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

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 variant was subsequently identified in one out of 515 Finnish individuals over age 85. Although the woman who carried the A673T variant had 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).

In 2012, the A673T variant was reported in an American woman with a family history of late-onset AD. The proband was originally reported as having late-onset AD, but a later study corrected the classification to unaffected at age 84. Of the 17 family members genotyped, only the proband's mother carried the variant. Like her daughter, she was cognitively healthy into advanced age. Although residing the United States, this family had Scandinavian ancestry (Cruchaga et al., 2012; Wang et al., 2014).

The A673T variant may be restricted primarily to Icelandic and Scandinavian populations. In Icelandic individuals the frequency of the A673T variant was reported as 0.13 percent in AD cases and 0.45 to 0.79 percent in controls. In other control cohorts, frequencies were reported as Norwegian (0.21 percent), Finnish (0.51 percent), and Swedish (0.42 percent) (Jonsson et al., 2012). Recent studies have shown that A673T is extremely rare in Caucasian individuals from the United States and may not play a substantial role in risk of AD in this population. Specifically, it was absent in 1,674 cases with late-onset AD and 2,644 elderly control subjects (Bamne et al., 2014). Another large genotyping study found just three heterozygous Caucasian individuals in North America. Of these, two were cognitively healthy at the ages of 77 and 82, and the third carrier, who was of Russian ancestry, developed AD at the age of 89. Therefore, the study reported a carrier frequency of 0.011 percent in American individuals with AD and 0.018 percent in cognitively normal controls. The same study also identified three heterozygous individuals in a Swedish cohort. All were cognitively healthy at the ages of 55, 59, and 72, respectively. Like Jonsson et al., 2012, this study also found a carrier frequency of 0.42 percent for Swedish controls (Wang et al., 2014).

The A673T variant may also be extremely 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

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).

Comments

Make a Comment

To make a comment you must login or register.

Comments on this content

No Available Comments

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. . Rarity of the Alzheimer Disease-Protective APP A673T Variant in the United States. JAMA Neurol. 2014 Dec 22; PubMed.
  6. . 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.
  7. . 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.
  8. . Absence of A673T variant in APP gene indicates an alternative protective mechanism contributing to longevity in Chinese individuals. Neurobiol Aging. 2013 Oct 12; PubMed.
  9. . The Alzheimer disease protective mutation A2T modulates kinetic and thermodynamic properties of amyloid-β (Aβ) aggregation. J Biol Chem. 2014 Nov 7;289(45):30977-89. Epub 2014 Sep 24 PubMed.
  10. . Molecular mechanisms of Alzheimer disease protection by the A673T allele of amyloid precursor protein. J Biol Chem. 2014 Nov 7;289(45):30990-1000. Epub 2014 Sep 24 PubMed.
  11. . 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

Learn More

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

View Table