Pathogenicity: Alzheimer's Disease : Pathogenic, Frontotemporal Dementia : Not Classified
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia
Reference Assembly: GRCh37/hg19
Position: Chr14:73640371 A>G
dbSNP ID: rs63750306
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATG to GTG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5
Research Models: 6


This mutation has been found in several families worldwide. It was first reported in three families with early onset AD known as Fin1, Man92/20, and NY5201 (Clark et al., 1995). In Fin1, a Swedish family of Finnish descent, there were three affected individuals, spanning three generations. The mean age of onset was 36 years. This family was also described in Haltia et al., 1994, and Schöll et al., 2011. In the Man92/20 family, there were two affected individuals, one with postmortem confirmation of a diagnosis of Alzheimer's disease. The mean age of onset in this family was 40 years. The third family, NY5201, had seven reported affected individuals spanning two generations, two with postmortem confirmation of the diagnosis. The mean age of onset in this family was 37 years. The mutation segregated with disease in all three families (Clark et al., 1995). Additional AD families carrying this mutation were identified by Cervenakova et al., 1996 and Rogaeva et al., 2001. In the latter report, the M146V mutation was co-inherited with a second PSEN1 mutation, S365Y.

The M146V mutation was also reported in an Argentine family with familial dementia, including 13 affected individuals spanning four generations (Riudavets et al., 2013).The family was originally from Lisbon, Portugal, then moved to Argentina in the early 20th century. In this family, the proband was a 51-year-old male who at age 39 sought medical attention due to personality changes, including apathy and disinhibition. Neuropsychological assessment revealed executive dysfunction and memory loss. He met diagnostic criteria (Lund and Manchester) for the behavioral variant of frontotemporal dementia. He developed extrapyramidal signs, including rigidity, akinesia, and movement disorders, but without tremor. Later he developed myoclonus, seizures, and mutism. Little is known about the clinical course of the disease in other affected family members, but according to relatives, the proband’s mother and five other family members died before the age of 50 with a clinical diagnosis of FTD.

This mutation was absent from two exome variant databases, EVS and ExAC (Hsu et al., 2020).


In two of the original families, Man92/20 and NY5201, there was postmortem confirmation of the diagnosis of AD, indicating neuropathology consistent with AD. In the Argentine family with a clinical presentation of FTD, autopsy of the proband was performed and detailed neuropathological findings reported (Riudavets et al., 2013). In brief, the postmortem examination revealed mainly frontal and temporal atrophy and the coexistence of both AD and Pick’s disease, including frequent Aβ deposits (CERAD Score C), occasionally with a cotton-wool appearance. Tangles were also observed (
Braak score VI). Pick bodies were seen throughout the cortex and hippocampus, sufficient for a diagnosis of Pick's disease. TDP-43-positive inclusions were absent.

Biological Effect

When expressed in HEK293 or COS-1 cells, this mutation impaired the carboxypeptidase-like γ-cleavage, but spared the endoproteolytic ε-cleavage activity of PSEN1, resulting in higher levels of secreted Aβ42 and an increased Aβ42/Aβ40 ratio (Murayama et al., 1999Li et al., 2016). An elevated Aβ42/Aβ40 ratio was also reported in mouse neuroblastoma cells which  secreted more Aβ42 and less Aβ40 than cells expressing wild-type PSEN1 (Hsu et al., 2020), as well as in neurons derived from induced pluripotent stem cells (iPSCs), which showed decreased total Aβ production and elevated levels of Aβ42 and Aβ43 in culture supernatants (Kwart et al., 2019, Aug 2019 news). M146V was also shown to promote the accumulation of APP β-C-terminal fragments which disrupt endosomes. A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicated that, in wild-type PSEN1, M146 closely contacts the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news).

Additional effects, beyond the alteration of APP processing, have been reported. For example, the mutation was found to lower wild-type PSEN1 gene expression in neuronal-like cells (Ahmadi and Wade-Martins, 2014). It also has been reported to inhibit store-operated calcium channel activity in human neuroblastoma SK-N-SH cells (Ryazantseva et al., 2013), and in hippocampal neurons from the PSEN1(M146V) knock-in mouse model, which results in loss of dendritic spines (Sun et al., 2014). Moreover, the mutation appears to increase calcineurin activity, impairing synaptic trafficking of glutamate AMPA receptors in mouse primary hippocampal neurons (Kim et al., 2015).

The mutation has also been reported to alter trophic factor function and cerebral blood flow. In cortical neuronal cultures from PSEN1(M146V) Knock-In mice, the mutant protein appeared to inhibit the neuroprotective functions of trophic factors eB1 and BDNF following glutamate excitotoxicity (Al Rahim et al., 2020). The effect was reported as dominant-negative, with mutant PSEN1 altering the stability of complexes formed between PSEN1, the glutamate NMDA receptor, and trophic factor receptors. Moreover, in brains from knock-in mice, the ability of cortical endothelial cells to sprout and form new blood vessels after ischemia was decreased, apparently due to reduced γ-secretase cleavage of the angiogenic peptide ephrinB2 (Yoon et al., 2020). Compromised cerebrovascular function in response to the potassium channel opener diazoxide was also reported in these mice (Liu et al., 2020).

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve) predicted this variant is damaging (Xiao et al., 2021Hsu et al., 2020). Based on their bioinformatic data, together with the genetic data and the authors' in vitro data on Aβ42 and Aβ40 production, Hsu and colleagues classified the mutation as probably pathogenic.

Research Models

This mutation was been introduced into several mouse models, including a knock-in animal, PSEN1(M146V) Knock-In; a transgenic, PS1(M146V); and a multi-transgenic, 3xTg. It has also been introduced into human induced pluripotent stem cells using CRISPR/Cas9 to generate heterozygous and homozygous cell lines (Paquet et al., 2016).

Last Updated: 13 Sep 2021


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Research Models Citations

  1. PSEN1(M146V) Knock-In
  2. PS1(M146V)
  3. 3xTg

News Citations

  1. Familial AD Mutations, β-CTF, Spell Trouble for Endosomes
  2. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. . Efficient introduction of specific homozygous and heterozygous mutations using CRISPR/Cas9. Nature. 2016 May 5;533(7601):125-9. Epub 2016 Apr 27 PubMed.
  2. . The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nat Genet. 1995 Oct;11(2):219-22. PubMed.
  3. . Chromosome 14-encoded Alzheimer's disease: genetic and clinicopathological description. Ann Neurol. 1994 Sep;36(3):362-7. PubMed.
  4. . Time course of glucose metabolism in relation to cognitive performance and postmortem neuropathology in Met146Val PSEN1 mutation carriers. J Alzheimers Dis. 2011;24(3):495-506. PubMed.
  5. . Identification of presenilin-1 gene point mutations in early-onset Alzheimer's disease families. Am J Hum Genet. 1996;59(Suppl):A252
  6. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  7. . Familial Dementia With Frontotemporal Features Associated With M146V Presenilin-1 Mutation. Brain Pathol. 2013 Mar 14; PubMed.
  8. . Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.
  9. . 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.
  10. . Effect of Presenilin Mutations on APP Cleavage; Insights into the Pathogenesis of FAD. Front Aging Neurosci. 2016;8:51. Epub 2016 Mar 11 PubMed.
  11. . 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.
  12. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  13. . Familial Alzheimer's disease coding mutations reduce Presenilin-1 expression in a novel genomic locus reporter model. Neurobiol Aging. 2014 Feb;35(2):443.e5-443.e16. PubMed.
  14. . Familial Alzheimer's disease-linked presenilin-1 mutation M146V affects store-operated calcium entry: does gain look like loss?. Biochimie. 2013 Jul;95(7):1506-9. PubMed.
  15. . Reduced synaptic STIM2 expression and impaired store-operated calcium entry cause destabilization of mature spines in mutant presenilin mice. Neuron. 2014 Apr 2;82(1):79-93. PubMed.
  16. . Reduction of increased calcineurin activity rescues impaired homeostatic synaptic plasticity in presenilin 1 M146V mutant. Neurobiol Aging. 2015 Dec;36(12):3239-46. Epub 2015 Sep 18 PubMed.
  17. . Presenilin1 familial Alzheimer disease mutants inactivate EFNB1- and BDNF-dependent neuroprotection against excitotoxicity by affecting neuroprotective complexes of N-methyl-d-aspartate receptor. Brain Commun. 2020;2(2):fcaa100. Epub 2020 Jul 20 PubMed.
  18. . PS1 FAD mutants decrease ephrinB2-regulated angiogenic functions, ischemia-induced brain neovascularization and neuronal survival. Mol Psychiatry. 2020 Jun 15; PubMed.
  19. . Age-related impairment of cerebral blood flow response to KATP channel opener in Alzheimer's disease mice with presenilin-1 mutation. J Cereb Blood Flow Metab. 2020 Nov 17;:271678X20964233. PubMed.
  20. . 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.

Other Citations

  1. S365Y

Further Reading


  1. . Predicting Cognitive Decline across Four Decades in Mutation Carriers and Non-carriers in Autosomal-Dominant Alzheimer's Disease. J Int Neuropsychol Soc. 2017 Mar;23(3):195-203. Epub 2017 Jan 12 PubMed.
  2. . Presenilin 1 mutations influence processing and trafficking of the ApoE receptor apoER2. Neurobiol Aging. 2017 Jan;49:145-153. Epub 2016 Oct 11 PubMed.
  3. . miR-342-5p decreases ankyrin G levels in Alzheimer's disease transgenic mouse models. Cell Rep. 2014 Jan 30;6(2):264-70. Epub 2014 Jan 16 PubMed.
  4. . Endogenous expression of FAD-linked PS1 impairs proliferation, neuronal differentiation and survival of adult hippocampal progenitors. Mol Neurodegener. 2013 Oct 20;8(1):41. PubMed.
  5. . Longitudinal cognitive decline in autosomal-dominant Alzheimer's disease varies with mutations in APP and PSEN1 genes. Neurobiol Aging. 2019 Oct;82:40-47. Epub 2019 Jul 4 PubMed.

Protein Diagram

Primary Papers

  1. . The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nat Genet. 1995 Oct;11(2):219-22. PubMed.

Other mutations at this position


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