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 Jr; 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 De Jager; Masashi Fujita; Vaishnavi Jadhav; Bruce T Lamb; Andy P Tsai; Isabel Castanho; Jonathan Mill; Michael W Weiner; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Department of Defense Alzheimer’s Disease Neuroimaging Initiative (DoD-ADNI); Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Study (A4 Study) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN); Australian Imaging, Biomarker & Lifestyle Study (AIBL); Andrew J Saykin

doi:10.1038/s41467-024-52298-2

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

Nat Commun. 2024 Sep 20;15(1):8251. doi: 10.1038/s41467-024-52298-2.

Authors

Kwangsik Nho^#^{1

2

3

4}, Shannon L Risacher^#^{1

3}, Liana G Apostolova^{1

3

5

6}, Paula J Bice^{1

3}, Jared R Brosch^{3

5}, Rachael Deardorff^{3

5}, Kelley Faber^{6

7}, Martin R Farlow^{3

5}, Tatiana Foroud^{3

6

7}, Sujuan Gao^{3

8}, Thea Rosewood^{1

2

3}, Jun Pyo Kim^{1

2

3}, Kelly Nudelman^{3

6

7}, Meichen Yu^{1

3}, Paul Aisen⁹, Reisa Sperling¹⁰, Basavaraj Hooli¹¹, Sergey Shcherbinin¹¹, Diana Svaldi¹¹, Clifford R Jack Jr¹², William J Jagust¹³, Susan Landau¹³, Aparna Vasanthakumar¹⁴, Jeffrey F Waring¹⁴, Vincent Doré^{15

16}, Simon M Laws¹⁷, Colin L Masters¹⁸, Tenielle Porter¹⁷, Christopher C Rowe^{16

18}, Victor L Villemagne^{16

19}, Logan Dumitrescu^{20

21}, Timothy J Hohman^{20

21}, Julia B Libby²⁰, Elizabeth Mormino²², Rachel F Buckley¹⁰, Keith Johnson^{10

23}, Hyun-Sik Yang^{10

24}, Ronald C Petersen²⁵, Vijay K Ramanan²⁵, Nilüfer Ertekin-Taner^{26

27}, Prashanthi Vemuri¹², Ann D Cohen¹⁹, Kang-Hsien Fan²⁸, M Ilyas Kamboh²⁸, Oscar L Lopez^{19

29}, David A Bennett³⁰, Muhammad Ali³¹, Tammie Benzinger³², Carlos Cruchaga^{31

33}, Diana Hobbs³², Philip L De Jager³⁴, Masashi Fujita³⁴, Vaishnavi Jadhav^{6

35}, Bruce T Lamb^{3

6

35}, Andy P Tsai^{22

35

36}, Isabel Castanho^{37

38}, Jonathan Mill³⁷, Michael W Weiner^{39

40}; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Department of Defense Alzheimer’s Disease Neuroimaging Initiative (DoD-ADNI); Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Study (A4 Study) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN); Australian Imaging, Biomarker & Lifestyle Study (AIBL); Andrew J Saykin^{41

42

43

44

45}

Affiliations

¹ Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, USA.
² Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, USA.
³ Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, USA.
⁴ Department of BioHealth Informatics, Indiana University, Indianapolis, USA.
⁵ Department of Neurology, Indiana University School of Medicine, Indianapolis, USA.
⁶ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, USA.
⁷ National Centralized Repository for Alzheimer's Disease and Related Dementias, Indiana University School of Medicine, Indianapolis, USA.
⁸ Department of Biostatistics, Indiana University School of Medicine, Indianapolis, USA.
⁹ Department of Neurology, Keck School of Medicine, University of Southern California, San Diego, USA.
¹⁰ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
¹¹ Eli Lilly and Company, Indianapolis, USA.
¹² Department of Radiology, Mayo Clinic, Rochester, USA.
¹³ UC Berkeley Helen Wills Neuroscience Institute, University of California - Berkeley, Berkeley, USA.
¹⁴ Genomics Research Center, AbbVie, North Chicago, USA.
¹⁵ CSIRO Health and Biosecurity, Melbourne, Australia.
¹⁶ Department of Molecular Imaging & Therapy, Austin Health, Heidelberg, Australia.
¹⁷ Centre for Precision Health, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Australia.
¹⁸ Florey Institute of Neuroscience and Mental Health and The University of Melbourne, Parkville, Australia.
¹⁹ Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, USA.
²⁰ Vanderbilt Memory & Alzheimer's Center, Vanderbilt University Medical Center, Nashville, USA.
²¹ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, USA.
²² Department of Neurology & Neurological Sciences, Stanford University, Stanford, USA.
²³ Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
²⁴ Center for Alzheimer's Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, USA.
²⁵ Department of Neurology, Mayo Clinic, Rochester, USA.
²⁶ Department of Neurology, Mayo Clinic, Jacksonville, USA.
²⁷ Department of Neuroscience, Mayo Clinic, Jacksonville, USA.
²⁸ Department of Human Genetics, University of Pittsburgh, Pittsburgh, USA.
²⁹ Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, USA.
³⁰ Department of Neurological Sciences, Rush Medical College, Rush University, Chicago, USA.
³¹ Department of Psychiatry, Washington University, St. Louis, USA.
³² Department of Radiology, Washington University School of Medicine, St. Louis, USA.
³³ NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, USA.
³⁴ Center for Translational and Computational Neuroimmunology, Department of Neurology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, USA.
³⁵ Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, USA.
³⁶ Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, USA.
³⁷ Department for Clinical and Biomedical Sciences, University of Exeter Medical School, University of Exeter, Exeter, UK.
³⁸ Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA.
³⁹ Departments of Radiology, Medicine, and Psychiatry, University of California-San Francisco, San Francisco, USA.
⁴⁰ Department of Veterans Affairs Medical Center, San Francisco, USA.
⁴¹ Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, USA. asaykin@iu.edu.
⁴² Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, USA. asaykin@iu.edu.
⁴³ Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, USA. asaykin@iu.edu.
⁴⁴ Department of Neurology, Indiana University School of Medicine, Indianapolis, USA. asaykin@iu.edu.
⁴⁵ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, USA. asaykin@iu.edu.

^# Contributed equally.

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.

MeSH terms

Aged
Aged, 80 and over
Alzheimer Disease* / diagnostic imaging
Alzheimer Disease* / genetics
Alzheimer Disease* / metabolism
Amyloid beta-Peptides / metabolism
Animals
Apolipoprotein E4 / genetics
Apolipoprotein E4 / metabolism
Cytochrome P-450 CYP1B1* / genetics
Cytochrome P-450 CYP1B1* / metabolism
Disease Models, Animal
Endophenotypes*
Female
Genome-Wide Association Study*
Humans
Male
Mice
Polymorphism, Single Nucleotide
Positron-Emission Tomography* / methods
tau Proteins* / genetics
tau Proteins* / metabolism

Substances

Amyloid beta-Peptides
Apolipoprotein E4
CYP1B1 protein, human
Cytochrome P-450 CYP1B1
tau Proteins
MAPT protein, human

Abstract

MeSH terms

Substances

Grants and funding