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
Mutation Type: Point, Missense
Codon Change: GCG to GAG
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 7
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 cultured cells, this mutation is associated with an increase in the Aβ42/Aβ total ratio (Murayama et al., 1999) and the Aβ42/Aβ40 ratio (Borchelt et al., 1996). In differentiating neural precursor cells and neurons derived from patient iPSCs, elevations in Aβ42 secretion, Aβ42/Aβ40 ratio, and phospho-tau were reported (Mahairaki et al., 2014; Yang et al., 2017; Armijo et al., 2017). The Aβ42/Aβ40 ratio was also elevated in the brains of young transgenic mice co-expressing PSEN1 A246E and APP with the Swedish mutation (APPSwe/PSEN1(A246E)) compared with mice either expressing APPSwe alone or co-expressing wild-type PSEN1 with APPSwe (Borchelt et al., 1996). In vitro experiments with isolated proteins recapitulated the elevated Aβ42/Aβ40 ratio observed in cells and animals, but revealed a dramatic decrease in the production of both Aβ peptides (Sun et al., 2017).

The mutation also appears to impair cellular health in several ways. The viability of iPSC-derived neurons dropped more dramatically than that of controls after exposure to increasing concentrations of Aβ42 oligomers (Armijo et al., 2017). In addition, premature neuronal differentiation with decreased proliferation and increased apoptosis was observed in neural precursor cells derived from patient iPSCs (Yang et al., 2017). The authors note that the differentiation alteration may be mediated, at least in part, by disruption of the Wnt-Notch pathway. Impairments in autophagy, mitophagy, and lysosomal functions were also reported in patient cells (Coffey et al., 2014; Martin-Maestro et al., 2017). Moreover, the A246E mutant was reported to abolish the activity of a calcium leak channel in the endoplasmic reticulum in patient fibroblasts (Nelson et al., 2007).

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). In addition, iPSC lines have been generated from mutation carriers (Mahairaki et al., 2014; Yang et al., 2017; Armijo et al., 2017; Muñoz et al., 2018).

Last Updated: 22 Mar 2019


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Research Models Citations

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

Paper Citations

  1. . 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.
  2. . Early pathogenic event of Alzheimer's disease documented in iPSCs from patients with PSEN1 mutations. Oncotarget. 2017 Jan 31;8(5):7900-7913. PubMed.
  3. . Increased susceptibility to Aβ toxicity in neuronal cultures derived from familial Alzheimer's disease (PSEN1-A246E) induced pluripotent stem cells. Neurosci Lett. 2017 Feb 3;639:74-81. Epub 2016 Dec 26 PubMed.
  4. . Generation and characterization of human induced pluripotent stem cell lines from a familial Alzheimer's disease PSEN1 A246E patient and a non-demented family member bearing wild-type PSEN1. Stem Cell Res. 2018 Aug;31:227-230. Epub 2018 Aug 13 PubMed.
  5. . Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995 Jun 29;375(6534):754-60. PubMed.
  6. . A family with histologically confirmed Alzheimer's disease. Arch Neurol. 1983 Apr;40(4):203-8. PubMed.
  7. . 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.
  8. . 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.
  9. . Presenilin 1 mutations in Polish families with early-onset Alzheimer's disease. Folia Neuropathol. 2004;42(1):9-14. PubMed.
  10. . Genetic study of familial cases of Alzheimer's disease. Acta Biochim Pol. 2004;51(1):245-52. PubMed.
  11. . 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.
  12. . 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.
  13. . Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron. 1996 Nov;17(5):1005-13. PubMed.
  14. . 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.
  15. . 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.
  16. . Mitophagy Failure in Fibroblasts and iPSC-Derived Neurons of Alzheimer's Disease-Associated Presenilin 1 Mutation. Front Mol Neurosci. 2017;10:291. Epub 2017 Sep 14 PubMed.
  17. . Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1. J Clin Invest. 2007 May;117(5):1230-9. Epub 2007 Apr 12 PubMed.

Further Reading


  1. . Self-Organizing 3D Human Neural Tissue Derived from Induced Pluripotent Stem Cells Recapitulate Alzheimer's Disease Phenotypes. PLoS One. 2016;11(9):e0161969. Epub 2016 Sep 13 PubMed.
  2. . Effect of potent γ-secretase modulator in human neurons derived from multiple presenilin 1-induced pluripotent stem cell mutant carriers. JAMA Neurol. 2014 Dec;71(12):1481-9. PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

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.

Other mutations at this position


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