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

Kwangsik Nho, Shannon L. Risacher, Liana G. Apostolova, Paula J. Bice, Jared R. Brosch, Rachael Deardorff, Kelley Faber, Martin R. Farlow, Tatiana Foroud, Sujuan Gao, Thea Rosewood, Jun Pyo Kim, Kelly Nudelman, Meichen Yu, Paul Aisen, Reisa Sperling, Basavaraj Hooli, Sergey Shcherbinin, Diana Svaldi, Clifford R. Jack, William J. Jagust, Susan Landau, Aparna Vasanthakumar, Jeffrey F. Waring, Vincent Doré, Simon M. Laws, Colin L. Masters, Tenielle Porter, Christopher C. Rowe, Victor L. Villemagne, Logan Dumitrescu, Timothy J. Hohman, Julia B. Libby, Elizabeth Mormino, Rachel F. Buckley, Keith Johnson, Hyun-Sik Yang, Ronald C. Petersen, Vijay K. Ramanan, Nilüfer Ertekin-Taner, Prashanthi Vemuri, Ann D. Cohen, Kang-Hsien Fan, M. Ilyas Kamboh, Oscar L. Lopez, David A. Bennett, Muhammad Ali, Tammie Benzinger, Carlos Cruchaga, Diana Hobbs, Philip L. Jager, Masashi Fujita, Vaishnavi Jadhav, Bruce T. Lamb, Andy P. Tsai, Isabel Castanho, Jonathan Mill, Michael W. Weiner and Andrew J. Saykin ()
Additional contact information
Kwangsik Nho: Indiana University School of Medicine
Shannon L. Risacher: Indiana University School of Medicine
Liana G. Apostolova: Indiana University School of Medicine
Paula J. Bice: Indiana University School of Medicine
Jared R. Brosch: Indiana University School of Medicine
Rachael Deardorff: Indiana University School of Medicine
Kelley Faber: Indiana University School of Medicine
Martin R. Farlow: Indiana University School of Medicine
Tatiana Foroud: Indiana University School of Medicine
Sujuan Gao: Indiana University School of Medicine
Thea Rosewood: Indiana University School of Medicine
Jun Pyo Kim: Indiana University School of Medicine
Kelly Nudelman: Indiana University School of Medicine
Meichen Yu: Indiana University School of Medicine
Paul Aisen: University of Southern California
Reisa Sperling: Harvard Medical School
Basavaraj Hooli: Eli Lilly and Company
Sergey Shcherbinin: Eli Lilly and Company
Diana Svaldi: Eli Lilly and Company
Clifford R. Jack: Mayo Clinic
William J. Jagust: University of California - Berkeley
Susan Landau: University of California - Berkeley
Aparna Vasanthakumar: AbbVie
Jeffrey F. Waring: AbbVie
Vincent Doré: CSIRO Health and Biosecurity
Simon M. Laws: Edith Cowan University
Colin L. Masters: Florey Institute of Neuroscience and Mental Health and The University of Melbourne
Tenielle Porter: Edith Cowan University
Christopher C. Rowe: Austin Health
Victor L. Villemagne: Austin Health
Logan Dumitrescu: Vanderbilt University Medical Center
Timothy J. Hohman: Vanderbilt University Medical Center
Julia B. Libby: Vanderbilt University Medical Center
Elizabeth Mormino: Stanford University
Rachel F. Buckley: Harvard Medical School
Keith Johnson: Harvard Medical School
Hyun-Sik Yang: Harvard Medical School
Ronald C. Petersen: Mayo Clinic
Vijay K. Ramanan: Mayo Clinic
Nilüfer Ertekin-Taner: Mayo Clinic
Prashanthi Vemuri: Mayo Clinic
Ann D. Cohen: University of Pittsburgh School of Medicine
Kang-Hsien Fan: University of Pittsburgh
M. Ilyas Kamboh: University of Pittsburgh
Oscar L. Lopez: University of Pittsburgh School of Medicine
David A. Bennett: Rush University
Muhammad Ali: Washington University
Tammie Benzinger: Washington University School of Medicine
Carlos Cruchaga: Washington University
Diana Hobbs: Washington University School of Medicine
Philip L. Jager: Columbia University Irving Medical Center
Masashi Fujita: Columbia University Irving Medical Center
Vaishnavi Jadhav: Indiana University School of Medicine
Bruce T. Lamb: Indiana University School of Medicine
Andy P. Tsai: Stanford University
Isabel Castanho: University of Exeter
Jonathan Mill: University of Exeter
Michael W. Weiner: University of California-San Francisco
Andrew J. Saykin: Indiana University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52298-2

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