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structural changes. Cerebrospinal fluid (CSF) system abnormalities, such as ventricular dilation, increased choroid plexus volume or positron emission tomography (PET) ligand uptake in the CSF, have also been consistently described. We aimed to examine whether changes in CSF production and clearance might be associated with brain protein aggregation across biological stages of Alzheimer\u2019s disease. We hypothesized an association between brain protein aggregation and changes on the CSF system. We examined 378 individuals from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort with T1-weighted magnetic resonance imaging (MRI), amyloid-PET and tau-PET assessments. We assessed the lateral ventricle and choroid plexus volumes, both corrected for intracranial volume, in the MRI native space. Non-specific ventricular tracer standardized uptake value ratio (SUVR), derived from amyloid- and tau-PET images, was used as an indirect marker of choroid plexus-related clearance activity and served as a metric of CSF dynamics. Linear models tested associations amongst lateral ventricular volume (reflecting CSF space enlargement), choroid plexus volume (reflecting secretory tissue morphology) and ventricular SUVR (reflecting tracer activity within the CSF compartment and serving as an indirect marker of choroid plexus-related clearance function and CSF dynamics) with A\u03b2 and tau aggregations. Analyses were restricted to within-modality associations, relating ventricular radioactivity to cortical pathology for each PET tracer. We found that when considered independently, larger ventricular and choroid plexus volumes were associated with higher neocortical A\u03b2-PET SUVR, particularly in the precuneus and cingulate cortices. Additionally, lower ventricular radioactivity (derived from amyloid-PET) showed strong negative associations in the dorsal apex of the neocortex. However, when all three ventricular parameters were included in the same model, these effects were mediated by ventricular volume. By contrast, the effect of the ventricular parameters on tau load was mediated by A\u03b2 in the neocortex. Therefore, ventricular enlargement appears to be associated with A\u03b2 load. Distinct from neurodegeneration, changes in ventricular parameters, particularly ventricular volume, are associated with upstream Alzheimer\u2019s disease pathophysiology. While ventricular volume significantly mediated ventricular amyloid clearance, no such effect was observed for tau, suggesting distinct clearance mechanisms for these pathologies in Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.1093\/braincomms\/fcag066","type":"journal-article","created":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T12:44:22Z","timestamp":1772801062000},"source":"Crossref","is-referenced-by-count":0,"title":["Ventricular enlargement is associated with early Alzheimer\u2019s disease pathophysiology"],"prefix":"10.1093","volume":"8","author":[{"given":"Seyyed Ali","family":"Hosseini","sequence":"first","affiliation":[{"name":"Translational Neuroimaging Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University , Montreal, Quebec H3A 2B4 ,","place":["Canada"]},{"name":"Department of Neurology and Neurosurgery, McGill University , Montreal, Quebec H3A 1A1 ,","place":["Canada"]},{"name":"The McGill University Research Center for Studies in Aging, Douglas Mental Health Institute , Montreal, Quebec H4H 1R3 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Etienne","family":"Aumont","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University , Montreal, Quebec H3A 2B4 ,","place":["Canada"]},{"name":"Department of Neurology and Neurosurgery, McGill University , Montreal, Quebec H3A 1A1 ,","place":["Canada"]},{"name":"The McGill University Research Center for Studies in Aging, Douglas Mental Health Institute , Montreal, Quebec H4H 1R3 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nesrine","family":"Rahmouni","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University , Montreal, Quebec H3A 2B4 ,","place":["Canada"]},{"name":"Department of Neurology and Neurosurgery, McGill University , Montreal, Quebec H3A 1A1 ,","place":["Canada"]},{"name":"The McGill University Research Center for Studies in Aging, Douglas Mental Health Institute , Montreal, Quebec H4H 1R3 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1306-2708","authenticated-orcid":false,"given":"Marcel S","family":"Woo","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University , Montreal, Quebec H3A 2B4 ,","place":["Canada"]},{"name":"Department of Neurology and Neurosurgery, McGill University , Montreal, Quebec H3A 1A1 ,","place":["Canada"]},{"name":"Translational Neurodegeneration Laboratory, Department of Neurology, University Medical Center Hamburg-Eppendorf , Hamburg 20246 ,","place":["Germany"]},{"name":"Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf , Hamburg 20246 ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arthur C","family":"Macedo","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University , Montreal, Quebec H3A 2B4 ,","place":["Canada"]},{"name":"Department of Neurology and Neurosurgery, McGill University , Montreal, Quebec H3A 1A1 ,","place":["Canada"]},{"name":"The McGill University Research Center for Studies in Aging, Douglas Mental Health Institute , Montreal, Quebec H4H 1R3 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brandon","family":"Hall","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University , Montreal, Quebec H3A 2B4 ,","place":["Canada"]},{"name":"Department of Neurology and Neurosurgery, McGill University , Montreal, Quebec H3A 1A1 ,","place":["Canada"]},{"name":"The McGill University Research Center for Studies in Aging, Douglas Mental Health Institute , Montreal, Quebec H4H 1R3 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5593-7717","authenticated-orcid":false,"given":"Lydia","family":"Trudel","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University , Montreal, Quebec H3A 2B4 ,","place":["Canada"]},{"name":"Department of Neurology and Neurosurgery, McGill University , Montreal, Quebec H3A 1A1 ,","place":["Canada"]},{"name":"The McGill University Research Center for Studies in Aging, Douglas Mental Health Institute , Montreal, Quebec H4H 1R3 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A","family":"Rudko","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery, McGill University , Montreal, Quebec H3A 1A1 ,","place":["Canada"]},{"name":"Department of Biomedical Engineering, McGill University , Montreal, Quebec H3A 2B4 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Serge","family":"Gauthier","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery, McGill University , Montreal, Quebec H3A 1A1 ,","place":["Canada"]},{"name":"The McGill University Research Center for Studies in Aging, Douglas Mental Health Institute , Montreal, Quebec H4H 1R3 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1422-4358","authenticated-orcid":false,"given":"Thomas","family":"Karikari","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, School of Medicine, University of Pittsburgh , Pittsburgh, PA 15213 ,","place":["USA"]},{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg , M\u00f6lndal 413 45 ,","place":["Sweden"]},{"name":"Department of Neurology, School of Medicine, University of Pittsburgh , Pittsburgh, PA 15213 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andr\u00e9a Lessa","family":"Benedet","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg , M\u00f6lndal 413 45 ,","place":["Sweden"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas J","family":"Ashton","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg , M\u00f6lndal 413 45 ,","place":["Sweden"]},{"name":"Wallenberg Centre for Molecular Medicine, University of Gothenburg , Gothenburg 413 45 ,","place":["Sweden"]},{"name":"King\u2019s College London, Institute of Psychiatry, Department of Psychology and Neuroscience, Maurice Wohl Institute Clinical Neuroscience Institute , London SE5 9NU ,","place":["UK"]},{"name":"NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation , London ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg , M\u00f6lndal 413 45 ,","place":["Sweden"]},{"name":"Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital , M\u00f6lndal SE-431 80 ,","place":["Sweden"]},{"name":"Department of Neurodegenerative Disease, UCL Institute of Neurology , London ,","place":["UK"]},{"name":"UK Dementia Research Institute at UCL , London ,","place":["UK"]},{"name":"Hong Kong Center for Neurodegenerative Diseases , Division of Life Science, Hong Kong 999077 ,","place":["China"]},{"name":"Wisconsin Alzheimer\u2019s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison , Madison, WI 53792 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maxime","family":"Montembeault","sequence":"additional","affiliation":[{"name":"The McGill University Research Center for Studies in Aging, Douglas Mental Health Institute , Montreal, Quebec H4H 1R3 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8953-1542","authenticated-orcid":false,"given":"Paolo","family":"Vitali","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery, 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