Pathogenicity: Alzheimer's Disease : Risk Modifier
Clinical Phenotype: None
Genome Build: 105
Position: Chr14:73673178 A>G
dbSNP ID: RS17125721
Coding/Non-Coding: Coding
Genomic Region: Exon 9
Mutation Type: Point, Missense
Codon Change: GAA to GGA


This variant was initially found in patients with early onset Alzheimer's disease (e.g., Taddei et al., 2002; Albani et al., 2007), but was also identified in healthy controls and individuals with late-onset AD (e.g., Mattila et al., 1998; Dermaut et al., 1999; Aldudo et al., 1998; Zekanowski et al., 2004; Helisalmi et al., 2000). The lack of segregation with disease argues against this variant being causative for familial early onset AD, but it may be a risk factor for late-onset AD.

In a study of individuals of Spanish descent, this variant was detected in two of 176 individuals with AD and three of 139 controls (Jin et al., 2012). The cases with AD were described as having sporadic early onset AD, with onset at 56.5 and 65.5 years of age. Further clinical details were not reported. The presence of this variant in controls led the authors to classify the variant as not pathogenic.

In 2013, this mutation turned up in a study that sequenced AD-associated genes in individuals with extreme levels of Aβ and tau in their cerebral spinal fluid. Specifically, this mutation was associated with elevated levels of total tau and phosphorylated tau. Notably, in APOE ε4 allele carriers it was also associated with Aβ deposition and faster cognitive decline. Furthermore, in a large case-control series of more than 5,000 individuals, it was found that people who carried both an APOE ε4 allele and the PSEN1 E318G variant had an elevated risk of developing AD, with similar risk as people carrying two APOE ε4 alleles, and twice that of APOE ε4 carriers who did not carry E318G. The mechanism underlying the interaction of these two genetic risk factors is currently unknown.

The same study found that the E318G variant was present in 5.3 percent of the families from a large clinical series of late-onset AD families (30 out of 565 families) and exhibits a higher frequency in familial late-onset AD than in sporadic late-onset AD (Benitez et al., 2013).

In a more recent study of 72 AD cases and 58 controls, the E318G variant was detected in one individual with AD and in one control, the latter lacking significant AD neuropathology postmortem. Additional information regarding these two mutation carriers, including their ages, was not reported (Frigerio et al., 2015).


At least one mutation carrier lacked AD neuropathology (Frigerio et al., 2015).

Biological Effect



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Paper Citations

  1. . Association between presenilin-1 Glu318Gly mutation and familial Alzheimer's disease in the Australian population. Mol Psychiatry. 2002;7(7):776-81. PubMed.
  2. . Presenilin-1 mutation E318G and familial Alzheimer's disease in the Italian population. Neurobiol Aging. 2007 Nov;28(11):1682-8. PubMed.
  3. . The Glu318Gly mutation of the presenilin-1 gene does not necessarily cause Alzheimer's disease. Ann Neurol. 1998 Dec;44(6):965-7. PubMed.
  4. . The Glu318Gly substitution in presenilin 1 is not causally related to Alzheimer disease. Am J Hum Genet. 1999 Jan;64(1):290-2. PubMed.
  5. . Missense mutation E318G of the presenilin-1 gene appears to be a nonpathogenic polymorphism. Ann Neurol. 1998 Dec;44(6):985-6. PubMed.
  6. . The E318G substitution in PSEN1 gene is not connected with Alzheimer's disease in a large Polish cohort. Neurosci Lett. 2004 Mar 11;357(3):167-70. PubMed.
  7. . Is the presenilin-1 E318G missense mutation a risk factor for Alzheimer's disease?. Neurosci Lett. 2000 Jan 7;278(1-2):65-8. PubMed.
  8. . Pooled-DNA sequencing identifies novel causative variants in PSEN1, GRN and MAPT in a clinical early-onset and familial Alzheimer's disease Ibero-American cohort. Alzheimers Res Ther. 2012 Aug 20;4(4):34. PubMed.
  9. . The PSEN1, p.E318G Variant Increases the Risk of Alzheimer's Disease in APOE-ε4 Carriers. PLoS Genet. 2013 Aug;9(8):e1003685. PubMed.
  10. . On the identification of low allele frequency mosaic mutations in the brains of Alzheimer's disease patients. Alzheimers Dement. 2015 Apr 29; PubMed.

Further Reading


  1. . Presenilin 1 Glu318Gly polymorphism: interpret with caution. Arch Neurol. 2005 Oct;62(10):1624-7. PubMed.
  2. . Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update. J Med Genet. 2005 Oct;42(10):793-5. Epub 2005 Jul 20 PubMed.
  3. . Early-onset Alzheimer disease in an Italian family with presenilin-1 double mutation E318G and G394V. Alzheimer Dis Assoc Disord. 2008 Apr-Jun;22(2):184-7. PubMed.
  4. . Late onset familial Alzheimer's disease: novel presenilin 2 mutation and PS1 E318G polymorphism. J Neurol. 2008 Apr;255(4):604-6. Epub 2008 Mar 25 PubMed.
  5. . Genetic testing in familial AD and FTD: mutation and phenotype spectrum in a Danish cohort. Clin Genet. 2009 Aug;76(2):205-9. Epub 2009 Jul 29 PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Missense mutations of the PS-1/S182 gene in German early-onset Alzheimer's disease patients. Ann Neurol. 1996 Aug;40(2):265-6. PubMed.
  2. . Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Hum Mol Genet. 1998 Jan;7(1):43-51. PubMed.
  3. . Missense mutation E318G of the presenilin-1 gene appears to be a nonpathogenic polymorphism. Ann Neurol. 1998 Dec;44(6):985-6. PubMed.