Pathogenicity: Alzheimer's Disease : Pathogenic, Atypical Dementia : Pathogenic
Clinical Phenotype: Atypical Dementia
Reference Assembly: GRCh37 (105)
Position: Chr14:73685863 C>G
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CTC to GTC
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 12


This mutation was documented in a young woman presenting with an early onset dementia syndrome with a complex clinical phenotype. At the age of 26 she developed symptoms of anorexia nervosa, followed by memory and attention deficits by age 30. Four years later she had developed changes in personality and behavior, including impulsivity and aggression. Her condition deteriorated, and she developed aphasia, stereotyped behaviors, myoclonus, and seizures. Possible diagnoses of Huntington's disease and sporadic Creutzfeldt-Jakob disease were considered and excluded. Her symptoms were indicative of frontal dysfunction reminiscent of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). No family members were affected by early onset dementia, although her maternal grandfather developed dementia after age 80. Segregation of the mutation with disease could not be assessed, but it was absent in 178 unrelated individuals (Robles et al., 2009).


Unknown. CT and SPECT imaging showed diffuse cortical and subcortical atrophy as well as hypoperfusion affecting the frontal, temporal, and parietal lobes.

Biological Effect

Compared with wild-type PSEN1, this mutation increased both Aβ40 and Aβ42 production, and doubled the Aβ42/Aβ40 ratio as assessed by in vitro assays using isolated proteins (Bai et al., 2015; Sun et al., 2017).

Last Updated: 21 May 2019


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Paper Citations

  1. . Clinical picture of a patient with a novel PSEN1 mutation (L424V). Am J Alzheimers Dis Other Demen. 2009 Feb-Mar;24(1):40-5. PubMed.
  2. . An atomic structure of human γ-secretase. Nature. 2015 Sep 10;525(7568):212-7. Epub 2015 Aug 17 PubMed.
  3. . 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.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Clinical picture of a patient with a novel PSEN1 mutation (L424V). Am J Alzheimers Dis Other Demen. 2009 Feb-Mar;24(1):40-5. PubMed.

Other mutations at this position


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