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Association of Superficial White Matter Microstructure With Cortical Pathology Deposition Across Early Stages of the AD Continuum
Shuyue Wang, Fan Zhang, Qingze Zeng, Hui Hong, Yao Zhang, Linyun Xie, Lin Miao, Yeerfan Jiaerken et al.. Neurology, 2025-06-19
Topic: Brain proteins, microglia and lab models
Background and Objectivesβ-amyloid (Aβ) and tau, 2 prominent pathologies of Alzheimer disease (AD), originate in cortical regions and primarily affect, and even spread along, the white matter tracts directly connected to these cortical regions. Superficial white matter (SWM), containing short-range association connections beneath the cortex, has been affected in mild cognitive impairment and AD, with gaps in understanding the disease's early stages. We perform a detailed investigation of individual SWM connections with cortical pathology deposition and cognition in the early stages of the AD continuum. MethodsWe enroll participants with Aβ PET, tau PET, diffusion MRI, and cognitive status from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Harvard Aging Brain Study (HABS). We stratify participants into disease stages following the Aβ/tau (AT) framework. We use diffusion MRI tractography to analyze SWM fiber clusters and assess their microstructure through free-water modeling, identifying significant differences between pathologically staged groups. We investigate associations of diffusion measures in SWM fiber clusters with regional pathology deposition (Aβ- and tau- PET uptake) and cognition. ResultsThe study includes 150 ADNI participants (mean age 73.6 years, 61.3% female) and 175 HABS participants (mean age 75.6 years, 61.1% female). We find the following: (1) SWM microstructure differs along the early-stage Alzheimer disease continuum, with primary abnormalities in posterior brain regions; (2) there are significant free-water alterations in cognitively intact but pathology-positive individuals (p < 0.05, false discovery rate [FDR] corrected); (3) associations are identified between free water in SWM connections and proximal pathologic deposition, as well as between free water in several connections and memory function (standardized β coefficient = [-0.297 to −0.352], all p < 0.05, FDR corrected); and (iv) free water of a temporal SWM connection mediates the impact of temporal tau on memory (95% CI = [−0.146 to −0.002], accounts for 15.0% of the total effect). DiscussionThe findings of this study suggest that the propagation of AD pathology and cognitive changes may involve SWM pathways even in the early stages, emphasizing the importance of SWM in developing AD therapies and early interventions.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Wang, S., Zhang, F., Zeng, Q., Hong, H., Zhang, Y., Xie, L., et al. (2025). Association of Superficial White Matter Microstructure With Cortical Pathology Deposition Across Early Stages of the AD Continuum. Neurology. https://doi.org/10.1212/wnl.0000000000213666
Vancouver
Wang S, Zhang F, Zeng Q, Hong H, Zhang Y, Xie L, et al. Association of Superficial White Matter Microstructure With Cortical Pathology Deposition Across Early Stages of the AD Continuum. Neurology. 2025. doi:10.1212/wnl.0000000000213666. PMID: 40537069.
BibTeX
@article{wang2025-40537069,
author = {Wang, Shuyue and Zhang, Fan and Zeng, Qingze and Hong, Hui and Zhang, Yao and Xie, Linyun and Miao, Lin and Jiaerken, Yeerfan and others},
title = {{Association of Superficial White Matter Microstructure With Cortical Pathology Deposition Across Early Stages of the AD Continuum}},
journal = {Neurology},
year = {2025},
doi = {10.1212/wnl.0000000000213666},
pmid = {40537069},
url = {https://doi.org/10.1212/wnl.0000000000213666}
}
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
Key findings
- We use diffusion MRI tractography to analyze SWM fiber clusters and assess their microstructure through free-water modeling, identifying significant differences between pathologically staged groups.
- We find the following: (1) SWM microstructure differs along the early-stage Alzheimer disease continuum, with primary abnormalities in posterior brain regions; (2) there are significant free-water alterations in cognitively intact but pathology-positive individuals (p < 0.05, false discovery rate [FDR] corrected); (3) associations are identified between free water in SWM connections and proximal pathologic deposition, as well as between free water in several connections and memory function (standardized β coefficient = [-0.297 to −0.352], all p < 0.05, FDR corrected); and (iv) free water of a temporal SWM connection mediates the impact of temporal tau on memory (95% CI = [−0.146 to −0.002], accounts for 15.0% of the total effect).
- DiscussionThe findings of this study suggest that the propagation of AD pathology and cognitive changes may involve SWM pathways even in the early stages, emphasizing the importance of SWM in developing AD therapies and early interventions.
Why it matters
This study examined the microstructure of superficial white matter connections in the brain and found differences along early stages of the Alzheimer's disease continuum, including in cognitively intact people with positive pathology. It is an observational imaging study and does not test any treatment, cure, or prevention.
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Study details
- Effect size61.3%; 61.1%; or 15.0
- Evidence strengthLow
How this study scored 50/100
Published in a leading specialty journal. Scored zero for study design, sample size, studied in people and randomised / blinded because the record does not state it. We have no data on senior author's track record, so that was left out: it earned 48 of the 96 points we could judge it on, which is 50 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Neurology) |
| Journal's citation record | 4 / 4 | Neurology: journal h-index 525 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 2 / 3 | Effect reported as a number, without an interval or test |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 13 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 4.3 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 4 / 6 | Cited 8.3× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 13 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | 3 / 3 | Harvard University: institution h-index 3,235 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 5 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40537069) |
| Free to read | 2 / 2 | Free to read |
| Points | 48 / 96 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 48 of the 96 points we could judge it on is 50 out of 100. |
| Total | 50 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1212/wnl.0000000000213666
- PubMed: 40537069
- Original source →
- Free full text: PubMed Central →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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