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POLYMORPHISM IN CYTOCHROME P450 GENE IS ASSOCIATED WITH ALZHEIMER’S PATHOLOGY

      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-β (Aβ) 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 Aβ 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]florbetapir- SUVR, adjusting for age, sex, and ApoE-e4carriage status. Significant signals were interrogated at the voxel level using RMINC-tool, and, separately, tested for associations with CSF Aβ and Aβ/p-tau ratio. Neuropathologic data from the Rush ROS and MAP cohorts were used to generalize the findings to Aβ 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; P=0.0005), 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 Aβ (P=0.003) and higher Aβ/p-tau ratio (P=0.01). In post-mortem brains, minor-allele carriers had a lower Aβ load (P=0.04), lower PHFtau tangle density (P=0.03) as well as better episodic memory (P=0.008).

      Conclusions

      The rs4388808, an intronic variant of the CYP2C19 gene is implicated in Aβ load, tau pathology and episodic memory, where the minor-allele protects against AD pathology.
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      Figure 1Comparison between non-carriers(-) and carriers(+) of the minor allele of rs4388808 (CYP2C19). A significant difference was observed in brain amyloid load (A), CSF Aβ levels (B) and CSF Aβ/p-tau ratio (C) using ADNI cohort. Results were generalized using post-mortem data from Rush ROS and MAP cohorts, where a concordant pattern was observed in amyloid load (D), PHF-tau tangle density (E) and episodic memory scores (F). The linear models were adjusted for age, gender and ApoE-e4 carriage status.
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      Figure 2Voxel-wise comparison between minor allele non-carriers(-) and carriers(+) of the polymorphism rs4388808 of CYP2C19. A significant difference was observed in the frontal and posterior cingulate cortices, as well as in the inferior parietal cortex. The voxel-wise analysis was adjusted for age, gender and ApoE-e4 carriage status.