White Matter Microstructural Alterations Mediate the Association between Polygenic Risk for Alzheimer's Disease and Cognitive Performance in Clinically Asymptomatic Adults.

Overview

1. Department of Radiology, Juntendo University Graduate School of Medicine, Tokyo, Japan
2. Department of Data Science, Juntendo University Graduate School of Medicine, Tokyo, Japan
3. Faculty of Health Data Science, Juntendo University, Urayasu, Chiba, Japan
4. Graduate School of Health Data Science, Juntendo University, Urayasu, Chiba, Japan

Abstract

Purpose: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder influenced by genetic factors, with a long preclinical phase characterized by subtle alterations in brain microstructure. Although the apolipoprotein E ε4 allele is a well-established genetic risk factor, AD is increasingly recognized as a polygenic condition. However, how polygenic risk manifests in white matter (WM) microstructure and cognition remains unclear. This study aims to investigate the associations between AD polygenic risk scores (ADPRS), WM microstructure, and cognitive performance in clinically asymptomatic adults.

Methods: Data from 36400 individuals (aged 45–83 years) in the UK Biobank were analyzed. Diffusion tensor imaging and neurite orientation dispersion and density imaging metrics were extracted from 48 WM tracts. General linear models were used to examine associations between ADPRS, WM integrity, and 10 cognitive measures. Mediation analyses were conducted to test whether WM microstructure mediated the relationship between ADPRS and cognitive performance.

Results: Higher ADPRS was significantly associated with reduced fractional anisotropy and intracellular volume fraction, and with increased mean, axial, and radial diffusivity, as well as isotropic volume fraction across limbic and association fibers, particularly in the cingulum hippocampus, fornix, posterior thalamic radiation, and superior fronto-occipital fasciculus. Higher ADPRS was also associated with poorer cognitive performance, most prominently on tests of executive function (Trail Making Test B), episodic memory (Paired Associate Learning), and processing speed (Symbol Digit Substitution). Mediation analysis revealed that WM microstructural alterations, especially increased radial diffusivity and reduced fractional anisotropy in the posterior thalamic radiation, partially mediated the association between ADPRS and cognitive performance, accounting for up to 4.88% of the total effect.

Conclusion: ADPRS is linked to selective WM microstructural alterations and subtle cognitive difference in clinically asymptomatic adults. WM microstructural changes partially mediate the association between ADPRS and cognitive performance.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

No file of the authors' code could be read here: it is described below, and read at its source.

The paper's code and data availability statement is in the Data section.

Tracing map

Proposed by the machine: these links were found in the paper and verified at the source, without human review. The map will receive a Zenodo DOI once one of the paper's authors has validated it with their ORCID.

What the map holds:

• 1 repository of the authors' code, each at its verified commit, with its license and how the link was found in the paper;
• 0 scripts, each with its path and the digest of its content;
• no match between paragraphs and code yet;
• neither the text of the paper nor the code itself.

Its JSON (tracing-map.json) is deposited on Zenodo with its DOI once the map is validated.

Data

No dataset and no data link were found in the paper.

Data and code availability

All data used in this study were obtained from the UKB (https://www.ukbiobank.ac.uk/). The specific imaging, ADPRS, and cognitive variables used are listed in Table S4.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 5 keywords, 12 MeSH terms, 3 funders, 51 references.

Cite

This paper

Zou, R., Takabayashi, K., Andica, C., Uchida, W., Kitagawa, T., Mizuta, K., Hagiwara, A., Kikuta, J., Aoki, S., & Kamagata, K. (2026). White Matter Microstructural Alterations Mediate the Association between Polygenic Risk for Alzheimer's Disease and Cognitive Performance in Clinically Asymptomatic Adults. Magnetic resonance in medical sciences : MRMS : an official journal of Japan Society of Magnetic Resonance in Medicine, 25(1), 2025-0182. https://doi.org/10.2463/mrms.mp.2025-0182

The tracing map gets a citation of its own once an author has validated it and it has a DOI.

Similar papers

The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.

[1] doi:10.7554/elife.108109 [code]

Multimodal MRI marker of cognition explains the association between cognition and mental health in the UK Biobank.

Journal: eLife

In common: structural MRI / diffusion, 7 references

[2] doi:10.1038/s41398-026-04292-z [code]

Regional juxtacortical microstructural changes and gene expression provide insights into neurodegeneration in Alzheimer's disease.

Journal: Translational psychiatry

In common: Alzheimer's / dementia, structural MRI / diffusion, genetics / omics, 4 references

[3] doi:10.1038/s41588-026-02722-8 [code]

A multiancestry polygenic risk score for Alzheimer's disease is associated with cognitive decline and neuropathological hallmarks in diverse populations.

Journal: Nature genetics

In common: Alzheimer's / dementia, genetics / omics, 3 references

[4] doi:10.12779/dnd.2026.25.2.115

Effects of Sarcopenia and Frailty on Cognitive Function, Brain Volume, and Dementia Risk: A Prospective Cohort Study Based on UK Biobank.

Journal: Dementia and neurocognitive disorders

In common: Alzheimer's / dementia, structural MRI / diffusion, 3 references

[5] doi:10.1016/j.ynirp.2026.100405

White matter microstructure and motor function in amnestic mild cognitive impairment and Alzheimer's dementia.

Journal: Neuroimage. Reports

In common: Alzheimer's / dementia, structural MRI / diffusion, 2 references

[6] doi:10.1371/journal.pone.0344566

Association of intraindividual differences in estimated glomerular filtration rates based on cystatin C and creatinine with dementia: A cohort study of the UK Biobank.

Journal: PloS one

In common: Alzheimer's / dementia, 3 references

[7] doi:10.1002/hbm.70635 [code]

Cerebral Cortical Structural Variation and General Cognitive Ability: Evidence From Mendelian Randomization.

Journal: Human brain mapping

In common: structural MRI / diffusion, genetics / omics, 3 references

[8] doi:10.1002/alz.71630 [code]

Genetic architecture of the limbic white matter microstructure in aging and Alzheimer's Disease.

Journal: Alzheimer's & dementia : the journal of the Alzheimer's Association

In common: Alzheimer's / dementia, structural MRI / diffusion, genetics / omics, 2 references

[9] doi:10.1371/journal.pbio.3003856 [code]

Aging and metabolism contribute separately to brain-body health.

Journal: PLoS biology

In common: structural MRI / diffusion, 3 references

[10] doi:10.1038/s42003-026-10030-4 [code]

Cell-type-aware transcriptome-wide association studies identify 91 independent risk genes for Alzheimer's disease dementia.

Journal: Communications biology

In common: Alzheimer's / dementia, genetics / omics, 3 references

Contribute

The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.

Request its removal

To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).

Discussion: questions and error reports about this paper and its code, from signed-in readers and its authors. It opens with sign-in.

Reproductions: reports from readers who ran the authors' code: what they reproduced, with which environment, commit and data. It opens with sign-in.

Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.