7724","authenticated-orcid":false,"given":"Niklas","family":"Mattsson-Carlgren","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Faculty of Medicine, Lund University , 22184 Lund ,","place":["Sweden"]},{"name":"Department of Neurology, Sk\u00e5ne University Hospital, Lund University , 22184 Lund ,","place":["Sweden"]},{"name":"Wallenberg Center for Molecular Medicine, Lund University , 22184 Lund ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8467-7286","authenticated-orcid":false,"given":"Oskar","family":"Hansson","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Faculty of Medicine, Lund University , 22184 Lund ,","place":["Sweden"]},{"name":"Memory Clinic, Sk\u00e5ne University Hospital , 21146 Malm\u00f6 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexa","family":"Pichet Binette","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Faculty of Medicine, Lund University , 22184 Lund 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