title: 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.
authors.affiliation: Department of Psychiatry, School of Medicine, Washington University, St Louis, Missouri, United States of America.
authors.forename: Bruno A
authors.initials: BA
authors.lastname: Benitez
authors.forename: Celeste M
authors.initials: CM
authors.lastname: Karch
authors.forename: Yefei
authors.initials: Y
authors.lastname: Cai
authors.forename: Sheng Chih
authors.initials: SC
authors.lastname: Jin
authors.forename: Breanna
authors.initials: B
authors.lastname: Cooper
authors.forename: David
authors.initials: D
authors.lastname: Carrell
authors.forename: Sarah
authors.initials: S
authors.lastname: Bertelsen
authors.forename: Lori
authors.initials: L
authors.lastname: Chibnik
authors.forename: Julie A
authors.initials: JA
authors.lastname: Schneider
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fagan
authors.forename: David
authors.initials: D
authors.lastname: Holtzman
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D053764:Presenilin-1 / Q000235:genetics*; D016875:tau Proteins / Q000134:cerebrospinal fluid / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; C508853:PSEN1 protein, human; D053764:Presenilin-1; D016875:tau Proteins