White matter microstructure disruption associated with PET and cognitive impairment in Alzheimer’s disease
Marlon Gonzales, Xiaojian Kang, Christian Cort, Maheen M. Adamson, Steven Z. Chao, Byung C. Yoon.
Abstract
Alzheimer’s disease (AD) is associated with regional brain atrophy as well as elevated positron emission tomography (PET) markers of amyloid-beta (e.g., [¹⁸F]florbetapir (FBP)) and tau protein (e.g., [¹⁸F]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.
Introduction
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment. Approximately 6.9 million individuals aged 65 years and older are affected by AD in the United States, with the prevalence projected to rise to 13.8 million by 2060 [1].
Methods
Data used in the preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative database (adni.loni.usc.edu) [23]. The ADNI was launched in 2003 as a public-private partnership, led by Principal Investigator Michael W. Weiner, MD.
Results
A total of 381 right-handed participants who underwent FBP, FTP, and brain MRI were included. There were 200 females and 181 males. The cohort was divided into four groups: FBP + /FTP+ (n = 38, F:M = 23:15), FBP + /FTP- (n = 133, F:M = 72:61), FBP-/FTP+ (n = 5, F:M = 1:4), and FBP-/FTP- (n = 205, F:M = 104:101).
Discussion
Direct comparisons between the DTI metrics and levels of FBP and FTP SUVR revealed substantially greater correlations with FBP than FTP. Both voxel-based metrics, FA and MD, and fixel-based metrics, CX and FN, showed statistically significant correlations with FBP SUVR (Table 1).
Conclusion
Distinctive associations between FBP/FTP levels and voxel-based analysis and fixel-based analysis derived DTI metrics were observed. FN exhibited the greatest degree of negative correlations with FBP SUVR, but not with FTP SUVR.
Citation: Gonzales M, Kang X, Cort C, Adamson MM, Chao SZ, Yoon BC, et al. (2026) White matter microstructure disruption associated with PET and cognitive impairment in Alzheimer’s disease. PLoS One 21(4): e0346661. https://doi.org/10.1371/journal.pone.0346661
Editor: Stephen D. Ginsberg, Nathan S Kline Institute, UNITED STATES OF AMERICA
Received: December 5, 2025; Accepted: March 23, 2026; Published: April 8, 2026
This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Data Availability: The data supporting the findings of this study (demographics, clinical assessments/diagnosis, PET data, and MRI data) are openly available via Alzheimer’s Disease Neuroimaging Initiative (https://ida.loni.usc.edu/explore/jsp/search_v2/search.jsp?project=ADNI; “Study Entry, PTDEMOG, MMSE, MOCA, SPAP_AVID_FLORBETAPIR, UCBERKELEY_AMY_6MM”).
Funding: This study was supported by the Veterans Affairs Palo Alto Early Career Development Program (awarded to b.c.y). Data collection and sharing for this project was also funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
