Clinical Phenotype and Mutation Spectrum of Alzheimer’s Disease with Causative Genetic Mutation in a Chinese Cohort

Mao, Chenhui; Li, Jie; Dong, Liling; Huang, Xin; Lei, Dan; Wang, Jie; Chu, Shanshan; Liu, Caiyan; Peng, Bin; Román, Gustavo C.; Gao, Jing

doi:10.2174/1567205018666210608120339

Cited by 7 publications

(5 citation statements)

References 32 publications

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“…Among 26 detected variants were novel discovered (among some variants were reported by our group previously). 22,23 16 patients (16/1277, 1.25%) have been identi ed carrying 11 causative APP variants, including 7 variants were novel; 16 patients (16/1277, 1.25%) have been identi ed carrying 13 causative PSEN1 variants, including 9 variants were novel; 14 patients (14/1277, 1.10%) have been identi ed carrying 12 causative PSEN2 variants, including 10 variants were novel.…”

Section: Resultsmentioning

confidence: 99%

Screening and functional validations of APP, PSEN1 and PSEN2 mutations from PUMCH dementia cohort

Dong

Sha

et al. 2023

Preprint

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Background: Presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) genes have been verified as causative genes for Alzheimer’s disease (AD). The present study aimed to (1) screen for pathogenic mutations in a large sample size Chinses dementia population (Peking Union Medical College Hospital dementia cohort, PUMCH dementia cohort), (2) determine the functional effect of the identified mutations by in-vitro study. Methods: Next generation sequencing was performed in patients from PUMCH dementia cohort and AD variants interpretation was determined by bioinformatic analysis. AD pathogenicity of the identified variants was determined by detecting the Aβ secretion of transfected HEK293 cells. Results: Among the 1277 participants from PUMCH dementia cohort, 46 patients with causative AD mutations (36 variants) were identified, with frequency of 3.60% (1.25% of APP, 1.25% of PSEN1 and 1.10% of PSEN2). The detected frequency of AD mutations was 6.95% (23/331), 4.24% (32/754), and 11.04% (17/154) in dementia population who have dementia family history, in early-onset dementia population, and in early-onset dementia population who have dementia family history, respectively. Among the 36 identified variants, 6 variants (PSEN1E72K, E363Q and Q223K, PSEN2 N141S, M239T and I368F) were identified to significantly increased the level of Aβ42, Aβ40 or the ratio of Aβ42/Aβ40 compared with wild-type variant by in-vitro study. Conclusion: This study provided the profile of AD mutations of PUMCH dementia cohort and demonstrated the possible AD pathogenicity of 6 variants by in-vitro study.

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Section: Resultsmentioning

confidence: 99%

Screening and functional validations of APP, PSEN1 and PSEN2 mutations from PUMCH dementia cohort

Dong

Sha

et al. 2023

Preprint

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“…The PSEN2 R62C was a published variant [ 10 ]. The PSEN2 M239T was reported by our group in 2021 [ 11 ]. The other seven variants were novel, including N141S, I368F, L396I, G117X, I146T, S147N, and H220Y.…”

Section: Resultsmentioning

confidence: 99%

“…The PSEN2 N141S and I368F mutations have not been reported before. Our group reported the PSEN2 M239T mutation in 2021 [ 11 ]. Li et al reported another Chinese early-onset AD patient harboring the PSEN2 M239T in 2021.…”

Section: Discussionmentioning

confidence: 99%

PSEN2 Mutation Spectrum and Novel Functionally Validated Mutations in Alzheimer’s Disease: Data from PUMCH Dementia Cohort

Dong

Liu

Sha

et al. 2022

JAD

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Background: The established causative mutations in the APP, PSEN1, and PSEN2 can explain less than 1%,Alzheimer’s disease (AD) patients. Of the identified variants, the PSEN2 mutations are even less common. Objective: With the genetic study from the dementia cohort of Peking Union Medical College Hospital (PUMCH), we aim to illustrate the PSEN2 mutation spectrum and novel functionally validated mutations in Chinese AD patients. Methods: 702 AD participants, aged 30–85, were identified in PUMCH dementia cohort. They all received history inquiry, physical examination, biochemical test, cognitive evaluation, brain CT/MRI, and next-generation DNA sequencing. Functional analysis was achieved by transfection of the HEK293 cells with plasmids harboring the wild-type PSEN2 or candidate mutations. Results: Nine PSEN2 rare variants were found, including two reported (M239T, R62C) and seven novel variants (N141S, I368F, L396I, G117X, I146T, S147N, H220Y). The HEK293 cells transfected with the PSEN2 N141S, M239T, I368F plasmids showed higher Aβ 42 and Aβ 42/Aβ 40 levels relative to the wild-type PSEN2. The PSEN2 L396I, G117X, S147N, H220Y, and R62C did not alter Aβ 42, Aβ 40 levels, or Aβ 42/Aβ 40 ratio. 1.9%,(13/702) subjects harbored rare PSEN2 variants. 0.4%,(3/702) subjects carried pathogenic/likely pathogenic PSEN2 mutations. The three subjects with the functionally validated PSEN2 mutations were all familial early-onset AD patients. The common symptoms included amnesia and mental symptom. Additionally, the M239T mutation carrier presented with dressing apraxia, visuospatial agraphia, dyscalculia and visual mislocalization. Conclusion: The PSEN2 N141S, M239T, and I368F are functionally validated mutations.

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“…Diets high in saturated fats and cholesterol exacerbate amyloid-beta (Aβ) peptide production and accumulation, worsening Alzheimer's disease development and progression, particularly in individuals with PSEN1 mutations. The typical Western diet, characterized by high intake of red meat, processed foods, and sugary snacks, is associated with increased Alzheimer's disease risk, promoting in ammation and oxidative stress, which can exacerbate neurodegeneration in those with PSEN1 mutations [41,55,56].…”

Section: Psen1 (Presenilin 1)mentioning

confidence: 99%

“…Moreover, cognitive reserve, which refers to the brain's ability to maintain normal cognitive function in the presence of brain pathology, can modify the effects of PSEN1 mutations on Alzheimer's disease phenotype. Factors such as education, occupational attainment, and engagement in mentally stimulating activities contribute to cognitive reserve [42,55].…”

Section: Variability In Disease Phenotypementioning

confidence: 99%

Alzheimer's Disease Investigated via Gene-Environment Interactions, Biochemical Pathways, Cellular Processes, and Disease Phenotype Variability

Shafi,

Siddiqui

2024

Preprint

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Background: Alzheimer's disease (AD) is a neurodegenerative disorder influenced by genetic and environmental factors. APOE, APP, PSEN1, PSEN2, CLU, SORL1, BIN1, CR1, PICALM, TREM2, ABCA7, and CD33 play key roles in AD pathogenesis, affecting biochemical pathways and cellular processes. However, the interaction between genetic predisposition and environmental factors, as well as the reasons for variability in disease phenotype, remain poorly understood. This study aims to investigate these interactions to improve our understanding of AD etiology and inform personalized interventions. Methods: A comprehensive search encompassing databases such as PubMed, MEDLINE, Google Scholar, and open access/subscription-based journals was conducted to retrieve relevant articles for the investigation of genes involved in Alzheimer's disease (AD) pathogenesis, including APOE, APP, PSEN1, PSEN2, CLU, SORL1, BIN1, CR1, PICALM, TREM2, ABCA7, and CD33. Articles were searched without any date restrictions. Utilizing the criteria delineated in the methodology section, studies were systematically reviewed to elucidate how environmental factors and genetics influence Alzheimer's disease onset, progression, symptom severity, and progression rates. This study adheres to relevant PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Results: Our investigation revealed the complicated interactions between genetic predisposition, environmental factors, biochemical pathways, and cellular processes in Alzheimer's disease (AD) pathogenesis. APOE, APP, PSEN1, PSEN2, CLU, SORL1, BIN1, CR1, PICALM, TREM2, ABCA7, and CD33 influence amyloid-beta production, tau pathology, lipid metabolism, and inflammation in AD. These genes interact with environmental factors such as diet, pollutants, head trauma, and lifestyle, modulating disease risk and progression. Additionally, we found variability in disease phenotype among individuals carrying similar genetic mutations, influenced by genetic modifiers, environmental factors, cognitive reserve, and neurobiological differences. Conclusion: Alzheimer's disease (AD) is a multifactorial disorder influenced by genetic and environmental factors. APOE, APP, PSEN1, PSEN2, CLU, SORL1, BIN1, CR1, PICALM, TREM2, ABCA7, and CD33 play critical roles in AD pathogenesis by affecting amyloid-beta production, tau pathology, lipid metabolism, and inflammation. These genes interact with environmental factors such as diet, pollutants, head trauma, and lifestyle, further modulating disease risk and progression. Understanding these complicated interactions is essential for developing personalized interventions to delay onset, reduce severity, and slow AD progression.

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Clinical Phenotype and Mutation Spectrum of Alzheimer’s Disease with Causative Genetic Mutation in a Chinese Cohort

Cited by 7 publications

References 32 publications

Screening and functional validations of APP, PSEN1 and PSEN2 mutations from PUMCH dementia cohort

Screening and functional validations of APP, PSEN1 and PSEN2 mutations from PUMCH dementia cohort

PSEN2 Mutation Spectrum and Novel Functionally Validated Mutations in Alzheimer’s Disease: Data from PUMCH Dementia Cohort

Alzheimer's Disease Investigated via Gene-Environment Interactions, Biochemical Pathways, Cellular Processes, and Disease Phenotype Variability

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