The PSEN1, p.E318G variant increases the risk of Alzheimer's disease in APOE-ε4 carriers

Abstract

The primary constituents of plaques (Aβ42/Aβ40) and neurofibrillary tangles (tau and phosphorylated forms of tau [ptau]) are the current leading diagnostic and prognostic cerebrospinal fluid (CSF) biomarkers for AD. In this study, we performed deep sequencing of APP, PSEN1, PSEN2, GRN, APOE and MAPT genes in individuals with extreme CSF Aβ42, tau, or ptau levels. One known pathogenic mutation (PSEN1 p.A426P), four high-risk variants for AD (APOE p.L46P, MAPT p.A152T, PSEN2 p.R62H and p.R71W) and nine novel variants were identified. Surprisingly, a coding variant in PSEN1, p.E318G (rs17125721-G) exhibited a significant association with high CSF tau (p = 9.2 × 10(-4)) and ptau (p = 1.8 × 10(-3)) levels. The association of the p.E318G variant with Aβ deposition was observed in APOE-ε4 allele carriers. Furthermore, we found that in a large case-control series (n = 5,161) individuals who are APOE-ε4 carriers and carry the p.E318G variant are at a risk of developing AD (OR = 10.7, 95% CI = 4.7-24.6) that is similar to APOE-ε4 homozygous (OR = 9.9, 95% CI = 7.2.9-13.6), and double the risk for APOE-ε4 carriers that do not carry p.E318G (OR = 3.9, 95% CI = 3.4-4.4). The p.E318G variant is present in 5.3% (n = 30) of the families from a large clinical series of LOAD families (n = 565) and exhibited a higher frequency in familial LOAD (MAF = 2.5%) than in sporadic LOAD (MAF = 1.6%) (p = 0.02). Additionally, we found that in the presence of at least one APOE-ε4 allele, p.E318G is associated with more Aβ plaques and faster cognitive decline. We demonstrate that the effect of PSEN1, p.E318G on AD susceptibility is largely dependent on an interaction with APOE-ε4 and mediated by an increased burden of Aβ deposition.

Figure 1. Distribution of PSEN1 p.E318G mutation carriers in CSF Biomarker quartiles.

A. CSF tau, Logistic regression model p = 6.0×10⁻⁴. B. CSF pTau, Logistic regression model p = 3.0×10⁻⁴. C. CSF Aβ42, Logistic regression model p = 0.38. White bars represent the number of non carriers. Black bars represent the number of carriers D. Association of PSEN1 gene with CSF tau. E. Association of PSEN1 gene with CSF ptau. F. Association of PSEN1 gene with CSF Aβ42. Plots are showing the most significant SNP at a given locus along with the combined-analysis results for SNPs in the region surrounding it (typically ±500 kb). Symbols are colored according to the LD of the SNP with the top SNP (r² color-based insert). The red line represents the threshold for significance. The light blue line represents the estimated recombination rate. G. LD Block for the most significant SNP associated with biomarker levels at PSEN1 genomic region: SNP rs76342307 based on the 1000 genome project for Europeans. Gene annotations are shown as dark green lines. H. LD Block for rs76342307 and rs17125721 in our own data set. I. Plot after the conditional analysis including both SNPs (rs76342307 and rs17125721) in the model.

Figure 2. Distribution of biomarker levels in PSEN1 p.E318G and APOE carriers.

Distribution of the covariate-adjusted residuals of the CSF tau, ptau, Aβ42, Tau∶Aβ42 and ptau∶Aβ42 ratio. A. APOE ε4 positive/PSEN1 p.E318G carriers and. B. APOE ε4 negative/PSEN1 p.E318G carriers. C. Forest plot of the odd ratios of the effect of PSEN1 p.E318G in APOE ε4 heterozygous. D. Pedigrees for some of the families with p.E318G carriers illustrating the segregation analysis and the presence of APOE ε4 allele. A/G or A/A is the genotype for p.E318G variant. 2/3, 3/3, 3/4, 4/4 is the APOE genotype. * Symbol means confirmed AD by autopsy. Δ Symbol indicates probable AD diagnosed using NINCDS-ADRDA criteria.