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


A673T is the first variant in APP associated with protection against amyloid pathology and Alzheimer's disease.

It was first reported in a Caucasian individual who died at the age of 65 with a history of ischemic stroke, but in good cognitive health. Postmortem examination revealed negligible cerebral amyloid in the parenchyma and vessels (Peacock et al., 1993). Two decades later, this rare variant was reported to be more prevalent in non-demented elderly Icelandic individuals than in those with Alzheimer’s disease. Specifically, the A673T variant was five times more common in dementia-free elderly individuals than in people with AD. The A673T variant was also found to protect against age-associated cognitive decline (Jonsson et al., 2012).

The A673T mutation was subsequently identified in one out of 515 Finnish individuals over age 85. Although the woman who carried the A673T variant did have dementia at the age of 104, her impairment was attributed to hippocampal sclerosis rather than to AD. Overall, her brain contained very little amyloid pathology (CERAD=0), although some vascular amyloid was observed in her meningeal arteries. The minimal amyloid pathology in this A673T carrier, along with her longevity, is regarded as further evidence supporting a protective effect of A673T against amyloid pathology and the development of AD (Kero et al., 2013).

This variant was additionally reported in one European family with a history of late-onset AD. The proband in this family was a mutation carrier and had AD, but further clinical details and postmortem evaluation were not available (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).


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

Biological Effect

The A673 residue of APP lies very near the primary β-secretase site, and after cleavage, the residue becomes part of the Aβ peptide. Recent in vitro studies suggest that the A673T mutation may reduce amyloid accumulation via effects on both APP and Aβ. Several studies have shown that this variant makes APP a less-favorable substrate for β-secretase, resulting in less Aβ production overall. In addition, the Aβ peptides that are generated are less prone to aggregation.

When overexpressed in HEK293 cells, APP with the A673 mutation produced about 40 percent less Aβ40 and Aβ42 than wild-type APP (Jonsson et al., 2012). Additional β-secretase cleavage products, such as sAPP-β and β-CTF, were likewise reduced. This effect was subsequently confirmed in primary mouse neurons expressing human APP (isoform 695) with A673T (Benilova et al., 2014; Maloney et al., 2014) and in iPSC-derived human neurons (Maloney et al., 2014).

In addition to lowering Aβ production, the A673T mutation lowers Aβ aggregation. The mutant Aβ, referred to as A2T because it corresponds to position 2 in Aβ, is less aggregation-prone than wild-type Aβ. It is currently unclear whether this reduction in aggregation is primarily due to effects on Aβ40, Aβ42, or both (see Benilova et al., 2014; Maloney et al., 2014).

The A673T variant does not appear to attenuate Aβ toxicity. At a range of concentrations, the neuronal toxicity associated with mutant Aβ40 and Aβ42 was comparable to wild-type Aβ peptides (Maloney et al., 2014). However, there is some evidence that the A673T variant may reduce Aβ-independent neurotoxicity. Neurons expressing APP with the A673T mutation were resistant to TGFβ2-induced cell death (Hashimoto et al., 2014).

Note: The residue A673T in isoform 770 corresponds to A598T in isoform 695, and the mutation is sometimes referred to by the name A598T (e.g., Hashimoto et al., 2014).


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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.

Other Citations

  1. Benilova et al., 2014

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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