Author Identifier

Tenielle Porter: https://orcid.org/0000-0002-7887-6622

Simon M. Laws: https://orcid.org/0000-0002-4355-7082

Document Type

Journal Article

Publication Title

Nature Communications

Volume

15

Issue

1

PubMed ID

39304655

Publisher

Nature

School

Centre for Precision Health / School of Medical and Health Sciences

RAS ID

72547

Funders

Northern California Institute for Research and Education / Mayo Foundation for Medical Education and Research / Alzheimer's Association / National Health and Medical Research Council / Further funding information available at: https://doi.org/10.1038/s41467-024-52298-2

Grant Number

NHMRC Numbers : GNT1161706, GNT1191535

Comments

Nho, K., Risacher, S. L., Apostolova, L. G., Bice, P. J., Brosch, J. R., Deardorff, R., ... & Saykin, A. J. (2024). CYP1B1-RMDN2 Alzheimer’s disease endophenotype locus identified for cerebral tau PET. Nature Communications, 15(1), 8251. https://doi.org/10.1038/s41467-024-52298-2

Abstract

Determining the genetic architecture of Alzheimer’s disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD.

DOI

10.1038/s41467-024-52298-2

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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