APP, PSEN1, and PSEN2 Mutations in Asian Patients with Early-Onset Alzheimer Disease

Abstract

The number of patients with Alzheimer’s disease (AD) is rapidly increasing in Asia. Mutations in the amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) genes can cause autosomal dominant forms of early-onset AD (EOAD). Although these genes have been extensively studied, variant classification remains a challenge, highlighting the need to colligate mutations across populations. In this study, we performed a genetic screening for mutations in the APP, PSEN1, and PSEN2 genes in 200 clinically diagnosed EOAD patients across four Asian countries, including Thailand, Malaysia, the Philippines, and Korea, between 2009 and 2018. Thirty-two (16%) patients presented pathogenic APP, PSEN1, or PSEN2 variants; eight (25%), 19 (59%), and five (16%) of the 32 patients presented APP, PSEN1, and PSEN2 variants, respectively. Among the 21 novel and known non-synonymous variants, five APP variants were found in Korean patients and one APP variant was identified in a Thai patient with EOAD. Nine, two, and one PSEN1 mutation was found in a Korean patient, Malaysian siblings, and a Thai patient, respectively. Unlike PSEN1 mutations, PSEN2 mutations were rare in patients with EOAD; only three variants were found in Korean patients with EOAD. Comparison of AD-causative point mutations in Asian countries; our findings explained only a small fraction of patients, leaving approximately 84% (p = 0.01) of autosomal dominant pedigrees genetically unexplained. We suggest that the use of high-throughput sequencing technologies for EOAD patients can potentially improve our understanding of the molecular mechanisms of AD.

APP, PSEN1, and PSEN2 Variants in Alzheimer’s Disease: Systematic Re-evaluation According to ACMG Guidelines

“…Our re-analysis found that most PSEN1 variants are located in exon 7, exon 5, exon 8, exon 6, exon 4, exon 11, and exon 12, most PSEN2 variants in exon 5, and exon 7, and most APP variants in exon 14, exon 16, exon 17, which was consistent with previous studies (Raux et al, 2005;Barber et al, 2016). In the Asain population, variants in exon 4, exon 7, exon 11, exon 14, and exon 17 of the APP, exon 4, exon 5, exon 6, exon 7, exon 8, and exon 12 of the PSEN1, as well as exon 5, exon 6, and exon 7 of the PSEN2 gene were discovered between 2009 and 2018 (Giau et al, 2019). In the French population, PSEN1 variants are located in exon 4, exon 5, exon 6, exon 7, exon 8, exon 9, exon 10, exon 11, and exon 12.…”

Real-Time 3D Imaging and Inhibition Analysis of Various Amyloid Aggregations Using Quantum Dots

“…Although enormous efforts have been made by many researchers, currently there are no effective disease-modifying therapies available. Mutations of the amyloid precursor and some external factors, such as heating, create large challenges for the treatment of amyloidosis [43,44]. At present, some proposals and research involve treatments for amyloidosis based on antibodies, metal ions, and RNA interference, but none have been certified as medicine for amyloidosis therapy and applied clinically [17,[45][46][47][48].…”

Mutational analysis in familial Alzheimer’s disease of Han Chinese in Taiwan with a predominant mutation PSEN1 p.Met146Ile

“…Over 300 mutations in PSEN1 have been reported in the literature, in which close to 270 were pathogenic. Until 2019, 57 mutations of PSEN1 were discovered in Asian countries, including Japan, Korea, the People’s Republic of China, Iran and Thailand 34 . A recently published systemic review disclosed that a PSEN1 mutation was found in 66.7% of Chinese FAD and 72.7% of Asian (Chinese, Korean, and Japanese) FAD families 35 .…”