Table 1.

Most prominent mutations in APP gene.

Mutation	Pathogenicity	Type of Mutation	Biological Effect	Citation
A673T (Icelandic)	Alzheimer’s Disease—Protective	Substitution	This particular type is linked to limited build-up of amyloid and is believed to guard against amyloid-related issues. It results in a decrease of approximately 40 percent in the production of amyloidogenic Aβ peptides, and the Aβ that is produced has a reduced tendency to form clumps.	[17,18,19,20]
A673V	Not Classified	Substitution	According to the CERAD criteria, a clear diagnosis of AD was made, as evidenced by substantial Aβ and tau pathology deposits (Braak stage VI) along with cerebral amyloid angiopathy. The deposits found contained elevated levels of Aβ40 and were notably larger, with fewer preamyloid deposits. Perivascular localization was frequently observed. In laboratory studies, it was discovered that A673V caused a shift in β-secretase processing of APP toward the amyloidogenic pathway and amplified Aβ aggregation.	[21,22]
E693Q (Dutch)	Hereditary Cerebral Hemorrhage with Amyloidosis—Pathogenic	Substitution	There is a substantial accumulation of amyloid in the cerebral blood vessels, accompanied by hemorrhages and some diffuse plaques in the brain tissue. In laboratory experiments, it was observed that this condition speeds up Aβ aggregation in vitro, leading to greater fibril formation, and may also modify APP processing.	[24,25]
E693del (Osaka, E693∆, E693delta	Alzheimer’s Disease—Pathogenic	Deletion	This variant led to an increased oligomerization and nucleation of Aβ aggregates in vitro. Furthermore, it was found that there was no alteration in the Aβ42/Aβ40 ratio, but there was a decrease in both Aβ42 and Aβ40. This variant was also discovered to be more resistant to degradation by neprilysin and insulin-degrading enzyme. Additionally, this variant had a greater inhibitory effect on long-term potentiation (LTP) compared to wild-type Aβ, which suggests a potential negative impact on synaptic plasticity.	[26,27,28,29]
E693K (Italian)	Hereditary Cerebral Hemorrhage with Amyloidosis—Pathogenic	Substitution	The observed symptoms include small to large hematomas, subarachnoid bleeding, scars with hemosiderin deposits, small infarcts, and cortical calcifications. Aβ immunoreactivity was observed in vessel walls and neuropil, but there was an absence of neurofibrillary changes and neuritic plaques. Despite a reduction in the Aβ42/Aβ40 ratio and a decrease in Aβ42 levels, the mutant peptide was found to be toxic in cells and aggregates at a faster rate.	[23]
E693G (Arctic, E22G)	Alzheimer’s Disease—Pathogenic	Substitution	Several carriers displayed neuropathology that was indicative of AD. Plaques were observed to have a “targetoid” shape, containing heterogeneous truncated Aβ peptides in the center and surrounded by Aβ42. Cell-based assays revealed a reduction in the production of both Aβ40 and Aβ42. Additionally, there was a decrease in proteolytic degradation of Aβ by neprilysin, a type of enzyme that breaks down proteins.	[23,25]
c.-488C>A (rs532314089)	Alzheimer’s Disease	Substitution	Predicted to disrupt binding of transcription factor EGR1. PHRED-scaled CADD = 0.26. Negative regulator in multiple cell types including PC12 neuronal-like rat chromaffin cells, SK-N-SH neuroblastoma cells, C6 glial cells and U373 astroctyoma cells among others	[30,31,32]
c.24+38G>A (rs373985746)	Alzheimer’s Disease	Substitution	Predicted benign in silico (PHRED-scaled CADD = 10).	[32]
c.24+288G>A (rs192348494)	Alzheimer’s Disease	Substitution	Predicted benign in silico (PHRED-scaled CADD = 12).	[32]
c.-23-377A>G (rs150375400)	Alzheimer’s Disease	Substitution	Predicted benign in silico (PHRED-scaled CADD = 10).	[32]
A18T	Alzheimer’s Disease, Cardiovascular Disease	Substitution	Predicted to disrupt signal peptide cleavage and affect APOE secretion. PHRED-scaled CADD = 22.	[32,33]

CADD—Combined Annotation-Dependent Depletion.