Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73664825 C>G
dbSNP ID: rs63751235
Coding/Non-Coding: Coding
Genomic Region: Exon 8
Mutation Type: Point, Missense
Codon Change: CTC to GTC
Research Models: 4


The L286V mutation was first identified in a German kindred in conjunction with the cloning of the PSEN1 gene in 1995 (Sherrington et al., 1995). The family, known as FAD2, was described previously to include 21 individuals affected by Alzheimer disease, three with an autopsy-confirmed diagnosis. Dementia was often accompanied by extrapyramidal features and myoclonus. Ancestors were traced through seven generations and the inheritance pattern was observed to be consistent with autosomal-dominant transmission (Frommelt et al., 1991).

More than a decade later, this mutation was reported in a Japanese individual with a family history of early onset dementia (Ikeuchi et al., 2008). The proband, P2712, experienced symptom onset at age 47. His pedigree included five affected individuals over three generations, all of whom displayed progressive memory impairment consistent with a clinical diagnosis of AD.


Neuropathology consistent with AD in at least three affected members of the FAD2 pedigree (Frommelt et al., 1991).

Biological Effect

In HEK-293 cells transfected with APP with the Swedish mutation, the L286V mutation was found to increase the Aβ42/Aβ total ratio (Citron et al., 1997; Kulic et al., 2000). A similar effect was seen in COS-1 cells transfected with APP695; compared with cells expressing wild-type PSEN1, the L286V mutation increased the Aβ42/Aβ total ratio (Murayama et al., 1999). It did not appear to affect Notch endoproteolysis (Kulic et al., 2000; Ikeuchi et al., 2008).

Research Models

This pathogenic mutation is one of five introduced into the popular 5xFAD model of AD. The model also contains the PSEN1 mutation M146L (A>C) and three mutations in APP (Swedish, Florida, and London).


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Research Models Citations

  1. 5xFAD

Mutations Citations

  1. PSEN1 M146L (A>C)
  2. APP KM670/671NL (Swedish)
  3. APP I716V (Florida)
  4. APP V717I (London)

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. . Familial Alzheimer disease: a large, multigeneration German kindred. Alzheimer Dis Assoc Disord. 1991;5(1):36-43. PubMed.
  3. . Mutational analysis in early-onset familial dementia in the Japanese population. The role of PSEN1 and MAPT R406W mutations. Dement Geriatr Cogn Disord. 2008;26(1):43-9. Epub 2008 Jun 28 PubMed.
  4. . Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nat Med. 1997 Jan;3(1):67-72. PubMed.
  5. . Separation of presenilin function in amyloid beta-peptide generation and endoproteolysis of Notch. Proc Natl Acad Sci U S A. 2000 May 23;97(11):5913-8. PubMed.
  6. . 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

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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