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We examined whether accelerated longitudinal tau accumulation mediates the vascular risk\u2010A\u03b2 interaction on cognitive decline.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We included 175 cognitively unimpaired older adults (age 70.5\u2009\u00b1\u20098.0\u2009years). Baseline vascular risk was quantified using the office\u2010based Framingham Heart Study general cardiovascular disease risk score (FHS\u2010CVD). Baseline A\u03b2 burden was measured with Pittsburgh Compound\u2010B positron emission tomography (PET). Tau burden was measured longitudinally (3.6\u2009\u00b1\u20091.5\u2009years) with Flortaucipir PET, focusing on inferior temporal cortex (ITC). Cognition was assessed longitudinally (7.0\u2009\u00b1\u20092.0\u2009years) using the Preclinical Alzheimer's Cognitive Composite. Linear mixed effects models examined the interactive effects of baseline vascular risk and A\u03b2 on longitudinal ITC tau. Additionally, moderated mediation was used to determine whether tau accumulation mediated the FHS\u2010CVD*A\u03b2 effect on cognitive decline.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We observed a significant interaction between elevated baseline FHS\u2010CVD and A\u03b2 on greater ITC tau accumulation (\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.004), even in individuals with A\u03b2 burden below the conventional threshold for amyloid positivity. Examining individual vascular risk factors, we found elevated systolic blood pressure and body mass index showed independent interactions with A\u03b2 on longitudinal tau (both\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001). ITC tau accumulation mediated 33% of the interactive association of FHS\u2010CVD and A\u03b2 on cognitive decline.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>Vascular risks interact with subthreshold levels of A\u03b2 to promote cognitive decline, partially by accelerating early neocortical tau accumulation. Our findings support vascular risk reduction, especially treating hypertension and obesity, to attenuate A\u03b2\u2010related tau pathology and reduce late\u2010life cognitive decline. ANN NEUROL 2022;92:745\u2013755<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.26460","type":"journal-article","created":{"date-parts":[[2022,7,26]],"date-time":"2022-07-26T16:30:18Z","timestamp":1658853018000},"page":"745-755","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Tau Mediates Synergistic Influence of Vascular Risk and A\u03b2 on Cognitive Decline"],"prefix":"10.1002","volume":"92","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7597-7647","authenticated-orcid":false,"given":"Wai\u2010Ying Wendy","family":"Yau","sequence":"first","affiliation":[{"name":"Department of Neurology Massachusetts General Hospital  Boston MA"},{"name":"Harvard Medical School  Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6854-9356","authenticated-orcid":false,"given":"Zahra","family":"Shirzadi","sequence":"additional","affiliation":[{"name":"Department of Neurology Massachusetts General Hospital  Boston MA"},{"name":"Harvard Medical School  Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8318-0443","authenticated-orcid":false,"given":"Hyun\u2010Sik","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neurology Massachusetts General Hospital  Boston MA"},{"name":"Harvard Medical School  Boston MA"},{"name":"Center for Alzheimer Research and Treatment, Department of Neurology Brigham and Women's Hospital  Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akpevweoghene P.","family":"Ikoba","sequence":"additional","affiliation":[{"name":"Department of Neurology Massachusetts General Hospital  Boston MA"},{"name":"Athinoula A. 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Martinos Center for Biomedical Imaging, Department of Radiology Massachusetts General Hospital  Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dylan R.","family":"Kirn","sequence":"additional","affiliation":[{"name":"Department of Neurology Massachusetts General Hospital  Boston MA"},{"name":"Harvard Medical School  Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron P.","family":"Schultz","sequence":"additional","affiliation":[{"name":"Department of Neurology Massachusetts General Hospital  Boston MA"},{"name":"Harvard Medical School  Boston MA"},{"name":"Athinoula A. 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