10.1002/(ISSN)2352-8729 DAD2 Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring Alzheimer's Dement. 2352-8729 2352-8729 10.1002/dad2.12585 DAD212585 RESEARCH ARTICLE RESEARCH ARTICLES Distinct patterns of voxel‐ and connection‐based white matter hyperintensity distribution and associated factors in early‐onset and late‐onset Alzheimer's disease HONG et al. Hong Hui https://orcid.org/0000-0003-2084-203X 1 2 Chen Yutong 2 Liu Weiran 2 Luo Xiao luoxiao1990@zju.edu.cn * 1 Zhang Minming zhangminming@zju.edu.cn * 1 for the Alzheimer's Disease Neuroimaging Initiative (ADNI) Department of Radiology The Second Affiliated Hospital of Zhejiang University School of Medicine Hangzhou China Department of Clinical Neurosciences University of Cambridge Cambridge UK CorrespondenceMinming Zhang, MD PhD and Xiao Luo, PhD, Department of Radiology, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, China. Email: zhangminming@zju.edu.cn and luoxiao1990@zju.edu.cn 22 04 2024 0406 2024 16 2 10.1002/dad2.v16.2 e12585 12 02 2024 08 11 2023 15 03 2024 © 2024 the Alzheimer's Association. © 2024 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association. 2024 © 2024 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. Abstract Introduction

The distribution of voxel‐ and connection‐based white matter hyperintensity (WMH) patterns in early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD), as well as factors associated with these patterns, remain unclear.

 Method

We analyzed the WMH distribution patterns in EOAD and LOAD at the voxel and connection levels, each compared with their age‐matched cognitively unimpaired participants. Linear regression assessed the independent effects of amyloid and vascular risk factors on WMH distribution patterns in both groups.

 Results

Patients with EOAD showed increased WMH burden in the posterior region at the voxel level, and in occipital region tracts and visual network at the connection level, compared to controls. LOAD exhibited extensive involvement across various brain areas in both levels. Amyloid accumulation was associated WMH distribution in the early‐onset group, whereas the late‐onset group demonstrated associations with both amyloid and vascular risk factors.

 Discussion

EOAD showed posterior‐focused WMH distribution pattern, whereas LOAD was with a wider distribution. Amyloid accumulation was associated with connection‐based WMH patterns in both early‐onset and late‐onset groups, with additional independent effects of vascular risk factors in late‐onset group.

 Highlights

Both early‐onset Alzheimer's disease (EOAD) and late‐onset AD (LOAD) showed increased white matter hyperintensity (WMH) volume compared with their age‐matched cognitively unimpaired participants.

EOAD and LOAD exhibited distinct patterns of WMH distribution, with EOAD showing a posterior‐focused pattern and LOAD displaying a wider distribution across both voxel‐ and connection‐based levels.

In both EOAD and LOAD, amyloid accumulation was associated with connection‐based WMH patterns, with additional independent effects of vascular risk factors observed in LOAD.

early‐onset Alzheimer's disease late‐onset Alzheimer's disease white matter hyperintensities National Natural Science Foundation of China http://dx.doi.org/10.13039/501100001809 81971577 82271936