Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73659540 C>A
dbSNP ID: rs63750526
Coding/Non-Coding: Coding
Genomic Region: Exon 7
Mutation Type: Point, Missense
Codon Change: GCG to GAG
Research Models: 4


This mutation was originally reported in 1995 in conjunction with the cloning of the PSEN1 gene (Sherrington et al., 1995). It was detected in a Canadian family of Anglo Saxon-Celtic origin known as FAD1. This pedigree is remarkable for its size and detail. It describes 531 individuals over eight generations and includes 52 affected family members (see Nee et al., 1983). The pattern of transmission is consistent with autosomal-dominant inheritance, and genetic analysis confirmed that the mutation segregated with disease. 

Thirty-nine members of the family were assessed at the NIH, and pathology was available for a subset of these. Clinical findings and pathology were consistent with AD. Diagnostic criteria for AD included: 1) insidious onset of memory disorder, intellectual dysfunction, and disintegration of social interaction and personal habits; 2) a gradually progressive course of failure in these functions for a minimum of 12 months; 3) exclusion of known reversible causes of dementia; and 4) the absence of stroke-like neurological episodes or deficits. The average age of onset in this family was 53 years, with a mean duration of six years.

The A246E was later found in a Polish patient from a pedigree called W.T. The patient met diagnostic criteria for probable AD according to NINCDS-ADRDA criteria (McKhann et al., 1984), with onset around age 50. He was thought to have autosomal dominant early onset AD; a parent and two siblings were also affected by dementia. Segregation could not be assessed (Kowalska et al., 2003; Kowalska et al., 2004). See Kowalska et al., 2004b for pedigree.


Postmortem data are available for several members of the FAD1 family. Generalized atrophy was present, most prominently in the frontal lobes and hippocampus. Neuronal loss was observed, as well as gliosis, neurofibrillary tangles, and plaques. Pick bodies were not seen. Autopsy of a presymptomatic carrier of the A246E mutation was reported to have accumulation of progranulin in the brain in addition to amyloid plaques (Gliebus et al., 2009).

Biological Effect

In vitro, this mutation is associated with an increase in the Aβ42/Aβ total ratio (Murayama et al., 1999).

Research Models

This mutation has been introduced into mouse models of disease, including the double mutant mice APP(V717I) x PS1(A246E) and APPSwe/PSEN1(A246E).


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Research Models Citations

  1. APP(V717I) x PS1(A246E)
  2. APPSwe/PSEN1(A246E)

Paper Citations

  1. . Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995 Jun 29;375(6534):754-60. PubMed.
  2. . A family with histologically confirmed Alzheimer's disease. Arch Neurol. 1983 Apr;40(4):203-8. PubMed.
  3. . Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984 Jul;34(7):939-44. PubMed.
  4. . Molecular genetics of Alzheimer's disease: presenilin 1 gene analysis in a cohort of patients from the Poznań region. J Appl Genet. 2003;44(2):231-4. PubMed.
  5. . Presenilin 1 mutations in Polish families with early-onset Alzheimer's disease. Folia Neuropathol. 2004;42(1):9-14. PubMed.
  6. . Genetic study of familial cases of Alzheimer's disease. Acta Biochim Pol. 2004;51(1):245-52. PubMed.
  7. . Progranulin and beta-amyloid distribution: a case report of the brain from preclinical PS-1 mutation carrier. Am J Alzheimers Dis Other Demen. 2009 Dec-2010 Jan;24(6):456-60. PubMed.
  8. . 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.

Further Reading


  1. . Lysosomal alkalization and dysfunction in human fibroblasts with the Alzheimer's disease-linked presenilin 1 A246E mutation can be reversed with cAMP. Neuroscience. 2014 Mar 28;263:111-24. Epub 2014 Jan 10 PubMed.
  2. . Induced pluripotent stem cells from familial Alzheimer's disease patients differentiate into mature neurons with amyloidogenic properties. Stem Cells Dev. 2014 Dec 15;23(24):2996-3010. PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

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Primary Papers

  1. . Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995 Jun 29;375(6534):754-60. PubMed.

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