Pathogenicity: Alzheimer's Disease : Pathogenic, Cerebral Amyloid Angiopathy : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Cerebral Amyloid Angiopathy
Reference Assembly: GRCh37 (105)
Position: Chr14:73683837 G>A
dbSNP ID: rs63750323
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GGA to GAA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 11


The G378E mutation has been detected in families of French, German, Japanese, and Chinese ancestry. It is associated with a clinical presentation typical for early onset Alzheimer’s disease.

The French pedigree reported four affected individuals over three generations. The proband first developed symptoms at age 34, beginning as memory impairment, but rapidly expanding to other cognitive domains. The mean age at onset in the family was 35 years with a mean age at death of 39 years. The mutation segregated with disease in this family. It was present in two affected individuals and two at-risk individuals who were below the mean onset age, but it was absent in a healthy family member aged 69. It was also absent in 50 unrelated controls (Besançon et al., 1998).

This mutation was also found in two purportedly unrelated German patients with early onset AD, reported as p.53 and p.44. Patient p.53 developed dementia in his 30s and died at age 52 with autopsy-confirmed AD. His mother died at age 39 with dementia. Patient p.44 was diagnosed with AD at age 42, onset age unknown. Her brother and mother were also affected, and both died at age 43 (Finckh et al., 2005).

A Japanese pedigree reported as P283 includes two affected individuals over two generations. The average age at onset in this family is 40 years and the proband met NINCDS-ADRDA criteria for probable AD. The proband was noted to have a clinical phenotype typical of AD, principally characterized by progressive memory loss. Segregation with disease could not be assessed due to lack of DNA from family members other than the proband. No mutations in APP, PSEN2, or MAPT were detected in the proband and the mutation was absent from 100 chromosomes of healthy Japanese people (Ikeuchi et al., 2008).

In addition, the mutation was reported in six of 17 members of a Chinese family. Five of the mutation carriers were diagnosed with dementia, while one was clinically normal, but under onset age. The mutation was absent in 10 patients with sporadic AD and 100 healthy subjects (Cao et al., 2014).


Neuropathological analysis of one affected family member from each of the French and German families revealed neuropathology consistent with AD. The German case also had notable cerebral amyloid angiopathy (CAA) (Finckh et al., 2005; Besançon et al., 1998).

Biological Effect

When co-expressed in HEK-293 expressing human APP with the Swedish mutation, the mutant presenilin-1 was associated with elevated secreted Aβ42 and an elevated Aβ42/Aβ40 ratio compared with cells expressing wild-type presenilin-1 (Ikeuchi et al., 2008). Consistent with this finding, an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed increased Aβ42 and decreased Aβ40 production, with a corresponding increase in the Aβ42/Aβ40 ratio (Sun et al., 2017). The mutation did not appear to affect γ-secretase cleavage of Notch, as NICD production was unchanged (Ikeuchi et al., 2008).

A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that G378 forms part of one of two PSEN1 β-strands induced by APP binding. These strands, together with an APP β-strand, form a hybrid, three-stranded β–sheet that appears to be indispensable for cleavage (Zhou et al., 2019; Jan 2019 news).

Last Updated: 09 Aug 2019


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News Citations

  1. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. . Missense mutation in exon 11 (Codon 378) of the presenilin-1 gene in a French family with early-onset Alzheimer's disease and transmission study by mismatch enhanced allele specific amplification. Mutations in brief no. 141. Online. besancon@rockefeller1. Hum Mutat. 1998;11(6):481. PubMed.
  2. . Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics. 2005 May;6(2):85-9. Epub 2005 Mar 18 PubMed.
  3. . Mutational analysis in early-onset familial dementia in the Japanese population. The role of PSEN1 and MAPT R406W mutations. Dement Geriatr Cogn Disord. 2008;26(1):43-9. Epub 2008 Jun 28 PubMed.
  4. . [Study of mutations of presenilin 1 gene in early-onset familial Alzheimers disease]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2014 Jun;31(3):298-301. PubMed.
  5. . Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.
  6. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Other Citations

  1. Swedish mutation

Further Reading


  1. . Comparative study of microRNA profiling in one Chinese Family with PSEN1 G378E mutation. Metab Brain Dis. 2018 Oct;33(5):1711-1720. Epub 2018 Jul 1 PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Missense mutation in exon 11 (Codon 378) of the presenilin-1 gene in a French family with early-onset Alzheimer's disease and transmission study by mismatch enhanced allele specific amplification. Mutations in brief no. 141. Online. besancon@rockefeller1. Hum Mutat. 1998;11(6):481. PubMed.

Other mutations at this position


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