Overview

Pathogenicity: Alzheimer's Disease : Protective
Clinical Phenotype: None
Reference Assembly: GRCh37 (105)
Position: Chr21:27269932 G>A
dbSNP ID: rs63750847
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GCA to ACA
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 16

Findings

A673T is the first variant in APP associated with protection against amyloid pathology and Alzheimer's disease. This variant appears to be restricted primarily to Icelandic and Scandinavian populations.

The A673T variant 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., 2015).

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., 2015).

In contrast to other Nordic populations, the A673T variant may be rare in Denmark. It was present in only 1 of 3,487 Danish individuals (0.014 percent), precluding an assessment of association with longevity or cognitive functioning (Mengel-From et al., 2015). 

The A673T variant appears to 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 A673T 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 not yet clear whether this reduced aggregation is primarily due to effects on Aβ40, Aβ42, or both (see Benilova et al., 2014; Maloney et al., 2014). A recent study using ion mobility-mass spectrometry showed that Aβ42 with the A2T mutation formed dimers, tetramers, and hexamers, but dodecamer formation was inhibited. In contrast no significant effects on Aβ40 assembly were observed (Zheng et al., 2015)

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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References

Paper Citations

1. Peacock ML Jr, Warren JT, Roses AD, Fink JK. 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. Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, Stefansson H, Sulem P, Gudbjartsson D, Maloney J, Hoyte K, Gustafson A, Liu Y, Lu Y, Bhangale T, Graham RR, Huttenlocher J, Bjornsdottir G, Andreassen OA, Jönsson EG, Palotie A, Behrens TW, Magnusson OT, Kong A, Thorsteinsdottir U, Watts RJ, Stefansson K. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature. 2012 Aug 2;488(7409):96-9. PubMed.
3. Kero M, Paetau A, Polvikoski T, Tanskanen M, Sulkava R, Jansson L, Myllykangas L, Tienari PJ. Amyloid precursor protein (APP) A673T mutation in the elderly Finnish population. Neurobiol Aging. 2013 May;34(5):1518.e1-3. PubMed.
4. Cruchaga C, Chakraverty S, Mayo K, Vallania FL, Mitra RD, Faber K, Williamson J, Bird T, Diaz-Arrastia R, Foroud TM, Boeve BF, Graff-Radford NR, St Jean P, Lawson M, Ehm MG, Mayeux R, Goate AM, . 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. Wang LS, Naj AC, Graham RR, Crane PK, Kunkle BW, Cruchaga C, Murcia JD, Cannon-Albright L, Baldwin CT, Zetterberg H, Blennow K, Kukull WA, Faber KM, Schupf N, Norton MC, Tschanz JT, Munger RG, Corcoran CD, Rogaeva E, Alzheimer's Disease Genetics Consortium, Lin CF, Dombroski BA, Cantwell LB, Partch A, Valladares O, Hakonarson H, St George-Hyslop P, Green RC, Goate AM, Foroud TM, Carney RM, Larson EB, Behrens TW, Kauwe JS, Haines JL, Farrer LA, Pericak-Vance MA, Mayeux R, Schellenberg GD, National Institute on Aging-Late-Onset Alzheimer’s Disease (NIA-LOAD) Family Study, Albert MS, Albin RL, Apostolova LG, Arnold SE, Barber R, Barmada MM, Barnes LL, Beach TG, Becker JT, Beecham GW, Beekly D, Bennett DA, Bigio EH, Bird TD, Blacker D, Boeve BF, Bowen JD, Boxer A, Burke JR, Buxbaum JD, Cairns NJ, Cao C, Carlson CS, Carroll SL, Chui HC, Clark DG, Cribbs DH, Crocco EA, DeCarli C, DeKosky ST, Demirci FY, Dick M, Dickson DW, Duara R, Ertekin-Taner N, Fallon KB, Farlow MR, Ferris S, Frosch MP, Galasko DR, Ganguli M, Gearing M, Geschwind DH, Ghetti B, Gilbert JR, Glass JD, Graff-Radford NR, Growdon JH, Hamilton RL, Hamilton-Nelson KL, Harrell LE, Head E, Honig LS, Hulette CM, Hyman BT, Jarvik GP, Jicha GA, Jin LW, Jun G, Kamboh MI, Karydas A, Kaye JA, Kim R, Koo EH, Kowall NW, Kramer JH, Kramer P, LaFerla FM, Lah JJ, Leverenz JB, Levey AI, Li G, Lieberman AP, Lopez OL, Lunetta KL, Lyketsos CG, Mack WJ, Marson DC, Martin ER, Martiniuk F, Mash DC, Masliah E, McCormick WC, McCurry SM, McDavid AN, McKee AC, Mesulam MM, Miller BL, Miller CA, Miller JW, Montine TJ, Morris JC, Murrell JR, Olichney JM, Parisi JE, Perry W, Peskind E, Petersen RC, Pierce A, Poon WW, Potter H, Quinn JF, Raj A, Raskind M, Reiman EM, Reisberg B, Reitz C, Ringman JM, Roberson ED, Rosen HJ, Rosenberg RN, Sano M, Saykin AJ, Schneider JA, Schneider LS, Seeley WW, Smith AG, Sonnen JA, Spina S, Stern RA, Tanzi RE, Thornton-Wells TA, Trojanowski JQ, Troncoso JC, Tsuang DW, Van Deerlin VM, Van Eldik LJ, Vardarajan BN, Vinters HV, Vonsattel JP, Weintraub S, Welsh-Bohmer KA, Williamson J, Wishnek S, Woltjer RL, Wright CB, Younkin SG, Yu CE, Yu L. Rarity of the Alzheimer disease-protective APP A673T variant in the United States. JAMA Neurol. 2015 Feb;72(2):209-16. PubMed.
6. Bamne MN, Demirci FY, Berman S, Snitz BE, Rosenthal SL, Wang X, Lopez OL, Kamboh MI. 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. Mengel-From J, Jeune B, Pentti T, McGue M, Christensen K, Christiansen L. The APP A673T frequency differs between Nordic countries. Neurobiol Aging. 2015 Oct;36(10):2909.e1-4. Epub 2015 Jul 11 PubMed.
8. Ting SK, Chong MS, Kandiah N, Hameed S, Tan L, Au WL, Prakash KM, Pavanni R, Lee TS, Foo JN, Bei JX, Yu XQ, Liu JJ, Zhao Y, Lee WL, Tan EK. 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.
9. Liu YW, He YH, Zhang YX, Cai WW, Yang LQ, Xu LY, Kong QP. Absence of A673T variant in APP gene indicates an alternative protective mechanism contributing to longevity in Chinese individuals. Neurobiol Aging. 2013 Oct 12; PubMed.
10. Benilova I, Gallardo R, Ungureanu AA, Castillo Cano V, Snellinx A, Ramakers M, Bartic C, Rousseau F, Schymkowitz J, De Strooper B. 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.
11. Maloney JA, Bainbridge T, Gustafson A, Zhang S, Kyauk R, Steiner P, van der Brug M, Liu Y, Ernst JA, Watts RJ, Atwal JK. 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.
12. Zheng X, Liu D, Roychaudhuri R, Teplow DB, Bowers MT. Amyloid β-Protein Assembly: Differential Effects of the Protective A2T Mutation and Recessive A2V Familial Alzheimer's Disease Mutation. ACS Chem Neurosci. 2015 Oct 21;6(10):1732-40. Epub 2015 Aug 12 PubMed.
13. Hashimoto Y, Matsuoka M. 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

1. Alzheimer Disease & Frontotemporal Dementia Mutation Database