Mutations

APP A713T

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic, Cerebral Amyloid Angiopathy : Pathogenic
Clinical Phenotype: Cerebral Amyloid Angiopathy
Genomic Mutation Name (MET1): g.275329G>A
Genomic Mutation Name (NT1): g.284025G>A
dbSNP ID: rs63750066
Coding/Non-Coding: Coding
Genomic Region: Exon 17
Mutation Type: Point, Missense
Codon Change: GCG to ACG

Findings

This mutation results in a variable/mixed clinical phenotype, with some mutation carriers exhibiting clinical and pathological features of Alzheimer's disease while others have a more complex presentation involving prominent cerebrovascular disease suggestive of cerebral amyloid angiopathy (CAA).

In one case, the proband was a 56-year-old-man with a history of progressive cognitive decline consistent with AD. Postmortem examination revealed generalized atrophy of the cerebral cortex, especially of the temporal lobes, and ventricular enlargement. In addition, widespread neurofibrillary tangles and senile plaques were observed, further supporting the diagnosis of AD (Armstrong et al., 2004).

In other mutation carriers the presentation is more complex. An Italian family has been described with a phenotype of autosomal-dominant dementia and strokes. In this pedigree, classic AD neuropathology was accompanied by features of CAA, similar to other APP pedigrees, namely the Flemish (A692G), Arctic (E693G), and Iowa (D694N) pedigrees (Rossi et al., 2004; Bernardi et al., 2009).

A French study found the A713T mutation in one of 130 people meeting NINCDS-ADRDA criteria for probable Alzheimer's disease. The individual was a 64-year-old woman who first experienced memory loss at age 59. She did not have a family history of dementia. The mutation was also found in five of her healthy family members, and therefore did not segregate with disease. The mutation was absent in 123 controls. In this case, the G>A variant was accompanied by a second G>A transition at codon 715, predicted to be silent. Because of the proximity of the two point mutations, the authors described their finding as a double point mutation (GCG.ACA.GTG to ACG.ACA.GTA) (Carter et al., 1992).

Neuropathology

In some cases, neuropathology is fairly typical of AD (e.g., Armstrong et al., 2004), whereas other cases exhibit prominent vascular involvement characteristic of CAA (e.g., Rossi et al., 2004; Bernardi et al., 2009).

Biological Effect

No change in the ratio of Aβ42/Aβ40 was observed in postmortem brain (Armstrong et al., 2004).

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References

Mutations Citations

  1. APP A692G (Flemish)
  2. APP E693G (Arctic)
  3. APP D694N (Iowa)

Paper Citations

  1. . Familial Alzheimer disease associated with A713T mutation in APP. Neurosci Lett. 2004 Nov 11;370(2-3):241-3. PubMed.
  2. . A family with Alzheimer disease and strokes associated with A713T mutation of the APP gene. Neurology. 2004 Sep 14;63(5):910-2. PubMed.
  3. . AbetaPP A713T mutation in late onset Alzheimer's disease with cerebrovascular lesions. J Alzheimers Dis. 2009;17(2):383-9. PubMed.
  4. . More missense in amyloid gene. Nat Genet. 1992 Dec;2(4):255-6. PubMed.

Further Reading

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database (single mutation) Alzheimer Disease & Frontotemporal Dementia Mutation Database (double mutation)

Primary Papers

  1. . More missense in amyloid gene. Nat Genet. 1992 Dec;2(4):255-6. PubMed.
  2. . Familial Alzheimer disease associated with A713T mutation in APP. Neurosci Lett. 2004 Nov 11;370(2-3):241-3. PubMed.

Other mutations at this position

View Table