Shared genetic architecture between brain iron deposition and Alzheimer's disease
- 1Brain and Mental Health Program, QIMR Berghofer, Brisbane, Queensland, Australia
Abstract
Brain iron accumulation is well established in Alzheimers disease (AD), but whether the two share a genetic basis remains unclear. Here, we performed genome-wide association analyses of brain iron across six iron-rich brain regions, quantified via quantitative susceptibility mapping (QSM) in 38,142 UK Biobank participants. Genetic pleiotropic overlap, genetic correlation and genomic structural equation modelling were used to identify shared genetic architecture between brain iron and risk of AD, and bidirectional Mendelian randomisation was used to test for causal relationships. We identified 116 independent genome-wide significant loci associated with brain iron (r2<0.1; p <5 x 10-8) and validated these signals in an independent cohort using polygenic scores, which explained between 8.9% and 25.4% of variance in regional iron. Genetic pleiotropy and correlation analyses revealed that brain iron and AD share a polygenic basis extending well beyond the canonical APOE locus. This shared liability is specific to basal ganglia structures relevant to cognition, specifically, iron deposition across the caudate nucleus, putamen, and globus pallidus loaded onto a single latent factor that correlated significantly with AD (rg = 0.13, P = 0.019). Multivariate genome-wide association analysis of the shared liability factor between AD and brain iron revealed 27 independent genome-wide significant loci implicating genes that modulate neuroimmune function. Mendelian randomisation provided no evidence of a causal effect in either direction. In summary, we identified region-specific shared genetic liability between brain iron and AD, and a putative neuroimmune mechanism underlying it.
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BibTeX
@misc{rahman2026shared,
title = {{Shared genetic architecture between brain iron deposition and Alzheimer's disease}},
author = {M. R. Rahman and Y. Xia and P. Raniga and A. Fazlollahi and T. Islam and A. Dhruva and J.-S. Ong and S. MacGregor and A. I. Bush and J. Fripp and M. K. Lupton},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.07.26362470},
url = {https://www.medrxiv.org/content/10.64898/2026.09.07.26362470v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Shared genetic architecture between brain iron deposition and Alzheimer's disease
AU - M. R. Rahman
AU - Y. Xia
AU - P. Raniga
AU - A. Fazlollahi
AU - T. Islam
AU - A. Dhruva
AU - J.-S. Ong
AU - S. MacGregor
AU - A. I. Bush
AU - J. Fripp
AU - M. K. Lupton
PY - 2026
DA - 2026/09/07
PB - medRxiv
DO - 10.64898/2026.09.07.26362470
UR - https://www.medrxiv.org/content/10.64898/2026.09.07.26362470v1
AB - Brain iron accumulation is well established in Alzheimers disease (AD), but whether the two share a genetic basis remains unclear. Here, we performed genome-wide association analyses of brain iron across six iron-rich brain regions, quantified via quantitative susceptibility mapping (QSM) in 38,142 UK Biobank participants. Genetic pleiotropic overlap, genetic correlation and genomic structural equation modelling were used to identify shared genetic architecture between brain iron and risk of AD, and bidirectional Mendelian randomisation was used to test for causal relationships. We identified 116 independent genome-wide significant loci associated with brain iron (r2<0.1; p <5 x 10-8) and validated these signals in an independent cohort using polygenic scores, which explained between 8.9% and 25.4% of variance in regional iron. Genetic pleiotropy and correlation analyses revealed that brain iron and AD share a polygenic basis extending well beyond the canonical APOE locus. This shared liability is specific to basal ganglia structures relevant to cognition, specifically, iron deposition across the caudate nucleus, putamen, and globus pallidus loaded onto a single latent factor that correlated significantly with AD (rg = 0.13, P = 0.019). Multivariate genome-wide association analysis of the shared liability factor between AD and brain iron revealed 27 independent genome-wide significant loci implicating genes that modulate neuroimmune function. Mendelian randomisation provided no evidence of a causal effect in either direction. In summary, we identified region-specific shared genetic liability between brain iron and AD, and a putative neuroimmune mechanism underlying it.
ER -