Available online 9 July 2025

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WMH yield early cortical thinning in AD beyond what expected due to amyloid and tau

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WMH-cortical thinning association primarily confined to temporal lobe

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WMH-cortical thinning relationship stronger in amyloid-positive individuals

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Cerebrovascular disease more than axonal damage links WMH to cortical thinning

Abstract

White matter hyperintensities (WMH) are associated with cortical thinning in distant brain regions. However, it is currently unclear how WMH affect neurodegeneration in early Alzheimer’s disease (AD). Here, we investigated associations between WMH and cortical thickness in temporal regions involved in early AD (AD cortical signature), while correcting for regional amyloid and tau accumulation assessed by PET. We performed cross-sectional (n = 551), and longitudinal (n = 125) analyses in older adults without dementia, also stratified by amyloid positivity. We evaluated WMH volume - as a measure of the global burden of WMH-related cerebrovascular pathology (GB-WMH) - and investigated the role of deep versus periventricular WMH. We also tested whether a higher focal burden of WMH in specific tracts connected to AD signature regions (FB-WMH) would lead to greater cortical thinning than expected solely from GB-WMH. We performed exploratory analyses in other brain regions to check the specificity of our findings to the temporal AD signature. GB-WMH damage, especially involving periventricular WMH, was cross-sectionally (not longitudinally) associated with cortical thinning in the fusiform, inferior and middle temporal gyri. Stronger associations were found in amyloid-positive individuals, including for the entorhinal cortex. Effects were mostly confined to regions of the temporal AD signature. FB-WMH did not yield higher cortical thinning than expected solely by GB-WMH. Cerebrovascular disease is associated with cortical thinning of temporal regions involved in early AD. Interventions aimed at improving cerebrovascular health might help to mitigate neurodegeneration in these regions.

Section snippetsBackground

Neurodegenerative disorders are characterized by selective neuronal vulnerability, as evidenced by disease-specific cortical thinning patterns (Kampmann 2024). In late-onset Alzheimer’s disease (AD), a specific pattern of neurodegeneration - termed AD cortical signature - involving the entorhinal, fusiform, and inferior and middle temporal regions is seen at the early stage of the disease (Jack et al., 2015, Parker et al., 2020, Keuss et al., 2024). This AD cortical signature has been shown to

Methods

The overall methodological workflow for this study is illustrated in Figure 1. Data used in the preparation of this article was obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). ADNI only included individuals in good health conditions, thus participants with a high burden of vascular disease (represented by a Hachinski score > 4) were not enrolled.

Results

Demographic baseline information for the whole cohort and for the amyloid-positive subgroup are provided in Table 1. After exclusions, 551 participants (aged 71.7 ± 7.3 years, 54.8% female, 63.5% without cognitive impairment) were included for cross-sectional analyses. Among them, 201 individuals (aged 73.3 ± 7.0 years, 57.2% females, 50.7% without cognitive impairment) were considered amyloid-positive according to a predefined cutoff.

Discussion

In this study, we used a multimodal imaging approach to examine the relationship between WMH and cortical thickness in four brain regions that comprise the previously defined temporal AD cortical signature. Consistent with prior findings, tau pathology was the strongest predictor of neurodegeneration. However, we observed that greater global WMH burden - particularly in periventricular areas - was cross-sectionally associated with reduced cortical thickness in these temporal regions, even after

Conclusions

Pathological cerebrovascular processes related to WMH are an important co-pathology in early AD that contributes to neuronal loss in AD-vulnerable temporal regions, resulting in significant additional neurodegeneration beyond that induced by amyloid and tau. Interventions aimed at improving cerebrovascular health might mitigate early neurodegeneration in AD, potentially slowing the development of cognitive symptoms.

Uncited references

Min Young et al. (2023); Wardlaw et al. (2015)

Funding

Open access publishing facilitated by the University of Bochum, as part of specific funds for Open Access publishing from the University Library. Funders of this study had no role in study design, data collection, data analysis, data interpretation, or writing.

CRediT authorship contribution statement

Riccardo Leone: Writing – review & editing, Writing – original draft, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Xenia Kobeleva: Writing – review & editing, Supervision, Methodology, Investigation, Formal analysis, Conceptualization.

Declaration of Competing Interest

All authors declare no competing interests.

Acknowledgements

Data collection and sharing for this project was 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;

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