Mutations in the gene encoding amyloid precursor protein (APP) cause autosomal dominant inherited Alzheimer’s disease (AD).
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 . 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 . Disease onset of APP mutation carriers commonly ranges between 45 and 60 years . There was also a reported case with disease onset even in the eighth decade . In fact, families carrying the same APP mutation  have a significantly different age at onset, suggesting that other genetic or environmental modifiers of the disease may exist . Moreover, there are significant differences between mutation types, resulting in some cases in onset in the third or fourth decade of life . The youngest individual with APP mutation causing AD  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 . With regard to this mutation, in vitro studies showed a marked increase in the Aβ42/40 ratio, suggesting reduced APP proteolysis by γ-secretase . These findings strengthen the inverse association between Aβ42/40 ratio and age of onset .
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 . Early neuropsychological findings are deficits in verbal memory with relatively preserved naming and object perception, executive dysfunction and disorientation . 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 . Seizures, on the other hand, were present in approximately 10% of patients and may represent the first presentation in monogenic AD cases . Indeed, amyloid β-peptides can induce neuronal hyperexcitability and trigger epileptic seizures . 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 . 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 ; 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 .
Most APP mutations are missense or nonsense mutations within or flanking the Aβ sequence and near the cleavage sites of secretases . 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 . However, recessive APP mutations have also been reported . The amino acid position can, in fact, predict pathogenicity . 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 . However, APP duplications are far less frequently reported than missense mutations . APP duplications display reduced penetrance and higher variability in age of onset, compared to missense mutations, which show a near-complete disease penetrance . The phenotype of APP duplications is not associated with the size of duplication .
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 . 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) . Mutations within the Aβ domain such as the Dutch , Flemish  and Iowa mutation  have variable effects on APP processing such as impaired α-secretase cleavage and increased aggregation of Aβ into fibrils . 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 ; here belongs the I716F mutation (Iberian) associated with the youngest age-at-onset . Moreover, a mutation in APP that decreases the production of Aβ (A673T)  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 .