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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.
[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).
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).
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.