Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PP2, PP3, BS1, BS2
Clinical Phenotype: Alzheimer's Disease, Cerebral Amyloid Angiopathy, Frontotemporal Dementia, None
Position: (GRCh38/hg38):Chr21:25891796 G>A
Position: (GRCh37/hg19):Chr21:27264108 G>A
dbSNP ID: rs63750066
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCG to ACG
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17

Findings

This variant has been classified by some researchers as a risk factor. It is associated with a variable phenotype, with some mutation carriers exhibiting clinical and neuropathological features typical of Alzheimer's disease, others having a more complex presentation, with prominent cerebrovascular disease and cerebral amyloid angiopathy (CAA), and at least one other presenting with a clinical phenotype of behavioral frontotemporal dementia (FTD). Unaffected mutation carriers also have been documented, including a carrier who, at age 88 (Carter et al., 1992), was past the broad range of reported ages at onset (52-82 years, Rossi et al., 2004; Bernardi et al., 2009). Moreover, the allele count and frequency of this variant in the gnomAD database were relatively high. It has been classified by some researchers as a risk factor.  

Of note, this variant was found in 11 unrelated families of European ancestry based on prospective screening of unrelated patients in the French national reference center for young AD patients (CNRMAJ, Rouen) across 25 years (personal communication, Gaël Nicolas 2022). Analyses using different datasets as controls, revealed an increased prevalence of the variant in affected individuals compared with controls (odds ratio > 5 in all cases).

A French study first reported this mutation in one of 130 people with probable AD, according to NINCDS-ADRDA criteria. The mutation carrier was a 64-year-old woman who experienced memory loss at age 59. She did not have a family history of dementia. The mutation was also detected in five unaffected relatives, including three over the age of 62, arguing against segregation with disease, although incomplete penetrance was offered as another potential explanation. It is also possible that the non-affected carriers developed symptoms later in life, since age at onset can be quite variable (see Bruni et al. 2015 comment below), with at least one case of late-onset AD having been reported (Wang et al., 2023, suppl table e-3). In the French family, the A713T G>A mutation was accompanied by a second G>A transition at codon 715, predicted to be silent. Because of the proximity of the two point mutations, the authors described their finding as a double point mutation (GCG.ACA.GTG to ACG.ACA.GTA) (Carter et al., 1992).

The A713T mutation was later reported in an Italian family affected by autosomal dominant AD and strokes (Rossi et al., 2004). The reported pedigree shows six individuals over three generations. DNA was available from three affected family members, and all were heterozygous carriers, suggesting segregation with disease. However, the ages of two unaffected non-carriers were not reported. For the three affected family members for whom details were known, onset ranged from 52 to 68 years of age, with death at 57 to 73 years. The proband developed cognitive decline at age 52 and also experienced stroke-like symptoms, such as temporary language disturbances and monoparesis, the partial loss of voluntary movement in a single limb. Autopsy showed features consistent with a diagnosis of AD, including widespread amyloid plaques and neurofibrillary tangles (Braak stage VI). CAA was also prominent.

Also in 2004, a Spanish group reported the A713T mutation in a 56-year-old-man with a seven-year history of progressive cognitive decline consistent with AD. His first symptoms were memory impairment and depression. His older brother was also affected by dementia, but a detailed family history was not reported, and segregation with disease could not be established (Armstrong et al., 2004).

More recently the A713T mutation was discovered in a large Italian family with both heterozygous and homozygous mutation carriers (Conidi et al., 2015). The pedigree of the “PEC family” shows eight affected individuals over six generations. This family is not known to be genealogically connected to other A713T pedigrees, but the authors speculate that the Italian families are most likely related based on haplotype analysis. Disease in this family was described as AD with cerebrovascular lesions. Three affected family members were shown to be homozygous for the mutation and two were heterozygous. Genotype did not affect onset age, which was comparable between heterozygotes (e.g., 62, 73) and homozygotes (e.g. 76, 70, 70). The mutation was absent in 400 control individuals from the same region of Italy. The authors concluded the mutation segregated with disease, however, Alzforum requires at least one healthy, non-carrier who is a family member and whose age is at least two standard deviations greater than the mean age at onset, as evidence for segregation (see Methods). In this family, the two healthy non-carriers were 57 and 63 years of age, both younger than the family’s mean age at onset.

This mutation was also identified in two unrelated women from the United Kingdom. Both were considered to be affected by sporadic early onset AD. One woman had neuropathologically confirmed AD, with onset at age 62. The other woman met clinical criteria for probable AD, with onset at age 61. Additional clinical details were not reported (Barber et al., 2015).

An Italian man with a clinical phenotype of behavioral FTD and symptom onset at age 50 was also found to carry the A713T variant (Lombardi et al., 2017). Neither of his parents, who died at ages 76 and 78, were reported to have a neurological disorder, but a maternal aunt had been affected by unspecified early onset dementia at age 55.

The allele count and frequency of this variant in the gnomAD database were 26 and 0.0092 percent, respectively (Koriath et al., 2018). Of note, 21 of 25 carriers in this database were of Latino/Admixed American ancestry (gnomAD v2.1.1, Oct 2021).

Neuropathology

The neuropathology associated with the A713T mutation is variable. Some cases accumulate pathology fairly typical of AD, notably atrophy of the cerebral cortex, and especially the temporal lobes, with widespread neurofibrillary tangles and amyloid plaques and minimal amyloid angiopathy (e.g., Armstrong et al., 2004). However, other cases exhibit prominent vascular involvement with prominent CAA and other vascular lesions (e.g., Rossi et al., 2004; Bernardi et al., 2009; Conidi et al., 2015).

In postmortem brain there was no change in the Aβ42/Aβ40 ratio (Armstrong et al., 2004). However, the plasma Aβ42/Aβ40 ratio was higher in asymptomatic mutation carriers than in non-mutation carrying relatives, due to a decrease in Aβ40 and an increase in Aβ42 (Conidi et al., 2015).

Of note, the Italian carrier who presented with an FTD phenotype had normal levels of Aβ42 in cerebrospinal fluid and no sign of pathological amyloid accumulation as assessed by florbetapir-PET (Lombardi et al., 2017).

Biological Effect

Mouse neuroblastoma cells expressing this variant secreted about half the amount of Aβ40 compared with cells expressing wild-type APP, resulting in an elevated Aβ42/Aβ40 ratio (Hsu et al., 2020). Moreover, a study that monitored Aβ peptides produced by γ-secretase cleavage of APP in vitro, indicated inefficient processing of longer forms of Aβ, resulting in increased levels of membrane-anchored, potentially pathogenic, Aβ45 and Aβ46 (Devkota et al., 2021, Feb 2021 news). Also, this variant reduced endoproteolysis at the ε cleavage site, and shifted cleavage in favor of the Aβ48 → Aβ45 → Aβ42 → Aβ38 pathway over the Aβ49 → Aβ46 → Aβ43 → Aβ40 pathway.

In addition, this variant (corresponding to A42T in the Aβ peptide) was found to accelerate nucleation in a yeast cell-based assay (Seuma et al., 2022, suppl 3). A42 is required for fast nucleation and substitution to a T appears to enhance the effect.  

In silico, the A713T mutation is predicted to be damaging (Conidi et al., 2015; CADD v1.6, Jan 2022).

This variant may be a risk factor. Koriath and co-workers predicted it had less than 10 percent penetrance due to its relatively high incidence in the gnomAD, and described it as "most likely benign" or causing an "only small increase in risk" (Koriath et al., 2018). However, taking into account their functional results, Hsu and colleagues classified it as a risk factor (Hsu et al., 2020). The prevalence analyses in the French cohort described above (Nicolas 2022) are consistent with the latter.

Pathogenicity

Alzheimer's Disease : Uncertain Significance*

*This variant, which has a damaging functional effect and is found in multiple affected individuals and families, may be a risk factor, a condition outside the scope of the ACMG-AMP guidelines.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

Comments

1. • Amalia Cecilia Bruni
     Azienda Sanitaria Provinciale Catanzaro
   • Maria Elena Conidi
     Regional Neurogenetic Centre
   • Livia Bernardi
     Regional Neurogenetic Centre
   • Posted: 29 May 2015

   We found that the A713T mutation segregated with disease in a large Italian family, strongly supporting the pathogenicity of this rare variant (Conidi et al., 2015). However, this mutation did not segregate with disease in a previously described family (Carter et al., 1992). Although we can only speculate, it may be that the four “healthy” A713T carriers in that family were, in fact, presymptomatic at age 62 and older (and in one case at age 88). Other studies have shown that carriers of this mutation exhibit a particularly variable age of symptom onset , ranging from 52 to 82 years (Rossi et al., 2004; Bernardi et al., 2009). It is also possible, as Carter and colleagues suggested, that genetic, epigenetic or environmental modifiers influence the penetrance of the A713T mutation.

   Of particular note, in the A713T family they studied, Carter and colleagues also detected a G>A transition in the codon for the nearby amino acid 715. This is a synonymous change and may simply be a rare polymorphism. It was not present in the Italian family we studied, nor reported in any of the other known A713T carriers. Given the apparent lack of segregation of A713T in the family studied by Carter, it is possible that the accompanying G>A transition at codon 715 may reduce the penetrance of the A713T mutation. It is increasingly recognized that “silent” mutations can have significant biological effects, and that synonymous codons are not necessarily equivalent (Berleant et al., 2009). 

   We observed that APP A713T increases the Aβ42/Aβ40 ratio in plasma (Conidi et al., 2015). Studies in cell culture may elucidate the effects of the mutation on APP processing, and whether the presence of the nearby silent mutation affects this.

   For reasons that are currently unclear, human carriers of A713T present with either classic Alzheimer’s pathology or prominent CAA with significant vascular lesions. It would be interesting to determine the pattern of amyloid pathology in a mouse model and to explore potential modifiers of that pathology.

   References:

   Conidi ME, Bernardi L, Puccio G, Smirne N, Muraca MG, Curcio SA, Colao R, Piscopo P, Gallo M, Anfossi M, Frangipane F, Clodomiro A, Mirabelli M, Vasso F, Cupidi C, Torchia G, Di Lorenzo R, Mandich P, Confaloni A, Maletta RG, Bruni AC. Homozygous carriers of APP A713T mutation in an autosomal dominant Alzheimer disease family. Neurology. 2015 Jun 2;84(22):2266-73. Epub 2015 May 6 PubMed.

   Carter DA, Desmarais E, Bellis M, Campion D, Clerget-Darpoux F, Brice A, Agid Y, Jaillard-Serradt A, Mallet J. More missense in amyloid gene. Nat Genet. 1992 Dec;2(4):255-6. PubMed.

   Rossi G, Giaccone G, Maletta R, Morbin M, Capobianco R, Mangieri M, Giovagnoli AR, Bizzi A, Tomaino C, Perri M, Di Natale M, Tagliavini F, Bugiani O, Bruni AC. A family with Alzheimer disease and strokes associated with A713T mutation of the APP gene. Neurology. 2004 Sep 14;63(5):910-2. PubMed.

   Bernardi L, Geracitano S, Colao R, Puccio G, Gallo M, Anfossi M, Frangipane F, Curcio SA, Mirabelli M, Tomaino C, Vasso F, Smirne N, Maletta R, Bruni AC. AbetaPP A713T mutation in late onset Alzheimer's disease with cerebrovascular lesions. J Alzheimers Dis. 2009;17(2):383-9. PubMed.

   Berleant D, White M, Pierce E, Tudoreanu E, Boeszoermenyi A, Shtridelman Y, Macosko JC. The genetic code--more than just a table. Cell Biochem Biophys. 2009;55(2):107-16. Epub 2009 Jul 29 PubMed.

   View all comments by Amalia Cecilia Bruni View all comments by Maria Elena Conidi View all comments by Livia Bernardi

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References

Book page Citations

1. Methods 6 Feb 2018

News Citations

1. Are the Long Aβ Peptides the Real Bad Guys? 5 Feb 2021

Paper Citations

1. Carter DA, Desmarais E, Bellis M, Campion D, Clerget-Darpoux F, Brice A, Agid Y, Jaillard-Serradt A, Mallet J. More missense in amyloid gene. Nat Genet. 1992 Dec;2(4):255-6. PubMed.
2. Rossi G, Giaccone G, Maletta R, Morbin M, Capobianco R, Mangieri M, Giovagnoli AR, Bizzi A, Tomaino C, Perri M, Di Natale M, Tagliavini F, Bugiani O, Bruni AC. A family with Alzheimer disease and strokes associated with A713T mutation of the APP gene. Neurology. 2004 Sep 14;63(5):910-2. PubMed.
3. Bernardi L, Geracitano S, Colao R, Puccio G, Gallo M, Anfossi M, Frangipane F, Curcio SA, Mirabelli M, Tomaino C, Vasso F, Smirne N, Maletta R, Bruni AC. AbetaPP A713T mutation in late onset Alzheimer's disease with cerebrovascular lesions. J Alzheimers Dis. 2009;17(2):383-9. PubMed.
4. Wang D, Scalici A, Wang Y, Lin H, Pitsillides A, Heard-Costa N, Cruchaga C, Ziegemeier E, Bis JC, Fornage M, Boerwinkle E, DeJager PL, Wijsman E, Dupuis J, Renton AE, Seshadri S, Goate AM, The Alzheimer's Disease Sequencing Project, DeStefano AL, Peloso GM. Frequency of Variants in Mendelian Alzheimer's Disease Genes within the Alzheimer's Disease Sequencing Project (ADSP). 2023 Oct 25 10.1101/2023.10.24.23297227 (version 1) medRxiv.
5. Armstrong J, Boada M, Rey MJ, Vidal N, Ferrer I. Familial Alzheimer disease associated with A713T mutation in APP. Neurosci Lett. 2004 Nov 11;370(2-3):241-3. PubMed.
6. Conidi ME, Bernardi L, Puccio G, Smirne N, Muraca MG, Curcio SA, Colao R, Piscopo P, Gallo M, Anfossi M, Frangipane F, Clodomiro A, Mirabelli M, Vasso F, Cupidi C, Torchia G, Di Lorenzo R, Mandich P, Confaloni A, Maletta RG, Bruni AC. Homozygous carriers of APP A713T mutation in an autosomal dominant Alzheimer disease family. Neurology. 2015 Jun 2;84(22):2266-73. Epub 2015 May 6 PubMed.
7. Barber IS, García-Cárdenas JM, Sakdapanichkul C, Deacon C, Zapata Erazo G, Guerreiro R, Bras J, Hernandez D, Singleton A, Guetta-Baranes T, Braae A, Clement N, Patel T, Brookes K, Medway C, Chappell S, Mann DM, ARUK Consortium, Morgan K. Screening exons 16 and 17 of the amyloid precursor protein gene in sporadic early-onset Alzheimer's disease. Neurobiol Aging. 2016 Mar;39:220.e1-7. Epub 2015 Dec 29 PubMed.
8. Lombardi G, Berti V, Tedde A, Bagnoli S, Piaceri I, Polito C, Lucidi G, Ferrari C, Ginestroni A, Moretti M, Pupi A, Nacmias B, Sorbi S. Low Florbetapir PET Uptake and Normal Aβ1-42 Cerebrospinal Fluid in an APP Ala713Thr Mutation Carrier. J Alzheimers Dis. 2017;57(3):697-703. PubMed.
9. Koriath C, Kenny J, Adamson G, Druyeh R, Taylor W, Beck J, Quinn L, Mok TH, Dimitriadis A, Norsworthy P, Bass N, Carter J, Walker Z, Kipps C, Coulthard E, Polke JM, Bernal-Quiros M, Denning N, Thomas R, Raybould R, Williams J, Mummery CJ, Wild EJ, Houlden H, Tabrizi SJ, Rossor MN, Hummerich H, Warren JD, Rowe JB, Rohrer JD, Schott JM, Fox NC, Collinge J, Mead S. Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Mol Psychiatry. 2018 Oct 2; PubMed.
10. Hsu S, Pimenova AA, Hayes K, Villa JA, Rosene MJ, Jere M, Goate AM, Karch CM. Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.
11. Devkota S, Williams TD, Wolfe MS. Familial Alzheimer's disease mutations in amyloid protein precursor alter proteolysis by γ-secretase to increase amyloid β-peptides of ≥45 residues. J Biol Chem. 2021;296:100281. Epub 2021 Jan 12 PubMed.
12. Seuma M, Lehner B, Bolognesi B. An atlas of amyloid aggregation: the impact of substitutions, insertions, deletions and truncations on amyloid beta fibril nucleation. Nat Commun. 2022 Nov 18;13(1):7084. PubMed.

Further Reading