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Xiromerisiou, G. Amyloid Precursor Protein Gene Mutations. Encyclopedia. Available online: (accessed on 11 December 2023).
Xiromerisiou G. Amyloid Precursor Protein Gene Mutations. Encyclopedia. Available at: Accessed December 11, 2023.
Xiromerisiou, Georgia. "Amyloid Precursor Protein Gene Mutations" Encyclopedia, (accessed December 11, 2023).
Xiromerisiou, G.(2021, December 21). Amyloid Precursor Protein Gene Mutations. In Encyclopedia.
Xiromerisiou, Georgia. "Amyloid Precursor Protein Gene Mutations." Encyclopedia. Web. 21 December, 2021.
Amyloid Precursor Protein Gene Mutations

Mutations in the gene encoding amyloid precursor protein (APP) cause autosomal dominant inherited Alzheimer’s disease (AD). 

amyloid precursor protein mutation

1. Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of insoluble forms of β-amyloid (Aβ) in plaques in extracellular spaces and in the walls of blood vessels as well as the aggregation of hyperphosphorylated protein tau in neurofibrillary tangles in neurons [1][2]. AD has a prevalence of 10–30% in the population over 65 years old [1]. The disease is characterized by progressive memory loss and the disturbance of other cognitive functions, namely word-finding, spatial cognition, reasoning, judgment and problem solving [2]. The disease has a long prodromal phase, which can occasionally extend over two decades and an average disease duration of 8–10 years [1].
A small proportion of patients (<1%) have autosomal dominant inherited AD [1][3]. This form is characterized by disease onset at a relatively young age (before 65 years of age) and usually positive family history for dementia [2][4]. It may manifest with atypical symptoms such as apraxia, aphasia, dyscalculia, visual symptoms or seizures [2]. It is caused by autosomal dominant penetrant mutations in the genes encoding amyloid precursor protein (APP) (OMIM 104760), presenilin 1 (PSEN1) (OMIM 104311) and 2 (PSEN2) (OMIM 600759), leading to overproduction of Aβ [1][2]. APP mutations or duplications are the second most common cause of monogenic forms of AD following PSEN1 mutations [5][6] and are responsible for approximately 15–20% of early-onset cases [4][5].
APP is a type I transmembrane protein with a large extracellular domain and a short cytoplasmic region; its coding gene is located on chromosome 21 (21q21.2-3) [7]. The APP gene contains 18 exons and encodes an alternatively spliced transcript, which in its longest isoform expresses a polypeptide of 770 amino acids [6]. Aβ is released from APP through two cleavage events, one in the extracellular area (β-secretase cleavage) and one in the transmembrane area (γ-secretase cleavage) [5][7]. If cleavage occurs at residue 712–713 the most common Aβ40 is produced, whereas if it occurs after residue 714 the longer Aβ42 is generated, which is prone to fibril formation and promotes Aβ aggregates [5]. Presenilins, the proteins encoded by PSEN1 and PSEN2 genes, are main components of the γ-secretase complex, responsible for the cleavage of APP into Aβ peptides [5][8]. PSEN mutations cause a shift of γ-secretase cleavage, increasing Aβ42 production [5][9]. APP and Aβ are the cornerstone of the ‘’amyloid cascade hypothesis’’ [10], which states that the accumulation of Aβ initiates a cascade of pathological processes such as tau hyperphosphorylation, neurofibrillary tangles formation, neuroinflammation, loss of synaptic junctions and neuronal death [4].

2. Amyloid Precursor Protein Gene Mutations 

2.1. Clinical Spectrum of APP Mutations: Age of Onset and Symptoms

Approximately 400 cases of APP mutations have been described so far, the majority of which are located on the Aβ domain or referring to the V717I, F or G mutation. Another case with the same mutation was recently described in a Greek patient as well [11]. This case had hereditary cerebral amyloid angiopathy with occipital calcifications, progressive cognitive decline and motor symptoms.

The mean age of disease onset of APP mutation carriers was 51.3 (±8.3) years, similar to previous published review studies and meta-analyses [3][12]. Disease onset of APP mutation carriers commonly ranges between 45 and 60 years [5][13]. There was also a reported case with disease onset even in the eighth decade [14]. In fact, families carrying the same APP mutation [15][16][17] have a significantly different age at onset, suggesting that other genetic or environmental modifiers of the disease may exist [12]. Moreover, there are significant differences between mutation types, resulting in some cases in onset in the third or fourth decade of life [12]. The youngest individual with APP mutation causing AD [18] was a patient with a positive family history of early-onset AD, disease onset at the age of 31 and death at age 36. He harbored the APP I716F mutation [19]. With regard to this mutation, in vitro studies showed a marked increase in the Aβ42/40 ratio, suggesting reduced APP proteolysis by γ-secretase [20]. These findings strengthen the inverse association between Aβ42/40 ratio and age of onset [20].

The most common symptoms of APP mutation carriers were cognitive symptoms and/or dementia (almost 98% of cases). In fact, the majority of monogenic AD cases have an amnestic presentation [5]. Early neuropsychological findings are deficits in verbal memory with relatively preserved naming and object perception, executive dysfunction and disorientation [21][22]. Visuospatial symptoms were also very common, occurring in almost one third of patients. Other cortical symptoms such as aphasia and apraxia were less common; aphasia occurred in less than 20% of patients. Indeed, atypical language presentation is rather rare in APP cases [5]. Seizures, on the other hand, were present in approximately 10% of patients and may represent the first presentation in monogenic AD cases [5]. Indeed, amyloid β-peptides can induce neuronal hyperexcitability and trigger epileptic seizures [23]. Furthermore, we found that a small proportion of patients (about 10%) presented with pyramidal (spasticity, hemiparesis, paraparesis) or extrapyramidal symptoms (mostly rigidity). Notably, extrapyramidal symptoms are very rare in APP mutation carriers and tend to appear after several years of disease [5][13]. Other movement disorders, such as ataxia, myoclonus or rest tremor, were also rare. With regard to psychiatric symptoms, depression and anxiety were encountered in less than one quarter of the patients. Other psychotic or behavioral symptoms, such as delusions, hallucinations, or aggression—which are common in sporadic cases—can also be found in monogenic APP cases [3][5]; however, as shown in our analysis they are rather rare. Concerning APP duplications carriers, apart from dementia, they may present with seizures and other focal cortical symptoms such as aphasia, apraxia and dyscalculia, extrapyramidal, pyramidal or behavioral symptoms [24][25][26][27].

Notably, certain APP mutations [15][28][29][30][31][32][33][34] and duplications [24][25] have been associated with variable white matter abnormalities up to leukoencephalopathy. The APP mutations associated with leukoencephalopathy were within the Aβ sequence [30][31] such as the Iowa mutation [28], near β-sekretase [29][33] or γ-sekretase [15][32][34] cleavage site. The age of onset was early in those cases (39–57 years) and they presented with both typical (dementia) and atypical i.e.aphasia, apraxia, seizures, psychiatric) symptoms.

2.2. Mutations in Amyloid Precursor Protein (APP) Gene: Location and Pathogenicity

Most APP mutations are missense or nonsense mutations within or flanking the Aβ sequence and near the cleavage sites of secretases [2]. More specifically, we confirmed that most APP mutations (93%) are located on exons 16 and 17, which constitute the transmembrane Aβ region and encode the Aβ sequence. This was observed independently of ethnicity, although data from African and Latin/Hispanic populations are limited. In most AD families due to APP mutation, the inheritance pattern is autosomal dominant, while homozygous carriers do not seem to be more severely affected [35]. However, recessive APP mutations have also been reported [36][37]. The amino acid position can, in fact, predict pathogenicity [19]. Indeed, mutations in exon 17 are associated with moderate to severe pathogenicity (CADD score), while mutations in exon 16 or other exons with mild to moderate pathogenicity. Additionally, mutations in the Aβ protein region were associated with severe pathogenicity, unlike mutations in the cytoplasmic or 717 positions, which were associated with moderate pathogenicity. Patients with mutations in the cytoplasmic region had the youngest age of onset (before the age of 50). These findings are reasonable, as these mutations affect the area encoding the Aβ sequence. Furthermore, duplications of variable size have been identified [2]. However, APP duplications are far less frequently reported than missense mutations [2]. APP duplications display reduced penetrance and higher variability in age of onset, compared to missense mutations, which show a near-complete disease penetrance [38]. The phenotype of APP duplications is not associated with the size of duplication [39].

Mutations in exons 16 and 17 alter the processing of the protein and cause the accumulation of Aβ42 fragments by decreasing Aβ40 peptide levels or increasing Aβ42 production [40][41]. Our patient was found to harbor a missense mutation located at position 688 of APP, between the β- and γ-secretase cleavage site. Most pathogenic mutations of APP occur near the β-secretase cleavage site (amino acids 670aa–682aa), near the γ-secretase cleavage site (amino acids 713aa–724aa) or in the Aβ sequence (amino acids 692aa–705aa) [39]. Mutations within the Aβ domain such as the Dutch [42][43], Flemish [44] and Iowa mutation [28] have variable effects on APP processing such as impaired α-secretase cleavage and increased aggregation of Aβ into fibrils [7][39]. Mutations in the C-terminal (e.g., in exon 17) influence the activity of γ- and e-secretases and result in a selective increase in the production of longer Aβ peptides, especially Aβ42, which are more hydrophobic and prone to the formation of fibrils [10][39]; here belongs the I716F mutation (Iberian) associated with the youngest age-at-onset [18][20]. Moreover, a mutation in APP that decreases the production of Aβ (A673T) [45] has been shown to have protective effects on late-onset AD. This substitution results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. The protective effect of A673T substitution against AD supports the hypothesis that reducing β-cleavage of APP may be an effective primary preventive strategy. Therefore, the Aβ42/40 ratio could be a useful indicator of the aggressiveness of the mutation [19].

2.3. Phenotypic Variability of APP Mutations

AD is a disease with phenotypic variability, especially in cases with early disease onset. APP gene mutations may act variably on disease expression, ranging from high penetrance (causal allele) and early age of onset to low penetrance (risk allele) and late-onset, depending on the effect of the mutant allele on protein function [46]. Different mutations at the same APP locus can segregate with different transmission patterns, that is, dominant, semi-dominant and recessive [33][36][37][47]. It is to be discovered whether this is associated with specific characteristics of the single mutations or genetic modifiers in those families [47]. Apart from pathogenic mutations, genetic variations, such as single nucleotide variants (SNVs) in the promoter region of APP, have been associated with increased susceptibility for AD [2]. In addition, epigenetic or other genetic factors may play a role in clinical variability of individuals carrying the same mutation [4]. Epigenetic dysregulation (DNA methylation, chromatin remodeling, non-coding RNAs expression) can affect gene expression in AD such as alteration in methylation in the promoter region of APP [48].

3. Conclusions

In summary, the phenotype of APP mutation carriers is heterogeneous. The age of disease onset ranges from the 40 s to 70 s. The main symptoms in patients harboring APP mutations are cognitive, while focal cortical, extrapyramidal symptoms, seizures, behavioral and psychiatric symptoms can also occur. Data from families that segregate a monogenic form of AD and patients with a known causal mutation provide the opportunity to identify mutation-specific effects and link genotypic changes with clinical and pathophysiological manifestations of the disease. In the future, different genetic causes of AD should be targeted with specific interventions. Asymptomatic carriers of APP mutations can also serve as candidates for disease-modifying treatment or prevention trials. Moreover, another direction for future research should be the identification of genetic and environmental modifiers of disease onset and progression [12]. Studying the mechanisms underlying these mutations can provide more insight into the pathways leading to AD pathology, in order to plan appropriate intervention strategies for the disease.


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