{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T16:25:55Z","timestamp":1790007955286,"version":"4.0.1"},"reference-count":44,"publisher":"American Medical Association (AMA)","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Neurol"],"published-print":{"date-parts":[[2022,10,1]]},"abstract":"Importance<\/jats:title>Preventive trials of anti-amyloid agents might preferably recruit persons showing earliest biologically relevant \u03b2-amyloid (A\u03b2) binding on positron emission tomography (PET).<\/jats:p><\/jats:sec>Objective<\/jats:title>To investigate the timing at which A\u03b2-PET binding starts showing associations with other markers of Alzheimer disease.<\/jats:p><\/jats:sec>Design, Setting, and Participants<\/jats:title>This longitudinal multicentric cohort study included 3 independent cohorts: Presymptomatic Evaluation of Experimental or Novel Treatments for Alzheimer Disease (PREVENT-AD) (data collected from 2012-2020), Alzheimer Disease Neuroimaging Initiative (ADNI) (data collected from 2005-2019), and Harvard Aging Brain Study (HABS) (data collected from 2011-2019). In a 3-tiered categorization of A\u03b2-PET binding spatial extent, individuals were assigned as having widespread A\u03b2 deposition if they showed positive signal throughout a designated set of brain regions prone to early A\u03b2 accumulation. Those with binding in some but not all were categorized as having regional deposition, while those who failed to show any criterion A\u03b2 signal were considered A\u03b2-negative. All participants who were cognitively unimpaired at their first A\u03b2 PET scan.<\/jats:p><\/jats:sec>Main Outcomes and Measures<\/jats:title>Differences in cerebrospinal fluid (CSF), genetics, tau-PET burden, and cognitive decline.<\/jats:p><\/jats:sec>Results<\/jats:title>A total of 817 participants were included, including 129 from the PREVENT-AD cohort (mean [SD] age, 63.5 [4.7] years; 33 [26%] male; 126 [98%] White), 400 from ADNI (mean [SD] age, 73.6 [5.8] years; 190 [47%] male; 10 [5%] Hispanic, 338 [91%] White), and 288 from HABS (mean [SD] age, 73.7 [6.2] years; 117 [40%] male; 234 [81%] White). Compared with A\u03b2-negative persons, those with regional A\u03b2 binding showed proportionately more APOE \u03b54 carriers (18 [64%] vs 22 [27%] in PREVENT-AD and 34 [31%] vs 38 [19%] in ADNI), reduced CSF A\u03b21-42 levels (F<\/jats:italic>\u2009=\u200924 and 71), and greater longitudinal A\u03b2-PET accumulation (significant \u03b2\u2009=\u20090.019 to 0.056). Participants with widespread amyloid binding further exhibited notable cognitive decline (significant \u03b2\u2009=\u2009\u22120.014 to \u22120.08), greater CSF phosphorylated tau181<\/jats:sub> (F<\/jats:italic>\u2009=\u20095 and 27), and tau-PET binding (all F<\/jats:italic>\u2009&amp;gt;\u20097.55). Using each cohort\u2019s specified dichotomous threshold for A\u03b2 positivity or a visual read classification, most participants (56% to 100%, depending on classification method and cohort) with regional A\u03b2 would have been classified A\u03b2-negative.<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>Regional A\u03b2 binding appears to be biologically relevant and participants at this stage remain relatively free from CSF phosphorylated tau181<\/jats:sub>, tau-PET binding, and related cognitive decline, making them ideal targets for anti-amyloid agents. Most of these individuals would be classified as negative based on classical thresholds of A\u03b2 positivity.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamaneurol.2022.2442","type":"journal-article","created":{"date-parts":[[2022,8,22]],"date-time":"2022-08-22T15:33:38Z","timestamp":1661182418000},"page":"1025","source":"Crossref","is-referenced-by-count":32,"title":["Spatial Extent of Amyloid-\u03b2 Levels and Associations With Tau-PET and Cognition"],"prefix":"10.1001","volume":"79","author":[{"given":"Hazal","family":"Ozlen","sequence":"first","affiliation":[{"name":"Centre for Studies on Prevention of Alzheimer's Disease (StoP-AD), Douglas Mental Health University Institute, Centre for Studies on the Prevention of Alzheimer's Disease (StoP-AD), Montreal, Quebec, Canada"},{"name":"Department of Psychiatry, McGill University, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexa","family":"Pichet Binette","sequence":"additional","affiliation":[{"name":"Centre for Studies on Prevention of Alzheimer's Disease (StoP-AD), Douglas Mental Health University Institute, Centre for Studies on the Prevention of Alzheimer's Disease (StoP-AD), Montreal, Quebec, Canada"},{"name":"Department of Psychiatry, McGill University, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa","family":"K\u00f6be","sequence":"additional","affiliation":[{"name":"Centre for Studies on Prevention of Alzheimer's Disease (StoP-AD), Douglas Mental Health University Institute, Centre for Studies on the Prevention of Alzheimer's Disease (StoP-AD), Montreal, Quebec, Canada"},{"name":"Department of Psychiatry, McGill University, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre-Fran\u00e7ois","family":"Meyer","sequence":"additional","affiliation":[{"name":"Centre for Studies on Prevention of Alzheimer's Disease (StoP-AD), Douglas Mental Health University Institute, Centre for Studies on the Prevention of Alzheimer's Disease (StoP-AD), Montreal, Quebec, Canada"},{"name":"Department of Psychiatry, McGill University, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Gonneaud","sequence":"additional","affiliation":[{"name":"Centre for Studies on Prevention of Alzheimer's Disease (StoP-AD), Douglas Mental Health University Institute, Centre for Studies on the Prevention of Alzheimer's Disease (StoP-AD), Montreal, Quebec, Canada"},{"name":"Department of Psychiatry, McGill University, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"St-Onge","sequence":"additional","affiliation":[{"name":"Centre for Studies on Prevention of Alzheimer's Disease (StoP-AD), Douglas Mental Health University Institute, Centre for Studies on the Prevention of Alzheimer's Disease (StoP-AD), Montreal, Quebec, 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