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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.

The PSEN1, p.E318G Variant Increases the Risk of Alzheimer's Disease in APOE-ε4 Carriers