New Alzheimer’s Gene? Cytochrome P450 Protein Linked to Tangles

To boost the statistical power to find Alzheimer’s genes, geneticists often use endophenotypes—measurable characteristics of the disease—in place of clinical diagnoses. Case in point: A genome-wide association study on more than 3,000 tau PET scans from 12 Alzheimer’s cohorts dug up a potential AD gene that had remained buried in traditional case-control GWAS. In the September 20 Nature Communications, scientists led by Andrew Saykin at Indiana University School of Medicine, Indianapolis, reported that a risk variant of CYP1B1, a member of the cytochrome P450 family of oxidizing enzymes, was associated with more cortical tangles. “This study demonstrates the power of the endophenotype approach,” Saykin noted.

  • Tau PET GWAS turned up a risk SNP associated with higher cortical tangle load.
  • The SNP revved up expression of cytochrome P450 gene CYP1B1.
  • This oxidizing enzyme is elevated in AD brain.

There have been at least three previous GWAS using tau PET scans. These strengthened associations with the known AD gene BIN1 and uncovered links to genes that regulate tau phosphorylation (Franzmeier et al., 2019; Ramanan et al., 2020; Guo et al., 2022). However, those studies were hampered by small sample sizes of a few hundred participants.

Hot Spot. GWAS of tau PET scans found a single locus where SNPs (circles) were associated with higher tangle loads. The strongest signal came from SNP rs2113389 (gray diamond). [Courtesy of Nho et al., Nature Communications.]

In the new study, joint first authors Kwangsik Nho and Shannon Risacher at IU went bigger. They performed a meta-analysis of 1,446 tau PET scans from these seven Alzheimer’s and/or aging cohorts: ADNI, ADNI-Department of Defense, Indiana Memory and Aging Study, Avid A05 clinical trial, A4 Study, Harvard Aging Brain Study, and the University of Pittsburgh Alzheimer’s Disease Research Center.

The GWAS turned up a single genome-wide significant locus, wedged between the CYP1B1 and RMDN2 genes (image above). The risk SNP, rs2113389, was associated with having more tangles in temporal, parietal, and frontal lobes (image below). The finding held up in a meta-analysis of 1,600 tau PET scans from five additional cohorts: the Australian Imaging, Biomarker, and Lifestyle Study; the Berkeley Aging Cohort Study; the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration Study; the Mayo Clinic Study of Aging; and the Memory and Aging Project at the Knight Alzheimer’s Disease Research Center.

In these cohorts, risk SNP rs2113389 explained 4.3 percent of the variance in tangle load. This was a larger effect than for AD gene APOE4, which accounted for 3.6 percent. Rs2113389 also correlated with higher total tau and p-tau181 in cerebrospinal fluid. Its effects were independent of plaques and APOE genotype, and were unaffected by clinical diagnosis or sex. The allele acted in a dominant fashion, with one copy having as harmful an effect as two. The risk SNP is relatively common in people of European ancestry, with a frequency of about 14 percent.

Widespread Effect. Risk SNP rs2113389 was associated with having more tangles (blue to red scale shows intensity) throughout the frontal, parietal, and temporal lobes. [Courtesy of Nho et al., Nature Communications.]

Through which of the two nearby genes might rs2113389 act? To answer this, the authors examined bulk RNA-Seq data from the AMP-AD Knowledge Portal. Rs2113389 did not affect RMDN2 expression, but was linked to more CYP1B1 in temporal cortex. This gene, cytochrome P450 Family 1 Subfamily B Member 1, is part of a group of more than 50 enzymes that help metabolize drugs, hormones, and fatty acids.

CYP1B1 is made in the brain, particularly in fibroblasts and excitatory neurons, and it can cause oxidative stress. The latter might help explain the effect on tangles, since oxidative stress worsens tau phosphorylation and misfolding, the authors noted (Mondragón-Rodríguez et al., 2013; Liu et al., 2015). Due to the enzyme’s multiple functions, other explanations are possible, and mechanistic studies in mice and cell cultures will be needed to sort this out, Saykin told Alzforum.

CYP1B1 had not previously been associated with AD. However, other risk SNPs in the gene were reported to correlate with higher CSF t-tau and p-tau (Deming et al., 2017; Jansen et al., 2022). Adding to the evidence that this gene might play a role in Alzheimer’s, in AMP-AD data the authors found more CYP1B1 in AD brains than in healthy controls. Similarly, in two tauopathy mouse models, but not an amyloidosis model, cortical CYP1B1 expression rose with age, the authors found.

Having cohorts of mostly European ancestry, and being on the small side for a GWAS, limit the power of the study. “Our findings require replication using large community studies or international collaborations,” the authors noted. Saykin said they plan to follow up with a larger GWAS in more diverse cohorts.—Madolyn Bowman Rogers

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References

Paper Citations

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Further Reading

Primary Papers

  1. Nho K, Risacher SL, Apostolova LG, Bice PJ, Brosch JR, Deardorff R, Faber K, Farlow MR, Foroud T, Gao S, Rosewood T, Kim JP, Nudelman K, Yu M, Aisen P, Sperling R, Hooli B, Shcherbinin S, Svaldi D, Jack CR Jr, Jagust WJ, Landau S, Vasanthakumar A, Waring JF, Doré V, Laws SM, Masters CL, Porter T, Rowe CC, Villemagne VL, Dumitrescu L, Hohman TJ, Libby JB, Mormino E, Buckley RF, Johnson K, Yang HS, Petersen RC, Ramanan VK, Ertekin-Taner N, Vemuri P, Cohen AD, Fan KH, Kamboh MI, Lopez OL, Bennett DA, Ali M, Benzinger T, Cruchaga C, Hobbs D, De Jager PL, Fujita M, Jadhav V, Lamb BT, Tsai AP, Castanho I, Mill J, Weiner MW, 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 AJ. CYP1B1-RMDN2 Alzheimer's disease endophenotype locus identified for cerebral tau PET. Nat Commun. 2024 Sep 20;15(1):8251. PubMed.

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