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.

Alzheimer’s Disease Genetics: From the Bench to the Clinic

“…For example, the PSEN2 variants, R62H and R71W, failed to show perfect segregation with AD status but were found to be associated with a lower age at onset. The hypothesis that variants in APP , PSEN1 and PSEN2 may serve as risk factors for AD is further supported by a later study in which next-generation sequencing technologies and biomarker levels were combined to identify additional risk variants (Benitez et al, 2013). PSEN1 E318G (rs17125721) was previously classified as non-pathogenic because it does not segregate with disease status in some families (Lindquist et al, 2009; Sandbrink et al, 1996).…”

“…Additional variants have been described in PSEN1 and PSEN2 that are non-pathogenic or whose pathogenicity remains unclear. Recent evidence suggests that some of these variants, such as PSEN1 E318G (Benitez et al, 2013) and PSEN2 R62H (Cruchaga et al, 2012a), may represent risk factors for AD (described below).…”

“…PSEN1 E318G (rs17125721) was previously classified as non-pathogenic because it does not segregate with disease status in some families (Lindquist et al, 2009; Sandbrink et al, 1996). This coding variant was strongly associated with CSF total Tau and pTau181 levels (Benitez et al, 2013). Analyses in case control series demonstrated that in APOEε4 carriers, PSEN1-E318G is associated with a 10-fold increase in risk of developing AD and an earlier age at onset of AD (Benitez et al, 2013).…”

Alzheimer’s Disease Risk Genes and Mechanisms of Disease Pathogenesis

“…: APP E599K) (26, 29). A polymorphism in PSEN1 , PSEN1 E318G, is associated with a 10-fold increase in LOAD risk in APOE4 carriers (27). Additionally, rare coding variants in ADAM10 , the major α-secretase involved in shedding of the APP ectodomain (30), co-segregate in seven LOAD families (8, 31).…”

Genetic studies of quantitative MCI and AD phenotypes in ADNI: Progress, opportunities, and plans

“…Other studies have related genes to cognition following the discovery of a primary association with a non-cognitive phenotype, including ASTND2 (astrotactin 2) and GRIN2B (glutamate receptor, ionotropic, N-methyl D-aspartate 2B) with hippocampal and temporal lobe atrophy on MRI [83, 84], PSEN1 (presenilin 1) with CSF amyloid levels [85], and DAT1 with AD case-control status [40]. Alternatively, pathway analysis has been used to elucidate collective effects of multiple genes on memory [86], executive functioning [87], and depressive symptoms [88].…”