{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T06:22:13Z","timestamp":1790662933049,"version":"4.1.0"},"reference-count":48,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T00:00:00Z","timestamp":1775606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is associated with regional brain atrophy as well as elevated positron emission tomography (PET) markers of amyloid-beta (e.g., [\u00b9\u2078F]florbetapir (FBP)) and tau protein (e.g., [\u00b9\u2078F]flortaucipir (FTP). White matter microstructures have also been shown to be disrupted in AD, but there is limited understanding of their specific associations with FBP, FTP, and cognitive impairment. Herein, we used both voxel-based and fixel-based analyses of diffusion tensor imaging (DTI) to characterize microstructural white matter changes associated with PET and cognitive changes in AD. A retrospective study was performed using the data from 381 ADNI-3 participants (F:M\u2009=\u2009200:181). FBP and FTP results were correlated with DTI metrics, including the apparent fiber density (AFD), complexity (CX), functional anisotropy (FA), fixel number (FN), and mean diffusivity (MD). Linear regression analysis was performed, adjusted for age, sex, education, and cognitive impairment. Greatest negative correlations were observed between FN and FBP standardized uptake value ratio (SUVR) in 15 out of 18 white matter tracts examined (beta coefficients of \u22120.3991 to \u22120.2877). No significant correlation was observed between DTI measures and FTP SUVR, independently. However, combined PET positivity (FBP\u2009+\u2009\/FTP+) generally showed the greatest reductions in CX, FN, and FA of various tracts, compared to single PET-positive or PET-negative groups. Widespread changes in FA were positively associated with cognitive impairment, with stronger associations seen with the Montreal Cognitive Assessment (MoCA) than the Mini-Mental State Examination (MMSE). Only females showed significant correlations between MD and FBP\/FTP levels and showed more widespread correlations between FA and MD changes and cognitive impairment. Taken together, these findings suggest specific patterns of white matter microstructure disruption in AD with underlying sex differences and support their potential role as early biomarkers.<\/jats:p>","DOI":"10.1371\/journal.pone.0346661","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T17:35:11Z","timestamp":1775669711000},"page":"e0346661","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["White matter microstructure disruption associated with PET and cognitive impairment in Alzheimer\u2019s disease"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-7302-7996","authenticated-orcid":true,"given":"Marlon","family":"Gonzales","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojian","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Cort","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maheen M.","family":"Adamson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven Z.","family":"Chao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2929-5677","authenticated-orcid":true,"given":"Byung C.","family":"Yoon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the Alzheimer\u2019s Disease Neuroimaging Initiative","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,4,8]]},"reference":[{"issue":"5","key":"pone.0346661.ref001","doi-asserted-by":"crossref","first-page":"3708","DOI":"10.1002\/alz.13809","article-title":"2024 Alzheimer\u2019s disease facts and figures","volume":"20","year":"2024","journal-title":"Alzheimers Dement"},{"issue":"1","key":"pone.0346661.ref002","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/s41392-024-01911-3","article-title":"Recent advances in Alzheimer\u2019s disease: Mechanisms, clinical trials and new drug development strategies","volume":"9","author":"J Zhang","year":"2024","journal-title":"Signal Transduct Target Ther"},{"issue":"1","key":"pone.0346661.ref003","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s40259-023-00633-2","article-title":"Anti-amyloid monoclonal antibodies for the treatment of Alzheimer\u2019s Disease","volume":"38","author":"J Cummings","year":"2024","journal-title":"BioDrugs"},{"key":"pone.0346661.ref004","article-title":"18F PET with florbetapir for the early diagnosis of Alzheimer\u2019s disease dementia and other dementias in people with mild cognitive impairment (MCI)","author":"G Mart\u00ednez","year":"2017","journal-title":"Cochrane Library"},{"issue":"7","key":"pone.0346661.ref005","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1001\/jamaneurol.2020.0528","article-title":"Positron Emission Tomography Imaging With [18F]flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes","volume":"77","author":"AS Fleisher","year":"2020","journal-title":"JAMA Neurol"},{"issue":"7","key":"pone.0346661.ref006","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s00259-021-05401-4","article-title":"A multicenter comparison of [18F]flortaucipir, [18F]RO948, and [18F]MK6240 tau PET tracers to detect a common target ROI for differential diagnosis","volume":"48","author":"A Leuzy","year":"2021","journal-title":"Eur J Nucl Med Mol Imaging"},{"issue":"1","key":"pone.0346661.ref007","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1186\/s40001-024-02172-0","article-title":"Research on magnetic resonance imaging in diagnosis of Alzheimer\u2019s disease","volume":"29","author":"G Zhao","year":"2024","journal-title":"Eur J Med Res"},{"issue":"2","key":"pone.0346661.ref008","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.mric.2009.02.003","article-title":"Update on diffusion tensor imaging in Alzheimer\u2019s disease","volume":"17","author":"CP Hess","year":"2009","journal-title":"Magnetic Resonance Imaging Clinics of North America"},{"key":"pone.0346661.ref009","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.neures.2023.01.009","article-title":"Fixel-based analysis of the diffusion properties of the patients with brain injury and chronic health symptoms","volume":"192","author":"X Kang","year":"2023","journal-title":"Neurosci Res"},{"key":"pone.0346661.ref010","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.gde.2021.03.002","article-title":"Structural and functional brain alterations revealed by neuroimaging in CNV carriers","volume":"68","author":"CA Moreau","year":"2021","journal-title":"Curr Opin Genet Dev"},{"key":"pone.0346661.ref011","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.neuroimage.2016.09.029","article-title":"Investigating white matter fibre density and morphology using fixel-based analysis","volume":"144","author":"DA Raffelt","year":"2017","journal-title":"Neuroimage"},{"issue":"3","key":"pone.0346661.ref012","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1111\/j.1552-6569.2011.00673.x","article-title":"Voxel-based statistical analysis of fractional anisotropy and mean diffusivity in patients with unilateral temporal lobe epilepsy of unknown cause","volume":"23","author":"SS Keller","year":"2013","journal-title":"J Neuroimaging"},{"issue":"6","key":"pone.0346661.ref013","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1136\/jnnp.72.6.742","article-title":"White matter damage in Alzheimer\u2019s disease assessed in vivo using diffusion tensor magnetic resonance imaging","volume":"72","author":"M Bozzali","year":"2002","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"pone.0346661.ref014","doi-asserted-by":"crossref","first-page":"633811","DOI":"10.3389\/fpsyt.2021.633811","article-title":"White matter fractional anisotropy is a superior predictor for cognitive impairment than brain volumes in older adults with confluent white matter hyperintensities","volume":"12","author":"Y Xing","year":"2021","journal-title":"Front Psychiatry"},{"key":"pone.0346661.ref015","doi-asserted-by":"crossref","first-page":"436","DOI":"10.3389\/fnagi.2018.00436","article-title":"Relationship between DTI metrics and cognitive function in Alzheimer\u2019s disease","volume":"10","author":"CD Mayo","year":"2018","journal-title":"Front Aging Neurosci"},{"key":"pone.0346661.ref016","doi-asserted-by":"crossref","first-page":"25424823251394399","DOI":"10.1177\/25424823251394399","article-title":"Comparative analysis of PET and multiparametric MRI biomarkers in Alzheimer\u2019s disease continuum cohort","volume":"9","author":"C Chiyanika","year":"2025","journal-title":"J Alzheimers Dis Rep"},{"issue":"4","key":"pone.0346661.ref017","doi-asserted-by":"crossref","DOI":"10.1212\/WNL.0000000000005864","article-title":"Loss of white matter integrity reflects tau accumulation in Alzheimer disease defined regions","volume":"91","author":"JF Strain","year":"2018","journal-title":"Neurology"},{"issue":"1","key":"pone.0346661.ref018","article-title":"White matter microstructure disruption in early stage amyloid pathology","volume":"13","author":"LE Collij","year":"2021","journal-title":"Alzheimers Dement (Amst)"},{"issue":"18","key":"pone.0346661.ref019","article-title":"Fixel-Based Analysis Reveals Tau-Related White Matter Changes in Early Stages of Alzheimer\u2019s Disease","volume":"44","author":"K Ahmadi","year":"2024","journal-title":"J Neurosci"},{"key":"pone.0346661.ref020","doi-asserted-by":"crossref","DOI":"10.1002\/alz.079454","article-title":"Fixel based analysis of white matter alterations in Mild cognitive impairment and Alzheimer\u2019s disease","volume":"19","author":"A Bhattarai","year":"2023","journal-title":"Alzheimer\u2019s & Dementia"},{"key":"pone.0346661.ref021","article-title":"Sex differences in Alzheimer\u2019s disease: A systematic review of two decades of neuroimaging research","author":"P Massoumzadeh","year":"2026","journal-title":"Br J Radiol"},{"issue":"1","key":"pone.0346661.ref022","doi-asserted-by":"crossref","first-page":"395","DOI":"10.3233\/JAD-210406","article-title":"Sex differences in Alzheimer\u2019s disease revealed by free-water diffusion tensor imaging and voxel-based morphometry","volume":"85","author":"M Bergamino","year":"2022","journal-title":"J Alzheimers Dis"},{"issue":"10","key":"pone.0346661.ref023","doi-asserted-by":"crossref","first-page":"7361","DOI":"10.1002\/alz.14167","article-title":"The alzheimer\u2019s disease neuroimaging initiative clinical core","volume":"20","author":"PS Aisen","year":"2024","journal-title":"Alzheimers Dement"},{"issue":"4","key":"pone.0346661.ref024","doi-asserted-by":"crossref","DOI":"10.1212\/WNL.0000000000011214","article-title":"Defining the lowest threshold for amyloid-PET to predict future cognitive decline and amyloid accumulation","volume":"96","author":"ME Farrell","year":"2021","journal-title":"Neurology"},{"issue":"1","key":"pone.0346661.ref025","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/s13195-022-00986-w","article-title":"What\u2019s the cut-point?: A systematic investigation of tau PET thresholding methods","volume":"14","author":"AJ Weigand","year":"2022","journal-title":"Alzheimers Res Ther"},{"issue":"11","key":"pone.0346661.ref026","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1001\/jama.2018.12917","article-title":"Discriminative accuracy of [18F]flortaucipir positron emission tomography for Alzheimer disease vs other neurodegenerative disorders","volume":"320","author":"R Ossenkoppele","year":"2018","journal-title":"JAMA"},{"issue":"11","key":"pone.0346661.ref027","doi-asserted-by":"crossref","first-page":"2381","DOI":"10.1038\/s41591-022-02049-x","article-title":"Amyloid and tau PET-positive cognitively unimpaired individuals are at high risk for future cognitive decline","volume":"28","author":"R Ossenkoppele","year":"2022","journal-title":"Nat Med"},{"key":"pone.0346661.ref028","doi-asserted-by":"crossref","first-page":"116137","DOI":"10.1016\/j.neuroimage.2019.116137","article-title":"MRtrix3: A fast, flexible and open software framework for medical image processing and visualisation","volume":"202","author":"J-D Tournier","year":"2019","journal-title":"Neuroimage"},{"issue":"2","key":"pone.0346661.ref029","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1016\/j.neuroimage.2007.12.035","article-title":"Stereotaxic white matter atlas based on diffusion tensor imaging in an ICBM template","volume":"40","author":"S Mori","year":"2008","journal-title":"Neuroimage"},{"issue":"3","key":"pone.0346661.ref030","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.neuroimage.2008.07.009","article-title":"Human brain white matter atlas: Identification and assignment of common anatomical structures in superficial white matter","volume":"43","author":"K Oishi","year":"2008","journal-title":"Neuroimage"},{"key":"pone.0346661.ref031","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.neuroimage.2017.08.047","article-title":"Harmonization of multi-site diffusion tensor imaging data","volume":"161","author":"J-P Fortin","year":"2017","journal-title":"Neuroimage"},{"issue":"1","key":"pone.0346661.ref032","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: A practical and powerful approach to multiple testing","volume":"57","author":"Y Benjamini","year":"1995","journal-title":"Journal of the Royal Statistical Society Series B: Statistical Methodology"},{"issue":"5","key":"pone.0346661.ref033","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.jalz.2012.10.001","article-title":"Comparative accuracies of two common screening instruments for the classification of Alzheimer\u2019s disease, mild cognitive impairment and healthy aging","author":"DR Roalf","year":"2013","journal-title":"Alzheimers Dement"},{"issue":"9","key":"pone.0346661.ref034","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1017\/S1355617724000341","article-title":"Comparing and linking the mini-mental state examination and montreal cognitive assessment in the amsterdam dementia cohort","volume":"30","author":"MA Dubbelman","year":"2024","journal-title":"J Int Neuropsychol Soc"},{"issue":"4","key":"pone.0346661.ref035","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1017\/S1041610218001370","article-title":"Is the Montreal Cognitive Assessment (MoCA) screening superior to the Mini-Mental State Examination (MMSE) in the detection of mild cognitive impairment (MCI) and Alzheimer\u2019s Disease (AD) in the elderly?","volume":"31","author":"TCC Pinto","year":"2019","journal-title":"Int Psychogeriatr"},{"issue":"1","key":"pone.0346661.ref036","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3390\/geriatrics8010012","article-title":"Mini-mental state examination: optimal cut-off levels for mild and severe cognitive impairment","volume":"8","author":"F Salis","year":"2023","journal-title":"Geriatrics"},{"issue":"1","key":"pone.0346661.ref037","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s10072-022-06422-z","article-title":"Optimal MoCA cutoffs for detecting biologically-defined patients with MCI and early dementia","volume":"44","author":"CR Ilardi","year":"2023","journal-title":"Neurol Sci"},{"issue":"3","key":"pone.0346661.ref038","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1093\/brain\/awx355","article-title":"Fibre-specific white matter reductions in Alzheimer\u2019s disease and mild cognitive impairment","volume":"141","author":"R Mito","year":"2018","journal-title":"Brain"},{"issue":"3","key":"pone.0346661.ref039","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1001\/jama.2025.7817","article-title":"Frequency and clinical outcomes associated with tau positron emission tomography positivity","volume":"334","author":"A Moscoso","year":"2025","journal-title":"JAMA"},{"issue":"1","key":"pone.0346661.ref040","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1186\/s13195-024-01450-7","article-title":"Impact of amyloid and tau positivity on longitudinal brain atrophy in cognitively normal individuals","volume":"16","author":"Alzheimer\u2019s Disease Neuroimaging Initiative","year":"2024","journal-title":"Alzheimers Res Ther"},{"issue":"9","key":"pone.0346661.ref041","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1001\/jamaneurol.2023.2338","article-title":"Prevalence and clinical implications of a \u03b2-amyloid-negative, tau-positive cerebrospinal fluid biomarker profile in Alzheimer disease","volume":"80","author":"P Erickson","year":"2023","journal-title":"JAMA Neurology"},{"issue":"7","key":"pone.0346661.ref042","article-title":"Mini-Mental State Examination (MMSE) for the early detection of dementia in people with mild cognitive impairment (MCI)","volume":"7","author":"I Arevalo-Rodriguez","year":"2021","journal-title":"Cochrane Database Syst Rev"},{"issue":"1","key":"pone.0346661.ref043","doi-asserted-by":"crossref","first-page":"7490","DOI":"10.1038\/s41598-018-25377-w","article-title":"Sex differences in cognitive decline in subjects with high likelihood of mild cognitive impairment due to Alzheimer\u2019s disease","volume":"8","author":"D Sohn","year":"2018","journal-title":"Sci Rep"},{"issue":"8","key":"pone.0346661.ref044","doi-asserted-by":"crossref","first-page":"5695","DOI":"10.1002\/alz.13844","article-title":"Sex and gender differences in cognitive resilience to aging and Alzheimer\u2019s disease","volume":"20","author":"EM Arenaza-Urquijo","year":"2024","journal-title":"Alzheimers Dement"},{"issue":"12","key":"pone.0346661.ref045","doi-asserted-by":"crossref","first-page":"8758","DOI":"10.1002\/alz.14330","article-title":"Microscopy assessment of a fluorescence [18F] flortaucipir analog (T726) shows neuropathological overlap with 3R and 4R tau lesions","volume":"20","author":"RG Gatto","year":"2024","journal-title":"Alzheimers Dement"},{"issue":"5","key":"pone.0346661.ref046","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0284182","article-title":"Comparative assessment of regional tau distribution by Tau-PET and Post-mortem neuropathology in a representative set of Alzheimer\u2019s & frontotemporal lobar degeneration patients","volume":"18","author":"RG Gatto","year":"2023","journal-title":"PLoS One"},{"key":"pone.0346661.ref047","doi-asserted-by":"crossref","first-page":"118417","DOI":"10.1016\/j.neuroimage.2021.118417","article-title":"Fixel-based analysis of diffusion MRI: methods, applications, challenges and opportunities","volume":"241","author":"T Dhollander","year":"2021","journal-title":"Neuroimage"},{"issue":"1","key":"pone.0346661.ref048","doi-asserted-by":"crossref","DOI":"10.1002\/brb3.3346","article-title":"Combined assessment of progressive apraxia of speech brain microstructure by diffusion tensor imaging tractography and multishell neurite orientation dispersion and density imaging","volume":"14","author":"RG Gatto","year":"2024","journal-title":"Brain Behav"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0346661","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T17:35:18Z","timestamp":1775669718000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0346661"}},"subtitle":[],"editor":[{"given":"Stephen D.","family":"Ginsberg","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,4,8]]},"references-count":48,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4,8]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0346661","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,8]]}}}