Overview

Pathogenicity: Alzheimer's Disease : Protective
Clinical Phenotype: None
Reference Assembly: GRCh37/hg19
Position: Chr21:27269932 G>A
dbSNP ID: rs63750847
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCA to ACA
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 16
Research Models: 1

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.

Cortical biopsies from three Finnish carriers with idiopathic normal pressure hydrocephalus (iNPH)—a condition whose treatment involves biopsy collection—showed no detectable Aβ, phospho-tau, or p62 pathology (Wittrahm et al., 2023). Importantly, approximately 50 percent of iNPH patients have AD-related brain pathology. Moreover, the three carriers had decreased levels of soluble APPβ (sAPPβ) and Aβ42 in cerebrospinal fluid (CSF) compared with those of three matched non-carriers. Although decreased Aβ42 levels in CSF can be associated with AD, in this case, they likely reflect reduced production of Aβ peptides (see Biological Effect below).

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. In vitro studies suggest that the A673T mutation may reduce amyloid accumulation via effects on both APP and Aβ. Although results vary, several studies indicate this variant shifts APP processing towards the non-amyloidogenic pathway, making APP a less-favorable substrate for β-secretase, and thus 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. Similar effects were subsequently observed 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, Wittrahm et al., 2023).

However, the mutation’s effects on APP processing appear to be more complex and vary between different model systems. In Chinese hamster ovary cells overexpressing APP A673T, for example, Aβ and sAPPβ peptides were reduced, but not CTFβ (Kokawa et al., 2015). The authors proposed the mutation caused a reduction in γ-secretase-mediated cleavage. Reduced levels of total Aβ with no change in total β-CTF was also observed in iPSC neurons (Kwart et al., 2019). These authors noted that, although not reaching statistical significance, C89 β-CTF—a non-amyloidogenic fragment—was increased. A673T expression did not result in endosomal enlargement, an alteration tied to elevated β-CTF levels.

Yet another  study suggested increased cleavage by BACE1 at the β′-site, rather than the β-site, based on increased Aβ (11-40) levels observed  in N2a cells expressing human A673T (Kimura et al., 2016). Moreover, in HEK cells and human neural cells expressing the mutant protein, sAPPβ was decreased, while sAPPα was increased, with no detectable changes in Aβ levels or the Aβ42/40 ratio (Wittrahm et al., 2023).

Two studies that examined the effects of A673T on cells also expressing pathogenic APP mutations yielded mixed results. When A673T was co-expressed with other APP mutations associated with AD in SH-SY5Y neuroblastoma cells, Aβ40 production decreased in 10, and Aβ42 decreased in 14, mutant-expressing cell populations (Guyon et al., 2020). Although less common, opposite effects were also observed: for three pathogenic mutations, Aβ40 increased, and for four mutations Aβ42 increased.  Moreover, in 2D and 3D cultures of human neuronal cells expressing pathogenic APP mutations K670N/M671L (Swedish) and V717I (London), APP A673T had no effect on Aβ levels, but the levels of sAPPα were increased while those of sAPPβ were decreased (Wittrahm et al., 2023). In Guyon and colleagues’ study, A673T decreased Aβ40 and Aβ42 when co-expressed with the London mutation but had no effect on Aβ production in the presence of the Swedish mutation. Wittrahm and co-workers suggested that the levels of sAPPα and sAPPβ might be more reliable measures of A673T’s protective effects.

The A673T mutation also appears to lower 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 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). Other studies have found that Aβ40 A2T, as well as short  N-terminal fragments of the peptide, can delay aggregation of both A2T and wildtype Aβ40 (Benilova et al., 2014; Lin et al., 2017). In one of these studies, Aβ42 A2T had little effect on aggregation (Benilova et al., 2014).

A2T’s effects on Aβ toxicity remain uncertain.  One study found that across 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). Also, plasma membrane binding and internalization of mutant Aβ40 in mouse primary cortical neurons were reduced compared with wildtype Aβ40 (Zhang et al., 2018), and mutant Aβ oligomers had substantially lower affinity for synapses in primary rat hippocampal/cortical neurons than wildtype oligomers (Limegrover et al., 2021). In primary cortical mouse neurons, mutant Aβ40 was reported to inhibit retrograde, and enhance anterograde, axonal transport of mitochondria, however, these effects were modest (Zhang et al., 2018).

Proteomic analyses of plasma and cerebrospinal fluid of three heterozygote carriers revealed differential expression of proteins involved in protein phosphorylation (particularly tau dephosphorylation), inflammation, and mitochondrial function (Wittrahm et al., 2023).

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).

Research Models

Several cell and rodent models carrying the A673T mutation have been generated. For example researchers have created induced pluripotent stem cell lines, including an isogenic line with the A673T mutation knocked in at both alleles (Kwart et al., 2017, Paquet et al., 2016) and a line derived from a skin biopsy of a healthy heterozygous Finnish carrier (Rolova et al., 2020). Moreover, the APP A673T variant was introduced into 2D and 3D cell culture models of human neural cells expressing either the Swedish K670N/M671L or London V717I pathogenic mutations (Wittrahm et al., 2023). A rat knockin model with a humanized Aβ sequence and carrying the A673T mutation has also been generated (Tambini et al., 2020).

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References

Mutations Citations

1. APP K670_M671delinsNL (Swedish)
2. APP V717I (London)

Paper Citations

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3. Rolova T, Wu YC, Koskuvi M, Voutilainen J, Sonninen TM, Kuusisto J, Laakso M, Hämäläinen RH, Koistinaho J, Lehtonen Š. Generation of a human induced pluripotent stem cell line (UEFi003-A) carrying heterozygous A673T variant in amyloid precursor protein associated with a reduced risk of Alzheimer's disease. Stem Cell Res. 2020 Oct;48:101968. Epub 2020 Sep 2 PubMed.
4. Wittrahm R, Takalo M, Kuulasmaa T, Mäkinen PM, Mäkinen P, Končarević S, Fartzdinov V, Selzer S, Kokkola T, Antikainen L, Martiskainen H, Kemppainen S, Marttinen M, Jeskanen H, Rostalski H, Rahunen E, Kivipelto M, Ngandu T, Natunen T, Lambert JC, Tanzi RE, Kim DY, Rauramaa T, Herukka SK, Soininen H, Laakso M, Pike I, Leinonen V, Haapasalo A, Hiltunen M. Protective Alzheimer's disease-associated APP A673T variant predominantly decreases sAPPβ levels in cerebrospinal fluid and 2D/3D cell culture models. Neurobiol Dis. 2023 Jun 15;182:106140. Epub 2023 Apr 28 PubMed.
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25. Limegrover CS, LeVine H 3rd, Izzo NJ, Yurko R, Mozzoni K, Rehak C, Sadlek K, Safferstein H, Catalano SM. Alzheimer's protection effect of A673T mutation may be driven by lower Aβ oligomer binding affinity. J Neurochem. 2021 May;157(4):1316-1330. Epub 2020 Oct 25 PubMed.

Further Reading