Double Mutations in a Patient with Early-Onset Alzheimer's Disease in Korea: An Val551Met and a His169Asn.

The etiology of early-onset Alzheimer's disease (EOAD) is associated with alterations in the production of amyloid beta (Aβ) species caused by mutations in the , , and genes. Mutations affect intra- or inter-molecular interactions and processes between the γ-secretase complex and amyloid precursor protein (APP), leading to the aberrant sequential cleavage of Aβ species. A 64-year-old woman presented with progressive memory decline, mild right hippocampal atrophy, and a family history of Alzheimer's dementia (AD). Whole exome sequencing was performed to evaluate AD-related gene mutations, which were verified by Sanger sequencing. A mutation-caused structural alteration of APP was predicted using in silico prediction programs. Two AD-related mutations, in (rs761339914; c.G1651A; p.V551M) and (rs533813519; c.C505A; p.H169N), were identified. The Val551Met mutation in the E2 domain may influence APP homodimerization through changes in intramolecular interactions between adjacent amino acids, altering Aβ production. The second mutation was His169Asn mutation, which was previously reported in five EOAD patients from Korea and China, with a relatively high frequency in the East Asian population. According to a previous report, the presenilin 2 protein was predicted to result in a major helical torsion by His169Asn mutation. Notably, the co-existence of Val551Met and His169Asn may induce a synergistic effect by both mutations. Future functional studies are needed to clarify the pathological effects of these double mutations.