Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73640278 T>C
dbSNP ID: rs63749962
Coding/Non-Coding: Coding
Genomic Region: Exon 5
Mutation Type: Point, Missense
Codon Change: TAT to CAT


This mutation was first identified in a small French kindred known as Family ALZ 025 or ALZ 25. This family had two affected individuals over two generations, the proband and the proband’s father, with onset at age 35 and 37. The mutation was absent in the proband’s unaffected mother, who was cognitively healthy at age 80, and absent in 50 unrelated control subjects. The proband’s paternal grandparents were unaffected by age 75, so the authors speculated the mutation may have arisen de novo in the proband’s father (Campion et al., 1995; Campion et al., 1999). A second family, also from France, has been identified. That family, known as ALZ 76, had three affected members over three generations, with age at onset ranging from 36 to 47 years (Campion et al., 1999).

The mutation was also found in a German kindred with at least four affected individuals over two generations. The proband was a 44-year-old patient ("Patient p.39") who died severely demented after three years. The proband’s sister also died around age 40 with symptoms including epileptic seizures and myoclonus. The proband’s brother died at age 43 after a very similar disease course; autopsy confirmed AD. The proband’s mother died severely demented in her early 40s (Finckh et al., 2005).


Postmortem analysis revealed pathology consistent with AD (Finckh et al., 2005).

Biological Effect

In various cell types, mutant PSEN1 increased the levels of secreted Aβ42 and the ratio of Aβ42/Aβ40 (Murayama et al., 1999Shioi et al., 2007). Additionally, the Y115H mutation decreased the intracellular levels of AB40 and increased the intracellular levels of AB42. Notch cleavage was also reduced (Sannerud et al., 2016).


No Available Comments

Make a Comment

To make a comment you must login or register.


Paper Citations

  1. . Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. Hum Mol Genet. 1995 Dec;4(12):2373-7. PubMed.
  2. . Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.
  3. . Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics. 2005 May;6(2):85-9. Epub 2005 Mar 18 PubMed.
  4. . Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease. Neurosci Lett. 1999 Apr 9;265(1):61-3. PubMed.
  5. . FAD mutants unable to increase neurotoxic Abeta 42 suggest that mutation effects on neurodegeneration may be independent of effects on Abeta. J Neurochem. 2007 May;101(3):674-81. Epub 2007 Jan 24 PubMed.
  6. . Restricted Location of PSEN2/γ-Secretase Determines Substrate Specificity and Generates an Intracellular Aβ Pool. Cell. 2016 Jun 30;166(1):193-208. Epub 2016 Jun 9 PubMed.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.

Primary Papers

  1. . Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. Hum Mol Genet. 1995 Dec;4(12):2373-7. PubMed.

Other mutations at this position