{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T13:17:57Z","timestamp":1782307077958,"version":"3.54.5"},"posted":{"date-parts":[[2025,9,28]]},"group-title":"Pathology","reference-count":72,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,28]],"date-time":"2025-09-28T00:00:00Z","timestamp":1759017600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,9,28]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Alzheimer\u2019s disease (AD) pathology is typically associated with reduced brain volume and cortical thickness, interpreted as neurodegeneration. However, several cross-sectional studies in cognitively unimpaired individuals have paradoxically reported larger brain volume and thicker cortex in the presence of amyloid-\u03b2 (A\u03b2), suggesting that A\u03b2\u2013brain structure associations may not follow a simple linear pattern early in the disease. We leveraged over a decade of longitudinal data from the PREVENT-AD cohort (N=367, mean follow-up 7.17 years, range 0\u201311.27 years) to investigate how A\u03b2 burden related to both cross-sectional levels and longitudinal changes in brain volume, cortical thickness, and cortical tissue mean diffusivity (MD\n                  <jats:sub>T<\/jats:sub>\n                  ) derived from free-water corrected diffusion tensor imaging. We examined associations separately in individuals below (A\u03b2\u2212) and above (A\u03b2+) the A\u03b2-positivity threshold, tested for nonlinearity across all participants, and aligned structural trajectories to the estimated years from A\u03b2-positivity onset. We found that higher A\u03b2 was associated with larger brain volume, higher cortical thickness and lower MD\n                  <jats:sub>T<\/jats:sub>\n                  in regions such as the fusiform gyrus, supramarginal gyrus, hippocampal volume, inferior parietal and middle temporal cortex in the A\u03b2\u2212 group. The opposite associations were found in the A\u03b2+ group. Across all participants, volume and thickness showed an inverse U-shaped relationship with A\u03b2, while MD\n                  <jats:sub>T<\/jats:sub>\n                  followed a U-shaped pattern. Longitudinally, the rate of cortical thickness change showed an inverse U-shaped association with A\u03b2, whereas A\u03b2 burden was associated with faster volume loss and greater MD\n                  <jats:sub>T<\/jats:sub>\n                  increase. When structural measures were aligned to the estimated time of A\u03b2 positivity onset, volume and thickness increased years before the expected A\u03b2 positivity onset and declined thereafter, while MD\n                  <jats:sub>T<\/jats:sub>\n                  showed no association with time relative to A\u03b2 positivity onset. Our results help reconcile inconsistencies across prior studies and suggest that brain structural changes related to A\u03b2 pathology start years before A\u03b2 positivity onset and follow nonlinear trajectories. These early structural changes might be due to pathological processes such as neuroinflammatory swelling early in the course of the disease.\n                <\/jats:p>","DOI":"10.1101\/2025.09.25.25336640","type":"posted-content","created":{"date-parts":[[2025,9,28]],"date-time":"2025-09-28T18:10:11Z","timestamp":1759083011000},"source":"Crossref","is-referenced-by-count":3,"title":["Tracking a decade of structural changes in preclinical and prodromal Alzheimer\u2019s disease: insights from amyloid-\u03b2 pathology"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-8209-4424","authenticated-orcid":false,"given":"Ting","family":"Qiu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0917-7905","authenticated-orcid":false,"given":"Zhen-Qi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1048-2352","authenticated-orcid":false,"given":"Jonathan","family":"Gallego-Rudolf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4181-8031","authenticated-orcid":false,"given":"Manon","family":"Edde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex Valcourt","family":"Caron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanchao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0759-5508","authenticated-orcid":false,"given":"M. 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Louis","family":"Collins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8018-4545","authenticated-orcid":false,"given":"Judes","family":"Poirier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Breitner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemma","family":"Salvad\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexa 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