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Martinos Center for Biomedical Imaging, Massachusetts General Hospital","doi-asserted-by":"publisher","award":["S10RR023401"],"award-info":[{"award-number":["S10RR023401"]}],"id":[{"id":"10.13039\/100018500","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,6,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Vascular dysfunction is increasingly recognized as an important contributor to the pathogenesis of Alzheimer\u2019s disease. Alterations in vascular endothelial growth factor (VEGF) pathways have been implicated as potential mechanisms. However, the specific impact of VEGF proteins in preclinical Alzheimer\u2019s disease and their relationships with other Alzheimer\u2019s disease and vascular pathologies during this critical early period remain to be elucidated.<\/jats:p>\n               <jats:p>We included 317 older adults from the Harvard Aging Brain Study, a cohort of individuals who were cognitively unimpaired at baseline and followed longitudinally for up to 12\u2005years. Baseline VEGF family protein levels (VEGFA, VEGFC, VEGFD, PGF and FLT1) were measured in fasting plasma using high-sensitivity immunoassays. Using linear mixed effects models, we examined the interactive effects of baseline plasma VEGF proteins and amyloid PET burden (Pittsburgh Compound-B) on longitudinal cognition (Preclinical Alzheimer Cognitive Composite-5). We further investigated if effects on cognition were mediated by early neocortical tau accumulation (flortaucipir PET burden in the inferior temporal cortex) or hippocampal atrophy. Lastly, we examined the impact of adjusting for baseline cardiovascular risk score or white matter hyperintensity volume.<\/jats:p>\n               <jats:p>Baseline plasma VEGFA and PGF each showed a significant interaction with amyloid burden on prospective cognitive decline. Specifically, low VEGFA and high PGF were associated with greater cognitive decline in individuals with elevated amyloid, i.e. those on the Alzheimer\u2019s disease continuum. Concordantly, low VEGFA and high PGF were associated with accelerated longitudinal tau accumulation in those with elevated amyloid. Moderated mediation analyses confirmed that accelerated tau accumulation fully mediated the effects of low VEGFA and partially mediated (31%) the effects of high PGF on faster amyloid-related cognitive decline. The effects of VEGFA and PGF on tau and cognition remained significant after adjusting for cardiovascular risk score or white matter hyperintensity volume. There were concordant but non-significant associations with longitudinal hippocampal atrophy.<\/jats:p>\n               <jats:p>Together, our findings implicate low VEGFA and high PGF in accelerating early neocortical tau pathology and cognitive decline in preclinical Alzheimer\u2019s disease. Additionally, our results underscore the potential of these minimally-invasive plasma biomarkers to inform the risk of Alzheimer\u2019s disease progression in the preclinical population. Importantly, VEGFA and PGF appear to capture distinct effects from vascular risks and cerebrovascular injury. This highlights their potential as new therapeutic targets, in combination with anti-amyloid and traditional vascular risk reduction therapies, to slow the trajectory of preclinical Alzheimer\u2019s disease and delay or prevent the onset of cognitive decline.<\/jats:p>","DOI":"10.1093\/brain\/awae034","type":"journal-article","created":{"date-parts":[[2024,2,4]],"date-time":"2024-02-04T04:53:41Z","timestamp":1707022421000},"page":"2158-2168","source":"Crossref","is-referenced-by-count":45,"title":["Plasma VEGFA and PGF impact longitudinal tau and cognition in preclinical Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"147","author":[{"given":"Hyun-Sik","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital , Boston, MA 02114 , USA"},{"name":"Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women\u2019s Hospital , Boston, MA 02115 , USA"},{"name":"Harvard Medical School , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7597-7647","authenticated-orcid":false,"given":"Wai-Ying Wendy","family":"Yau","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital , Boston, MA 02114 , USA"},{"name":"Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women\u2019s Hospital , Boston, MA 02115 , USA"},{"name":"Harvard Medical School , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1491-3217","authenticated-orcid":false,"given":"Becky C","family":"Carlyle","sequence":"additional","affiliation":[{"name":"Harvard Medical School , Boston, MA 02115 , USA"},{"name":"Alzheimer\u2019s Clinical and Translational Research Unit, Department of Neurology, Massachusetts General Hospital , Charlestown, MA 02129 , USA"},{"name":"Department of Physiology, Anatomy and Genetics, Kavli Institute for Nanoscience Discovery, University of Oxford , Oxford OX1 3PT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca A","family":"Trombetta","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Clinical and Translational Research Unit, Department of Neurology, Massachusetts General Hospital , Charlestown, MA 02129 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Can","family":"Zhang","sequence":"additional","affiliation":[{"name":"Harvard Medical School , Boston, MA 02115 , USA"},{"name":"Alzheimer\u2019s Clinical and Translational Research Unit, Department of Neurology, Massachusetts General Hospital , Charlestown, MA 02129 , USA"},{"name":"Genetics and Aging Research Unit, McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Harvard Medical School , Charlestown, MA 02129 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahra","family":"Shirzadi","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital , Boston, MA 02114 , USA"},{"name":"Harvard Medical School , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron P","family":"Schultz","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital , Boston, MA 02114 , USA"},{"name":"Harvard Medical School , Boston, MA 02115 , USA"},{"name":"Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital , Charlestown, MA 02129 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy J","family":"Pruzin","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital , Boston, MA 02114 , USA"},{"name":"Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women\u2019s Hospital , Boston, MA 02115 , USA"},{"name":"Harvard Medical School , Boston, MA 02115 , USA"},{"name":"Department of Neurology, Banner Alzheimer\u2019s Institute , Phoenix, AZ 85006 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colleen D","family":"Fitzpatrick","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital , Boston, MA 02114 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dylan R","family":"Kirn","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital , Boston, MA 02114 , USA"},{"name":"Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women\u2019s Hospital , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4754-2221","authenticated-orcid":false,"given":"Jennifer S","family":"Rabin","sequence":"additional","affiliation":[{"name":"Harquail Centre for Neuromodulation and Hurvitz Brain Sciences Program, Sunnybrook Research Institute , Toronto, ON M4N 3M5 , Canada"},{"name":"Department of Medicine, Rehabilitation Sciences Institute, University of Toronto , Toronto, ON M5G 1V7 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5356-5537","authenticated-orcid":false,"given":"Rachel F","family":"Buckley","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital , Boston, MA 02114 , USA"},{"name":"Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women\u2019s Hospital , Boston, MA 02115 , USA"},{"name":"Harvard Medical School , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3377-7014","authenticated-orcid":false,"given":"Timothy J","family":"Hohman","sequence":"additional","affiliation":[{"name":"Vanderbilt Memory and Alzheimer\u2019s Center, Department of Neurology, Vanderbilt University Medical Center , Nashville, TN 37212 , USA"},{"name":"Vanderbilt Genetics Institute, Vanderbilt University Medical Center , Nashville, TN 37212 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorene M","family":"Rentz","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital , Boston, MA 02114 , USA"},{"name":"Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women\u2019s Hospital , Boston, MA 02115 , USA"},{"name":"Harvard Medical School , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudolph E","family":"Tanzi","sequence":"additional","affiliation":[{"name":"Harvard Medical School , Boston, MA 02115 , USA"},{"name":"Genetics and Aging Research Unit, McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Harvard Medical School , Charlestown, MA 02129 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5916-6043","authenticated-orcid":false,"given":"Keith A","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital , Boston, MA 02114 , USA"},{"name":"Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women\u2019s Hospital , Boston, MA 02115 , USA"},{"name":"Harvard Medical School , Boston, MA 02115 , USA"},{"name":"Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital , Charlestown, MA 02129 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reisa A","family":"Sperling","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital , Boston, MA 02114 , USA"},{"name":"Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women\u2019s Hospital , Boston, MA 02115 , USA"},{"name":"Harvard Medical School , Boston, MA 02115 , USA"},{"name":"Athinoula A. 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