Tranfa, Mario;
Pieperhoff, Leonard;
Pontillo, Giuseppe;
Luckett, Emma S;
Collij, Lyduine E;
Oliveira, Tiago Gil;
Tesi, Niccoló;
... Lorenzini, Luigi; + view all
(2025)
Polygenic pathways shape white matter vulnerability to Alzheimer's disease-related pathophysiological changes.
Alzheimer's Research & Therapy
, 17
, Article 240. 10.1186/s13195-025-01888-3.
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Abstract
Background: The accumulation of amyloid-β1−42 (Aβ1−42) peptides and phosphorylated-Tau181 (p-Tau181) tangles from the preclinical stages of Alzheimer’s disease (AD) has led to a biological definition of the disease. However, among Aβ1−42-positive individuals, cognitive decline onset varies, and some never develop symptoms. Genetic influences on molecular pathways and their interactions with proteinopathy may underlie this heterogeneity. Leveraging data from a large sample of cognitively intact older adults in the European Prevention of Alzheimer Dementia (EPAD) cohort, we examined how AD-related pathophysiological changes (i.e., Aβ1−42 and p-Tau181), polygenic pathways and their interaction are associated with WM micro- and macrostructural properties. / Methods: We selected 803 individuals (mean age = 64.7 ± 7.3 years, 458 [57.0%] females, 275 [34.2%] APOE-ε4 carriers) with CSF-Aβ1−42 and p-Tau181 measurements available, full genotyping, and structural and diffusion MRI. Polygenic risk scores (PRSs) were computed using 85 AD-related genetic variants. These were mapped to their corresponding genes and, after excluding those belonging to the APOE locus, clustered by function into six pathway-specific PRSs (i.e., immune activation, signal transduction, inflammation, lipid, amyloid, and clearance pathways). Diffusion MRIs were processed through the fixel-based analysis framework to derive fiber density (FD) and fiber cross-section (FC) metrics, which were averaged within WM tracts. Linear models assessed the effects of AD-related pathophysiological changes, global and pathway-specific PRSs, and their interactions on FD and FC at both the tract and fixel levels. Models were corrected for multiple comparisons. / Results: P-Tau181 was primarily associated with greater FD. The lipid pathway was associated with greater FD and FC, with these effects predominantly occurring in the left hemisphere, consistent with evidence of hemispheric dominance. The clearance pathway moderated the effect of Aβ1−42 on FD, with a positive slope in A + compared to A- individuals. The immune activation pathway moderated the effect of p-Tau181 on FD, with a negative slope in T + compared to T- individuals. / Conclusions: Pathway-specific genetic vulnerability to AD is associated with alterations in WM tracts both directly and by moderating the effects of AD-related pathophysiological changes. AD-associated genetic risk should be integrated into the AD diagnostic framework to enable targeted screening and intervention for future preclinical trials aimed at specific biological pathways.
| Type: | Article |
|---|---|
| Title: | Polygenic pathways shape white matter vulnerability to Alzheimer's disease-related pathophysiological changes |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1186/s13195-025-01888-3 |
| Publisher version: | https://doi.org/10.1186/s13195-025-01888-3 |
| Language: | English |
| Additional information: | This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. |
| Keywords: | Alzheimer's disease, Polygenic risk scores, Polygenic pathways, White matter, Fixel-based analysis, Diffusion magnetic resonance imaging |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Med Phys and Biomedical Eng |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10217815 |
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