CYP1B1-RMDN2 Alzheimer’s disease endophenotype locus identified for cerebral tau PET

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.

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Publication Details

Journal
Nature Communications
Published
2024-09-20
DOI
https://doi.org/10.1038/s41467-024-52298-2
Citations
9
Primary Topic
Alzheimer's disease research and treatments
Type
article
Field-Weighted Citation Impact
2.94

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article

CYP1B1-RMDN2 Alzheimer’s disease endophenotype locus identified for cerebral tau PET

Tammie L.S. Benzinger, Vincent Doré, Reisa Anne Sperling, Clifford R. Jack et al.
9 citations
Nature Communications
Alzheimer's disease research and treatments
2.94
article

CYP1B1-RMDN2 Alzheimer’s disease endophenotype locus identified for cerebral tau PET

Tammie L.S. Benzinger, Vincent Doré, Reisa Anne Sperling, Clifford R. Jack, Masashi Fujita, Jun Pyo Kim, Timothy J. Hohman, Shannon L. Risacher, Christopher C. Rowe, Keith A. Johnson, Ann D. Cohen, Andrew J. Saykin, Kang-Hsien Fan, Logan C. Dumitrescu, Vijay K. Ramanan, Rachel F. Buckley, Bruce T. Lamb, Sergey Shcherbinin, Liana G. Apostolova, Paul S. S Aisen, Isabel Castanho, Julia B. Libby, Sujuan Gao, Diana Otero Svaldi, Andy P. Tsai, Carlos C Cruchaga, Prashanthi Vemuri, Ronald Carl Petersen, Colin L. Masters, Tatiana Foroud, Muhammad Ali, Philip L. De Jager, Jonathan S. Mill, Victor L. Villemagne, Hyun‐Sik Yang, William J. Jagust, Paula J. Bice, Basavaraj Hooli, Thea Rosewood, Vaishnavi Jadhav, Kelly Nudelman, Martin R. Farlow, Diana A. Hobbs, Jared R. Brosch, Nilüfer Ertekin‐Taner, Elizabeth C. Mormino, Rachael Deardorff, Tenielle Porter, M. Ilyas Kamboh, Simon M. Laws, Meichen Yu, Susan Landau, Kwangsik Nho, Jeffrey F. Waring, Oscar L. López, Aparna Vasanthakumar, Michael Walter Weiner, Kelley Faber, David A. Bennett
article en
9 citations

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.

Nature CommunicationsVol. 15(1)
University of Southern California (US), Edith Cowan University (AU), Brigham and Women's Hospital (US), Rush University Medical Center (US), San Francisco VA Medical Center (US), Beth Israel Deaconess Medical Center (US), Mayo Clinic (US), Berkeley College (US), Harvard University (US), Eli Lilly (United States) (US), University of Pittsburgh (US), University of California, San Francisco (US), Neurosciences Institute (US), Washington University in St. Louis (US), University of Exeter (GB), Florey Institute of Neuroscience and Mental Health (AU), WinnMed (US), AbbVie (United States) (US), Massachusetts General Hospital (US), Alzheimer’s Disease Neuroimaging Initiative (US), CSIRO Health and Biosecurity (AU), Mayo Clinic in Florida (US), Austin Health (AU), Indiana University School of Medicine, Indiana University – Purdue University Indianapolis (US), Vanderbilt University Medical Center (US), Southern States University (US), University of California, Berkeley (US), Stanford University (US)
U.S. Department of Defense, Foundation for the National Institutes of Health, Michael J. Fox Foundation for Parkinson's Research, Mayo Clinic, Alzheimer's Association, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, Biogen, University of Southern California, Mayo Foundation for Medical Education and Research, Meso Scale Diagnostics, Arizona Department of Health Services, Alzheimer's Disease Neuroimaging Initiative, BioClinica, University of Pittsburgh, Novartis Pharmaceuticals Corporation, CurePSP, Rush University, Northern California Institute for Research and Education, Wellcome Trust, Hope Center for Neurological Disorders, Chan Zuckerberg Initiative, GHR Foundation, Elsie and Marvin Dekelboum Family Foundation, Eisai, Schuler-Stiftung, Servier, H. Lundbeck A/S, IXICO, Arizona Biomedical Research Commission, National Institutes of Health, Genentech, Avid Radiopharmaceuticals, Canadian Institutes of Health Research, Medical Research Council, National Institute on Aging, National Institute of Neurological Disorders and Stroke, Lawrence Berkeley National Laboratory
Good health and well-being
Openalex Percentile: Top 8%
Alzheimer's disease research and treatments
2.94
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