Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73659517 C>G
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATC to ATG
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 7


This mutation was identified in an African-American woman diagnosed with probable Alzheimer’s disease who had a family history of AD/dementia. Her presentation was fairly typical of AD, starting with short-term memory loss, poor concentration, an inability to multitask, and increased anxiety. These symptoms began at age 50 and gradually progressed to multiple cognitive domains and impairment of activities of daily living. This patient was enrolled in the ongoing longitudinal study, the Dominantly Inherited Alzheimer Network (DIAN).

The patient's father was diagnosed with AD in his late 50s and died at the age of 65. Her paternal aunt and grandmother also died with dementia, but age of onset and age at death were not known.

It was not possible to confirm disease segregation in this family, as DNA was not available from other affected members (who were all deceased) or unaffected members of the family. Probable pathogenicity was suspected based on the early onset of symptoms, the family history of dementia, the absence of the mutation in more than 2,000 African-Americans screened in the NHLBI GO sequencing project, and the demonstrated in vitro effects on Aβ levels (Ting et al., 2014).


Unknown; MRI showed progressive cerebral atrophy. PET showed hypometabolism in the frontal and temporal lobes.

Biological Effect

When expressed in HEK293 cells expressing APP with the Swedish mutation, the mutant PSEN1 increased Aβ40, Aβ42, and the Aβ42/Aβ40 ratio compared with cells expressing wild-type PSEN1 (Ting et al., 2014; see also Ringman et al., 2011). However, in an in vitro assay using purified proteins to test the mutant's ability to cleave the APP-C99 substrate, the mutation appeared to abrogate production of both Aβ40 and Aβ42 (Sun et al., 2017).

Last Updated: 30 Oct 2019


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Paper Citations

  1. . A novel PSEN1 mutation (I238M) associated with early-onset Alzheimer's disease in an African-American woman. J Alzheimers Dis. 2014;40(2):271-5. PubMed.
  2. . Biochemical, neuropathological, and neuroimaging characteristics of early-onset Alzheimer's disease due to a novel PSEN1 mutation. Neurosci Lett. 2011 Jan 10;487(3):287-92. Epub 2010 Nov 19 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.

External Citations

  1. the Dominantly Inherited Alzheimer Network (DIAN)
  2. NHLBI GO sequencing project

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A novel PSEN1 mutation (I238M) associated with early-onset Alzheimer's disease in an African-American woman. J Alzheimers Dis. 2014;40(2):271-5. PubMed.

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