{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T15:42:01Z","timestamp":1792078921253,"version":"4.4.0"},"reference-count":58,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T00:00:00Z","timestamp":1769385600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T00:00:00Z","timestamp":1769385600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Sporadic late\u2010onset Alzheimer's disease (AD) is characterized by a long pre\u2010clinical phase where amyloid\u2010beta (A\u03b2) and tau begin to accumulate in the brain. The primary objective was to determine the age at which AD starts by finding the average population age when both positron emission tomography (PET) A\u03b2 (A\u03b2\u2010PET) and plasma A\u03b242\/40 become abnormal.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Two high performance immunoprecipitation\u2010mass spectrometry (IP\u2010MS) assays (WashU\/C2N and Shimadzu) were tested on samples from 1,450 participants who were diagnosed as cognitively unimpaired (CU), mild cognitive impairment (MCI), or AD\u2010dementia across 4 international cohorts. Natural history modeling and trajectory analyses of the combined A\u03b2\u2010PET and plasma A\u03b242\/40 data were analyzed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Data from both assays demonstrated A\u03b242\/40 undergoes a rapid change at approximately 15 Centiloid (CL), at an average population disease age at 66\u2009years. On average, plasma A\u03b242\/40 becomes abnormal approximately 2\u2009years before A\u03b2\u2010PET, whereby it falls sharply to a stable level at the onset of preclinical AD. Average disease age where A\u03b242\/40 becomes abnormal, and the corresponding Centiloid level are lower for\n                      <jats:italic>APOE<\/jats:italic>\n                      allele carriers compared with non\u2010carriers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      Plasma A\u03b242\/40 ratio presents a step\u2010like function of peripheral change shortly before the detection of plaques by A\u03b2\u2010PET. Results are consistent with plasma A\u03b242\/40 falling to a steady\u2010state level in participants with A\u03b2\u2010PET levels greater than approximately 14CL for both assays. The age at which this occurs is dependent on\n                      <jats:italic>APOE \u03b5<\/jats:italic>\n                      4 carriership, consistent with the approximate 7\u2010year age difference in Centiloid abnormality between carriers and non\u2010carriers. ANN NEUROL 2026;99:1327\u20131342\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.78163","type":"journal-article","created":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T12:14:33Z","timestamp":1769429673000},"page":"1327-1342","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["When Does Alzheimer's Disease Start? Plasma A\u03b242\/40 Assays Show Steep Changes at A\u03b2\u2010\n                    <scp>PET<\/scp>\n                    Centiloid 15, Mean Age of 66\u2009Years"],"prefix":"10.1002","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3987-8884","authenticated-orcid":false,"given":"Rodrigo","family":"C\u00e1novas","sequence":"first","affiliation":[{"name":"Australian E\u2010Health Research Centre CSIRO  Parkville Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Cox","sequence":"additional","affiliation":[{"name":"Australian E\u2010Health Research Centre CSIRO  Canberra Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Dor\u00e9","sequence":"additional","affiliation":[{"name":"Australian E\u2010Health Research Centre CSIRO  Parkville Australia"},{"name":"Department of Molecular Imaging and Therapy Austin Health  Heidelberg 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