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CYP2C19 Variant Mitigates Alzheimer Disease Pathophysiology in Vivo and Postmortem

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CYP2C19 Variant Mitigates Alzheimer Disease Pathophysiology in Vivo and Postmortem ARTICLE OPEN ACCESS CYP2C19 variant mitigates Alzheimer disease pathophysiology in vivo and postmortem Andr´ea L. Benedet, MSc, Lei Yu, PhD, Aur´elie Labbe, PhD, Sulantha Mathotaarachchi, MSc, Correspondence Tharick A. Pascoal, MD, Monica Shin, MSc, Min-Su Kang, BSc, Serge Gauthier, MD, Guy A. Rouleau, MD, PhD, Dr. Rosa-Neto [email protected] Judes Poirier, PhD, David A. Bennett, MD, and Pedro Rosa-Neto, MD, PhD, for the Alzheimer’s Disease Neuroimaging Initiative Neurol Genet 2018;4:e216. doi:10.1212/NXG.0000000000000216 Abstract Objective To verify whether CYP polymorphisms are associated with amyloid-β (Aβ) pathology across the spectrum of clinical Alzheimer disease using in vivo and postmortem data from 2 in- dependent cohorts. Methods A candidate-gene approach tested the association between 5 genes (28 single nucleotide polymorphisms) and Aβ load measured in vivo by the global [18F]florbetapir PET standardized uptake value ratio (SUVR) in 338 Alzheimer’s Disease Neuroimaging Initiative participants. Significant results were then tested using plasma Aβ and CSF Aβ and Aβ/phosphorylated tau (Aβ/p-tau) ratio in the same cohort. The significant association was also generalized to postmortem Aβ load measurement in the Rush Religious Orders Study/Memory and Aging Project cohorts. In addition, global cognition was used as a phenotype in the analysis in both cohorts. Results Analysis of Aβ PET identified a variant in the CYP2C19 gene (rs4388808; p = 0.0006), in which carriers of the minor allele (MA) had a lower global SUVR. A voxel-wise analysis revealed that the variant is associated with a lower Aβ load in the frontal, inferior temporal, and posterior cingulate cortices. MA carriers also had higher CSF Aβ (p = 0.003) and Aβ/p-tau ratio (p = 0.02) but had no association with Aβ plasma levels. In postmortem brains, MA carriers had a lower Aβ load (p = 0.03). Global cognition was higher in MA carriers, which was found to be mediated by Aβ. Conclusions Together, these findings point to an association between CYP2C19 polymorphism and Aβ pathology, suggesting a protective effect of the MA of rs4388808. Despite the several possi- bilities in which CYP2C19 affects brain Aβ, the biological mechanism by which this genetic variation may act as a protective factor merits further investigation. From the Translational Neuroimaging Laboratory (A.L.B., S.M., T.A.P., M.S., M.-S.K., P.R.-N.), and Alzheimer’s Disease Research Unit (S.G., P.R.-N.), McGill University Research Centre for Studies in Aging, Montreal, Canada; CAPES Foundation (A.L.B.), Ministry of Education of Brazil, Bras´ılia, Brazil; Rush Alzheimer’s Disease Center (L.Y., D.A.B.), Rush University Medical Center, Chicago, IL; Department of Decision Sciences (A.L.), HEC Montreal, Montreal, Canada; Department of Epidemiology (A.L.), Biostatistics & Occupational Health, McGill University, Montreal, Canada; Department of Neurology and Neurosurgery (G.A.R., J.P., P.R.-N.), Douglas Hospital Research Centre (J.P., P.R.-N.), and Department of Psychiatry (J.P.), McGill University, Montreal, Canada; and Montreal Neurological Institute (G.A.R., P.R.-N.), Canada. Coinvestigators are listed at http://links.lww.com/NXG/A21. Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NG The Article Processing Charge was funded by the authors. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1 Glossary AA = arachidonic acid; Aβ = amyloid-β; AD = Alzheimer disease; ADNI = AD Neuroimaging Initiative; APP = amyloid precursor protein; CDR = clinical dementia rating; CN = cognitively normal; CYP = cytochrome P450; EET = epoxyeicosatrienoic acid; LD = linkage disequilibrium; MA = minor allele; MAF = minor allele frequency; MAP = Memory and Aging Project; MCI = mild cognitive impairment; MMSE = Mini-Mental State Examination; PHF = paired helical filament; p- tau = phosphorylated tau; ROS = Religious Orders Study; SNP = single nucleotide polymorphism; SUVR = standardized uptake value ratio. In sporadic Alzheimer disease (AD), accumulation of amy- operational criteria adopted for mild cognitive impairment loid-β (Aβ) seems to be associated with reduced Aβ clearance, (MCI) were participants who had an MMSE score equal to but little is known about the biochemical pathways underlying or greater than 24, a CDR of 0.5, subjective memory con- cerebral Aβ metabolism. cern, objective memory loss measured by education- adjusted scores on delayed recall of 1 paragraph from Cytochrome P450 (CYP) is a family of enzymes known to Wechsler Memory Scale Logical Memory II (≥16 years: ≤8; metabolize several endogenous and exogenous substrates. 8–15 years: ≤4; and 0–7years:≤2), and essentially normal Besides metabolizing drugs, brain CYPs are also involved in activities of daily living. Participants with AD were individ- the modulation of blood flow, metabolism of fatty acids, uals with an MMSE score lower or equal to 26, CDR higher cholesterol, and neurotransmitters, and mobilization of in- than 0.5, who met the National Institute of Neurological and – tracellular calcium,1 3 all pathways that have been somehow Communicative Disorders and Stroke–Alzheimer’sDisease linked to AD and/or amyloid metabolism. In addition, studies and Related Disorders Association criteria for probable AD. have shown that CYP proteins and their genetic variants are All individuals had absence of any other neuropsychiatric associated with the brain immune response2 and neurode- disorders. The ADNI inclusion/exclusion criteria are de- generative diseases.2,4,5 scribedindetailatadni-info.org. Although previous evidence shows CYP expression in areas Our report also used data from the Religious Orders Study affected by AD such as the amygdala, frontal and temporal (ROS) and Rush Memory and Aging Project (MAP), 2 longi- cortices, and the hippocampus,6,7 there are only a few reports tudinal clinical pathologic cohort studies of aging and documenting a link between CYPs and AD pathophysiology. dementia.11,12 All participants enrolled without known dementia In one study, the overexpression of human amyloid pre- and agreed to annual clinical and neuropsychological assess- cursor protein (APP) on the Tg2576 mice model was as- ments and brain donations after death. The clinical diagnosis of sociated with elevated CYP hepatic function, while their dementia and AD followed the National Institute of Neuro- renal counterparts were depressed.8 In addition, another logical and Communicative Disorders and Stroke–Alzheimer’s study presented evidence that Aβ stimulates NADPH- Disease and Related Disorders Association recommendations. cytochrome P450 reductase (POR), a CYP inducer, in APP The MCI diagnosis is given to participants who were rated as transgenic mice and human AD brains, which may affect the impaired based on MMSE and on the Consortium to redox status.9 Establish a Registry for Alzheimer’s Disease (CERAD) neuro- psychological measures but who were not found to have de- In line with the evidence that Aβ can stimulate metabolic cas- mentia by the examining neurologist. Our study includes only cades in a similar fashion as foreign compounds,9,10 and MCI participants with 1 impaired domain and no other cause of knowing that brain CYP could potentially affect amyloid me- cognitive impairment. Notably, the studies are conducted by the tabolism also through other mechanisms, we tested the hy- same team of investigators and share a large common core of pothesis that variants in CYP genes could be associated with Aβ testing batteries, which allow for combined analyses. and, consequently, have an impact in cognitive performance. We examined the association of CYP variants with biomarkers The discovery sample consisted of a subset of ADNI partic- of Aβ load in vivo and postmortem, as further specified. ipants who had [18F]florbetapir PET, genetic data, and CSF data available. The findings obtained with the discovery sample were then generalized to the Rush-ROS/MAP par- Methods ticipants who died at age 90 years or younger. Study participants Discovery analysis data were obtained from the AD Neu- Standard protocol approvals, registrations, roimaging Initiative (ADNI) database (adni.loni.usc.edu). and patient consents For this study, cognitively normal (CN) individuals had This secondary analysis study followed all institutional review a Mini-Mental State examination (MMSE) score of 24 or board regulations, which are detailed in the supplementary higher and a clinical dementia rating (CDR) of 0. The methods. 2 Neurology: Genetics | Volume 4, Number 1 | February 2018 Neurology.org/NG Phenotypes Cognitive function was evaluated in both the ADNI and Rush- From the ADNI, we obtained demographics, neurocognitive ROS/MAP. For the ADNI, the global cognition scores were scores, CSF, and plasmatic data available after passing rigor- developed by making a z-score of the sum of the memory and ous quality control. The preprocessed imaging and genetic the executive function composite scores. In the Rush-ROS/ data underwent additional processing and quality control MAP, the global cognitive scores were based on 17 cognitive before the statistical analysis in our study as described below. performance tests, and we included only participants who From Rush, all the data used in this project to perform sta- underwent autopsies; thus, the last valid cognitive score tistical analyses were already processed and quality controlled proximate to death was used for this analysis (for further with very rigorous criteria. details, see e-Methods, http://links.lww.com/NXG/A20). In the ADNI cohort, the brain Aβ load was estimated using We used gene expression data to examine cis expression quan- the [18F]florbetapir PET standardized uptake value ratio titative trait loci (eQTL).
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