APP A692G (Flemish)


Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genome Build: 105
Position: Chr21:27264170 C>G
dbSNP ID: rs63750671
Coding/Non-Coding: Coding
Genomic Region: Exon 17
Mutation Type: Point, Missense
Codon Change: GCA to GGA


This mutation was first reported in a four-generation Flemish pedigree. Affected individuals were diagnosed with Alzheimer's disease or cerebral hemorrhage associated with cerebral amyloid angiopathy. The mean age at onset in this family was 45.7 ± 7.3 years (Hendriks et al., 1992).

A second pedigree of three generations was reported with five affected individuals. Dementia was the primary clinical feature in these patients. The proband also had a cerebral hemorrhage, but other affected family members did not. Neuropathologic examination confirmed AD, congophilic angiopathy, and hemorrhagic infarction. In this family, dementia onset ranged from 39 to 54 years of age (Brooks et al., 2004).


The Flemish mutation is associated with variable pathology, but generally involves amyloid deposition in the blood vessels of the brain. Many plaques were described as containing large amyloid cores, often more than 30 microns in diameter and surrounded by dystrophic neurites (Cras et al., 1998). In contrast to the amyloid deposits observed in many familial AD cases, deposits in patients with the Flemish mutation contain primarily Aβ40 (Kumar-Singh et al., 2002).

Biological Effect

The A692G mutation falls within the Aβ region of APP. It is also called A21G because it affects the 21st amino acid in the Aβ sequence. In vitro it has been shown to increase levels of secreted Aβ42 and Aβ40, approximately two- to fourfold (Haass et al., 1994; De Jonghe et al., 1998).

Aβ peptides carrying the Flemish mutation have relatively low aggregation propensity in vitro, including dimerization (Murakami et al., 2002; Meinhardt et al., 2007; Huet et al., 2006). Conformational changes are thought to explain the Flemish mutation's inhibitory effect on self-assembly and nucleation. However, fibril formation was promoted through interaction with gangliosides in the vascular wall, which may partly explain the propensity of Flemish Aβ to deposit in the vasculature (Yamamoto et al., 2005; Yagi-Utsumi and Dobson 2015).

The Flemish mutation falls within a region of APP shown to inhibit the production of Aβ42 by γ-secretase. Specifically, the Flemish mutation occurs within the amino acid sequence LVFFAED, which, when deleted, increases the relative production of Aβ40 10-fold (Tian et al., 2010). This effect was attenuated by the Flemish mutation substitution, which alters secondary structure in the vicinity (Tang et al., 2014).


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Paper Citations

  1. . Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the beta-amyloid precursor protein gene. Nat Genet. 1992 Jun;1(3):218-21. PubMed.
  2. . Hemorrhage is uncommon in new Alzheimer family with Flemish amyloid precursor protein mutation. Neurology. 2004 Nov 9;63(9):1613-7. PubMed.
  3. . Presenile Alzheimer dementia characterized by amyloid angiopathy and large amyloid core type senile plaques in the APP 692Ala-->Gly mutation. Acta Neuropathol. 1998 Sep;96(3):253-60. PubMed.
  4. . Dense-core senile plaques in the Flemish variant of Alzheimer's disease are vasocentric. Am J Pathol. 2002 Aug;161(2):507-20. PubMed.
  5. . Mutations associated with a locus for familial Alzheimer's disease result in alternative processing of amyloid beta-protein precursor. J Biol Chem. 1994 Jul 1;269(26):17741-8. PubMed.
  6. . Flemish and Dutch mutations in amyloid beta precursor protein have different effects on amyloid beta secretion. Neurobiol Dis. 1998 Oct;5(4):281-6. PubMed.
  7. . Synthesis, aggregation, neurotoxicity, and secondary structure of various A beta 1-42 mutants of familial Alzheimer's disease at positions 21-23. Biochem Biophys Res Commun. 2002 May 31;294(1):5-10. PubMed.
  8. . Similarities in the thermodynamics and kinetics of aggregation of disease-related Abeta(1-40) peptides. Protein Sci. 2007 Jun;16(6):1214-22. PubMed.
  9. . Impact of the mutation A21G (Flemish variant) on Alzheimer's beta-amyloid dimers by molecular dynamics simulations. Biophys J. 2006 Nov 15;91(10):3829-40. PubMed.
  10. . Assembly of hereditary amyloid beta-protein variants in the presence of favorable gangliosides. FEBS Lett. 2005 Apr 11;579(10):2185-90. PubMed.
  11. . Conformational Effects of the A21G Flemish Mutation on the Aggregation of Amyloid β Peptide. Biol Pharm Bull. 2015;38(10):1668-72. PubMed.
  12. . An APP inhibitory domain containing the Flemish mutation residue modulates gamma-secretase activity for Abeta production. Nat Struct Mol Biol. 2010 Feb;17(2):151-8. PubMed.
  13. . Conformational changes induced by the A21G Flemish mutation in the amyloid precursor protein lead to increased Aβ production. Structure. 2014 Mar 4;22(3):387-96. Epub 2014 Jan 23 PubMed.

Further Reading


  1. . Presentation of amyloidosis in carriers of the codon 692 mutation in the amyloid precursor protein gene (APP692). Brain. 2000 Oct;123 ( Pt 10):2130-40. PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the beta-amyloid precursor protein gene. Nat Genet. 1992 Jun;1(3):218-21. PubMed.