Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659540 C>A
dbSNP ID: rs63750526
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: 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.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).


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

PSEN1 A246E affects APP processing in several ways. Early studies in cultured cells showed it 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 induced pluripotent stem cells (iPSCs), elevations in Aβ42 and Aβ43 secretion, Aβ42/Aβ40 ratio, Aβ aggregate formation, and phospho-tau were reported (Mahairaki et al., 2014; Yang et al., 2017; Armijo et al., 2017; Kwart et al., 2019; Schrank et al., 2020, Vanova et al., 2023). 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 (Sun et al., 2017). (This study also found the production of both Aβ42 and Aβ40 to be robustly reduced, but others have noted limitations to this assay (Liu et al., 2021)). 

Moreover, a comprehensive analysis of Aβ peptides produced by mouse embryonic fibroblasts expressing the variant on a PSEN null background and transduced with human APP-C99 showed this mutation decreased the Aβ (37 + 38 + 40) / (42 + 43) ratio (Petit et al., 2022, Apr 2022 news). This ratio was reported to outperform the Aβ42/Aβ40 ratio as an indicator of AD pathogenicity and correlate with AD age at onset.

In addition to affecting Aβ peptide production, A246E promotes the accumulation of APP β-C-terminal fragments (β-CTFs) which appears to disrupt endosomes (Kwart et al., 2019, Aug 2019 news). Enlarged endosomes and altered expression of genes involved in endocytic vesicle pathways were observed in iPSC-derived neurons. This phenotype correlated with β-CTF, but not Aβ, levels.

Studies using APP substrates with photosensitive cross-linkable amino acids revealed the mutant likely causes mispositioning of the APP C99 cleavage domain (Fukumori and Steiner, 2016; Trambauer et al., 2020). In particular, altered cross-linking at T48 and L49, the initial substrate cleavage sites of C99, was reported. Moreover, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that this residue is apposed to the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news). Also, in silico modeling of the structure of the mutant PSEN1 predicted a reduced distance between transmembrane domains 6 and 7 which could impair the interaction between APP and the PSEN1 active site (Soto-Ospina et al., 2021).

Interestingly, this variant may also fuel tau pathology. Injection of exosomes from neurons derived from patient induced pluripotent stem cells (iPSCs) were reported to induce tau deposits in mouse brains (Podvin et al., 2021; see also Hook et al., 2023). Their protein cargo differed from that of non-carrier exosomes, including increased levels of APP, and altered levels of phosphatases and kinases involved in regulating tau phosphorylation.

Also of note, this mutation appears to impair cellular health in multiple ways. For example, 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, several studies suggest A246E alters neuronal development. 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 noted that this may be mediated, at least in part, by disruption of the Wnt-Notch pathway. Another study using iPSC neurons reported dedifferentiation associated with changes in histone methylation, transcriptional signatures of the non-ectoderm lineage, and cell cycle reentry (Caldwell et al., 2020). Yet another study, using cerebral organoids derived from patient iPSCs and single-cell RNAseq, revealed faster maturation of mutant organoids with limited tissue patterning (Vanova et al., 2023). The authors noted these defects may result in inadequate stimulation of neural progenitor differentiation leading to premature neuronal differentiation and lower diversity in cell populations. 

Impairments in autophagy, mitophagy, lysosomal functions, and signaling associated with cellular stress, were also reported in patient cells (Coffey et al., 2014; Martin-Maestro et al., 2017, Lopez-Toledo et al., 2022). Moreover, the mutant appears to disrupt intracellular calcium dynamics. PSEN1 has been reported to act as a passive calcium leak channel in the endoplasmic reticulum, and the A246E mutant was reported to abolish this activity in mouse embryonic fibroblasts and primary fibroblasts from a patient (Nelson et al., 2007). Additionally, iPSC-derived neurons were found to release elevated levels of calcium from the endoplasmic reticulum in response to ryanodine receptor stimulation, a response that was normalized by incubation with dantrolene, a negative allosteric modulator (Schrank et al., 2020). 

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021).


Alzheimer's Disease : Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.


Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.


Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. A246E: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.


Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.


Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. A246E: At least one family with >=3 affected carriers and >=1 unaffected noncarriers.


Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.


Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Research Models

Several research models expressing this mutation have been generated. Mouse models of disease include the double mutant mice APP(V717I) x PS1(A246E) and APPSwe/PSEN1(A246E). In addition, induced pluripotent stem cell (iPSC) lines have been generated from mutation carrier cells (Mahairaki et al., 2014; Yang et al., 2017; Armijo et al., 2017; Muñoz et al., 2018; Caldwell et al., 2020Podvin et al., 2021; Raska et al., 2021), and CRISPR technology has been used to generate a collection of isogenic iPSCs with familial AD mutations, including A246E (Kwart et al., 2019). Also, three-dimensional cell culture models that recapitulate Aβ aggregation and elevated tau phosphorylation have been created using mutant iPSC-derived neurons (Raja et al., 2016Hernández-Sapiéns et al., 2020). Interestingly, neuronal cell models have been generated directly from adult fibroblasts (Chou et al., 2023, Sun et al., 2023Jun 2023 news). Unlike neurons differentiated from induced pluripotent stem cells, these transdifferentiated neurons, called tNeurons, retain epigenetic marks of aging.

Last Updated: 21 Dec 2023


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Research Models Citations

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

News Citations

  1. Better Cell Model? Transdifferentiated Neurons Capture AD-Like Changes
  2. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?
  3. Familial AD Mutations, β-CTF, Spell Trouble for Endosomes
  4. CryoEM γ-Secretase Structures Nail APP, Notch Binding

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. . Dedifferentiation and neuronal repression define familial Alzheimer's disease. Sci Adv. 2020 Nov;6(46) Print 2020 Nov PubMed.
  6. . Mutant Presenilin 1 Dysregulates Exosomal Proteome Cargo Produced by Human-Induced Pluripotent Stem Cell Neurons. ACS Omega. 2021 May 25;6(20):13033-13056. Epub 2021 May 13 PubMed.
  7. . Generation of six human iPSC lines from patients with a familial Alzheimer's disease (n = 3) and sex- and age-matched healthy controls (n = 3). Stem Cell Res. 2021 May;53:102379. Epub 2021 Apr 30 PubMed.
  8. . A Large Panel of Isogenic APP and PSEN1 Mutant Human iPSC Neurons Reveals Shared Endosomal Abnormalities Mediated by APP β-CTFs, Not Aβ. Neuron. 2019 Oct 23;104(2):256-270.e5. Epub 2019 Aug 12 PubMed.
  9. . 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.
  10. . A Three-Dimensional Alzheimer's Disease Cell Culture Model Using iPSC-Derived Neurons Carrying A246E Mutation in PSEN1. Front Cell Neurosci. 2020;14:151. Epub 2020 Jun 12 PubMed.
  11. . Proteostasis and lysosomal quality control deficits in Alzheimer's disease neurons. 2023 Mar 27 10.1101/2023.03.27.534444 (version 1) bioRxiv.
  12. . Endogenous recapitulation of Alzheimers disease neuropathology through human 3D direct neuronal reprogramming. 2023 May 25 10.1101/2023.05.24.542155 (version 1) bioRxiv.
  13. . Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995 Jun 29;375(6534):754-60. PubMed.
  14. . A family with histologically confirmed Alzheimer's disease. Arch Neurol. 1983 Apr;40(4):203-8. PubMed.
  15. . 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.
  16. . 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.
  17. . Presenilin 1 mutations in Polish families with early-onset Alzheimer's disease. Folia Neuropathol. 2004;42(1):9-14. PubMed.
  18. . Genetic study of familial cases of Alzheimer's disease. Acta Biochim Pol. 2004;51(1):245-52. PubMed.
  19. . 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.
  20. . 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.
  21. . 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.
  22. . Human-Induced Neurons from Presenilin 1 Mutant Patients Model Aspects of Alzheimer's Disease Pathology. Int J Mol Sci. 2020 Feb 4;21(3) PubMed.
  23. . Cerebral organoids derived from patients with Alzheimer's disease with PSEN1/2 mutations have defective tissue patterning and altered development. Cell Rep. 2023 Nov 28;42(11):113310. Epub 2023 Oct 20 PubMed.
  24. . 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.
  25. . Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides. J Biol Chem. 2021;296:100393. Epub 2021 Feb 8 PubMed.
  26. . Aβ profiles generated by Alzheimer's disease causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset. Mol Psychiatry. 2022 Jun;27(6):2821-2832. Epub 2022 Apr 1 PubMed.
  27. . Substrate recruitment of γ-secretase and mechanism of clinical presenilin mutations revealed by photoaffinity mapping. EMBO J. 2016 Aug 1;35(15):1628-43. Epub 2016 May 23 PubMed.
  28. . Aβ43-producing PS1 FAD mutants cause altered substrate interactions and respond to γ-secretase modulation. EMBO Rep. 2020 Jan 7;21(1):e47996. Epub 2019 Nov 25 PubMed.
  29. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  30. . Protein Predictive Modeling and Simulation of Mutations of Presenilin-1 Familial Alzheimer's Disease on the Orthosteric Site. Front Mol Biosci. 2021;8:649990. Epub 2021 Jun 2 PubMed.
  31. . Emerging evidence for dysregulated proteome cargoes of tau-propagating extracellular vesicles driven by familial mutations of tau and presenilin. Extracell Vesicles Circ Nucl Acids. 2023;4(4):588-598. Epub 2023 Nov 21 PubMed.
  32. . 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.
  33. . 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.
  34. . Patient-Derived Fibroblasts With Presenilin-1 Mutations, That Model Aspects of Alzheimer's Disease Pathology, Constitute a Potential Object for Early Diagnosis. Front Aging Neurosci. 2022;14:921573. Epub 2022 Jul 1 PubMed.
  35. . 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.
  36. . APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

External Citations

  1. gnomAD v2.1.1

Further Reading


  1. . 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.
  2. . The effect of citalopram treatment on amyloid-β precursor protein processing and oxidative stress in human hNSC-derived neurons. Transl Psychiatry. 2022 Jul 18;12(1):285. PubMed.
  3. . Endotype reversal as a novel strategy for screening drugs targeting familial Alzheimer's disease. Alzheimers Dement. 2022 Jan 27; PubMed.
  4. . Carvedilol suppresses ryanodine receptor-dependent Ca2+ bursts in human neurons bearing PSEN1 variants found in early onset Alzheimer's disease. 2023 Sep 16 10.1101/2023.09.15.558029 (version 1) bioRxiv.

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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