Nature communications · 2024

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

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

Аннотация

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.

Предметные рубрики MeSH

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

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

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Аннотация

Предметные рубрики MeSH