Mutations

APP A673T

Overview

Pathogenicity: Alzheimer's Disease : Protective
Clinical Phenotype: None
Genomic Mutation Name (MET1): g.269505G>A
Genomic Mutation Name (NT1): g.278201G>A
dbSNP ID: rs63750847
Coding/Non-Coding: Coding
Genomic Region: Exon 16
Mutation Type: Point, Missense
Codon Change: GCA to ACA

Findings

This variant was first identified in a Caucasian individual who died at age 65 with a history of ischemic strokes but was cognitively intact. Postmortem examination was unremarkable, revealing negligible amyloid deposition in the brain parenchyma and cerebral vessels (Peacock et al., 1993). Decades later, this rare variant was found to be significantly more common in nondemented elderly individuals than in those with Alzheimer’s disease. Specifically, dementia-free elderly individuals were five times likelier to carry this variant than people with AD. Therefore, A673T is thought to represent the first example of an APP variant that confers protection against AD. The variant was also found to protect against age-associated cognitive decline (Jonsson et al., 2012).

Although the possible protective effect of A673T was first suggested in an Icelandic population, it was subsequently identified in one woman out of 515 Finnish individuals aged 85 and older in a population-based study. Although she was demented at age 104, her impairment was attributed to hippocampal sclerosis rather than to AD. Her brain contained very little amyloid pathology (CERAD=0), although some vascular amyloid was detected in meningeal arteries. The minimal amyloid pathology in this A673T carrier, and her exceptional longevity, further supports a protective role for A673T against amyloid pathology and AD (Kero et al., 2013).

This variant was additionally reported in one European family with one affected carrier, but further details were not available. It was predicted benign by PolyPhen-2 and classified by the authors as nonpathogenic (Cruchaga et al., 2012).

The overall frequency of the A673T variant is not known, nor whether it is associated with particular ethnicities or geographic regions. The variant was absent in a screen of Caucasian individuals from North America (1,674 with late-onset AD and 2,644 elderly control subjects) (Bamne et al., 2014). It may be particularly rare in Asian populations. It was absent in a screen of 8,721 Asian individuals (Ting et al., 2013), as well as in 1,237 long-lived Chinese individuals (mean age 96.9 years) (Liu et al., 2013).

Neuropathology

This variant is associated with minimal amyloid deposition and is thought to protect against amyloid pathology.

Biological Effect

A673T corresponds to position 2 in Aβ. In vitro, this protective mutation was found to lower the formation of amyloidogenic peptides by approximately 40 percent (Jonsson et al., 2012). In addition, it may attenuate Aβ-independent neurotoxicity; the neuronal death induced by TGFβ2 in cells expressing wild-type APP was not observed in cells expressing APP with the A673T mutation (Hashimoto et al., 2014). Note: The position A673T in isoform 770 corresponds to position A598T in isoform 695, the most abundant neuronal isoform of APP.

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References

Paper Citations

  1. . Novel polymorphism in the A4 region of the amyloid precursor protein gene in a patient without Alzheimer's disease. Neurology. 1993 Jun;43(6):1254-6. PubMed.
  2. . A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature. 2012 Aug 2;488(7409):96-9. PubMed.
  3. . Amyloid precursor protein (APP) A673T mutation in the elderly Finnish population. Neurobiol Aging. 2013 May;34(5):1518.e1-3. PubMed.
  4. . Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families. PLoS One. 2012;7(2):e31039. PubMed.
  5. . Investigation of an amyloid precursor protein protective mutation (A673T) in a North American case-control sample of late-onset Alzheimer's disease. Neurobiol Aging. 2014 Jul;35(7):1779.e15-6. Epub 2014 Jan 23 PubMed.
  6. . Absence of A673T amyloid-β precursor protein variant in Alzheimer's disease and other neurological diseases. Neurobiol Aging. 2013 Oct;34(10):2441.e7-8. PubMed.
  7. . Absence of A673T variant in APP gene indicates an alternative protective mechanism contributing to longevity in Chinese individuals. Neurobiol Aging. 2013 Oct 12; PubMed.
  8. . A mutation protective against Alzheimer's disease renders amyloid β precursor protein incapable of mediating neurotoxicity. J Neurochem. 2014 Jul;130(2):291-300. Epub 2014 Apr 10 PubMed.

Further Reading

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Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Novel polymorphism in the A4 region of the amyloid precursor protein gene in a patient without Alzheimer's disease. Neurology. 1993 Jun;43(6):1254-6. PubMed.
  2. . A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature. 2012 Aug 2;488(7409):96-9. PubMed.

Other mutations at this position

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