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P2‐093: Polymorphism in Cytochrome P450 Gene is Associated with Alzheimer’s Pathology
Author(s) -
Benedet Andrea Lessa,
Yu Lei,
Labbe Aurelie,
Mathotaarachchi Sulantha S.,
Shin Monica,
Pascoal Tharick A.,
Kang Min-Su,
Beaudry Thomas,
Gauthier Serge,
Bennett David A.,
Rosa-Neto Pedro
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.1298
Subject(s) - posterior cingulate , minor allele frequency , single nucleotide polymorphism , apolipoprotein e , medicine , biology , alzheimer's disease , alzheimer's disease neuroimaging initiative , endocrinology , neuroscience , pathology , genetics , genotype , cortex (anatomy) , gene , disease
IS ASSOCIATEDWITH ALZHEIMER’S PATHOLOGY Andrea Lessa Benedet, Lei Yu, Aurelie Labbe, Sulantha S. Mathotaarachchi, Monica Shin, Tharick A. Pascoal, Min-Su Kang, Thomas Beaudry, Serge Gauthier, David A. Bennett, Pedro Rosa-Neto, Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Montreal, QC, Canada; Rush University Medical Center, Chicago, IL, USA; McGill University, Montreal, QC, Canada; 4 McGill University Research Centre for Studies in Aging, Verdun, QC, Canada; 5 Translational Neuroimaging Laboratory-McGill University, Verdun, QC, Canada; Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging-McGill University, Montreal, QC, Canada; 7 McGill Centre for Studies in Aging, Montreal, QC, Canada; 8 Douglas Hospital Research Centre, Verdun, QC, Canada. Contact e-mail: tharick.alipascoal@mail. mcgill.ca Background:The cytochromes P450 (CYP) are known for their role in metabolizing several endogenous and exogenous substrates. In the brain, they modulate blood-flow regulation, metabolize cholesterol, and participate in neuroinflammatory processes. CYP activity is also implicated in Alzheimer’s disease (AD), particularly in amyloid-b (Ab) accumulation in CSF. We examined whether genetic polymorphisms of CYP are associated with AD pathology. Methods: [18F]florbetapir-PET imaging was employed to assess brain Ab levels in 256 subjects from a discovery cohort (ADNI: 186CN, 105 lMCI, 47AD). Linear regression models examined the association of 30 SNPs from four genes of CYP (CYP3A4, CYP2C9, CYP2C19 and CYP1A1) with global [18F]florbetapirSUVR, adjusting for age, sex, and ApoE-e4carriage status. Significant signals were interrogated at the voxel level using RMINCtool, and, separately, tested for associations with CSF Ab and Ab/p-tau ratio. Neuropathologic data from the Rush ROS and MAP cohorts were used to generalize the findings to Ab load and PHFtau tangle density by immunocytochemistry in post-mortem brains (302 CN, 180 aMCI, 259 AD). Results: The analysis of [18F]florbetapir identified an intronic variant in the CYP2C19 gene (rs4388808; P1⁄40.0005), in which carriers of the minor-allele (G) had lower global SUVR (Figure 1). The voxel-wise analysis showed a significant effect of the SNP in the frontal and posterior cingulate cortices, as well as in the inferior parietal cortex (Figure 2). Carriers of the minor-allele were also associated with higher CSF Ab (P1⁄40.003) and higher Ab/p-tau ratio (P1⁄40.01). In postmortem brains, minor-allele carriers had a lower Ab load (P1⁄40.04), lower PHFtau tangle density (P1⁄40.03) as well as better episodic memory (P1⁄40.008). Conclusions: The rs4388808, an intronic variant of the CYP2C19 gene is implicated in Ab load, tau pathology and episodic memory, where the minor-allele protects against AD pathology.