Pathogenicity: Alzheimer's Disease : Pathogenic, Frontotemporal Dementia : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia
Reference Assembly: GRCh37 (105)
Position: Chr14:73640371 A>G
dbSNP ID: rs63750306
Coding/Non-Coding: Coding
Genomic Region: Exon 5
Mutation Type: Point, Missense
Codon Change: ATG to GTG
Research Models: 6


This mutation was first reported in three families known as Fin1, Man92/20 and NY5201 (Clark et al., 1995). In Fin1, a Swedish family of Finnish descent, there were three affected individuals reported over 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 Man92/20 there were two affected individuals reported, 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 over 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).

The M146V mutation was found in one individual with AD, but no further details were provided, other than that it was co-inherited with a second PSEN1 mutation, S365Y (Rogaeva et al., 2001).

This mutation was also reported in Cervenakova et al., 1996.

More recently, the M146V mutation was reported in an Argentine family with familial dementia with 13 affected individuals over 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.


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). Additionally, the mutation affects store-operated calcium channel activity in human neuroblastoma SK-N-SH cells, specifically, causing inhibition (Ryazantseva et al., 2013).

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.


No Available Comments

Make a Comment

To make a comment you must login or register.


Research Models Citations

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

Mutations Citations

  1. PSEN1 S365Y

Paper Citations

  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.
  2. . Chromosome 14-encoded Alzheimer's disease: genetic and clinicopathological description. Ann Neurol. 1994 Sep;36(3):362-7. PubMed.
  3. . 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.
  4. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. 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. . Familial Dementia With Frontotemporal Features Associated With M146V Presenilin-1 Mutation. Brain Pathol. 2013 Mar 14; PubMed.
  7. . 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.
  8. . Effect of Presenilin Mutations on APP Cleavage; Insights into the Pathogenesis of FAD. Front Aging Neurosci. 2016;8:51. Epub 2016 Mar 11 PubMed.
  9. . 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.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

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


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.