Investigating the Genetics of Sporadic Early‐Onset Alzheimer’s Disease
Kelly NudelmanTrever JacksonMalia RumbaughAni EloyanJulian V. PentchevKelley M. FaberCasey SnoddyTatiana ForoudMaría C. CarrilloBrad C. DickersonGil D. RabinoviciLiana G. Apostolova
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Abstract Background Only a small percentage of early‐onset Alzheimer’s disease (EOAD) participants are known to carry autosomal dominant pathogenic variants in the amyloid beta precursor protein (APP) gene or in presenilin 1 or 2 (PSEN1/2); more research is needed to identify additional causative genetic variants. This study presents results of the initial genetic analyses in the Longitudinal Early Onset Alzheimer’s Disease Study (LEADS) and planned next steps. Methods Whole exome sequencing (WES) is being performed for all cognitively impaired participants, including individuals with EOAD or frontotemporal dementia. Sequencing data is processed using GATK best practices and all variants for APP , PSEN1/2 , progranulin (GRN), and microtubule associated protein tau (MAPT) are reviewed for previously reported pathogenic variants. C9ORF72 is also assessed for pathogenic repeat expansions. WES was analyzed with CANOES and CoNIFER for copy number variants (CNVs). WES data has been reviewed for reported pathogenic variants in other neurodegenerative disease‐associated genes. Gene burden testing is being done for the LEADS cases and age‐matched controls from the Parkinson’s Progression Markers Initiative for rare variants in these genes. Results To date, WES has been generated for 301 cases, and GWAS for 384 participants (290 cases, 89 controls). Reported pathogenic variants or repeat expansions in C9ORF72 , PSEN1 , GRN , and MAPT were identified in 2% of cases for the six screened genes. No CNVs were detected in APP, PSEN1/2 , GRN , or MAPT . Review also identified individuals with pathogenic variants or CNVs in genes linked with diseases including Parkinson’s disease and Niemann‐Pick disease, including reported or predicted pathogenic variants in GBA , LRRK2 , and SMPD1 . Surprisingly, results do not show enrichment of functional TREM2 variants compared to population frequency. Conclusions Initial results indicate that LEADS is strongly enriched for novel genetic risk and/or causative factors, as only 2% have a reported pathogenic variant or repeat expansion in APP , PSEN1/2 , GRN , MAPT , or C9ORF72 . Review of reported pathogenic variants in other neurodegenerative disease‐associated genes indicates that while a small portion of disease etiology may be explained by these variants, more research is needed to identify additional causative and risk factors contributing to EOAD.Keywords:
PSEN1
C9ORF72
Genome-wide Association Study
Early-onset Alzheimer's disease
Medical genetics
Although mutations in three genes, amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2), have been identified as genetic causes of earlyonset Alzheimer s disease (EOAD), there has been a single report on a PSEN1 mutation in Koreans.In the present study, we performed a genetic analysis of six Korean patients with EOAD.Direct sequencing analysis of the APP, PSEN1 and PSEN2 genes revealed two different mutations of the PSEN1 gene (G206S and M233T) and one mutation of the APP gene (V715M) in three patients with age-atonset of 34, 35, and 42 yr, respectively.In addition, two patients with age-at-onset of 55 and 62 yr, respectively, were homozygous for APOE 4 allele.One woman had no genetic alterations.These findings suggest that PSEN1 and APP gene mutations may not be uncommon in Korean patients with EOAD and that genetic analysis should be provided to EOAD patients not only for the identification of their genetic causes but also for the appropriate genetic counseling.
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Apolipoprotein E
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Neuroradiology
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Amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are associated with autosomal-dominant early-onset Alzheimer’s disease (AD). Most mutations have been identified in the PSEN1 gene. We discovered a PSEN1 mutation (Tyr389His) in a Korean patient with early-onset AD who presented memory decline at 41 years of age followed by language, memory, and visuospatial dysfunctions. As this is the third such patient identified in Korea, this mutation may be involved in AD pathogenesis, suggesting that routine screening is necessary in this population. Altered intra-molecular interactions with the mutated amino acid may result in the destabilization of γ-secretase. In the future, a panel incorporating genes with relatively high-frequency rare variants, along with the APOE4 gene, may predict the onset of AD and facilitate customized treatment.
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Early-Onset Familial Alzheimer's Disease (EOFAD) has been reported to be associated with Presenilin 1 (PSEN1), Presenilin 2 (PSEN2), and Amyloid Precursor Protein (APP) genes. The spectrum of mutations in Chinese patients with EOFAD was rarely investigated.To investigate the spectrum of mutations in patients with EOFAD in Chinese population.We performed whole-exome sequencing and described relevant clinical features in a total of 67 subjects from 3 families with EOFAD.A splice mutation (p.S290C) in PSEN1 and a missense mutation (p.V717I) in APP were identified.The variant p. S290C (c.869-2>G) in PSEN1 in Chinese EOAD family revealed different clinical phenotypes when compared with that of Europeans.
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Exome
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Presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) mutations are responsible for autosomal dominant early-onset Alzheimer's disease (AD-EOAD). To analyze the phenotypes and genotypes of EOAD patients, we performed comprehensive clinical assessments as well as mutation screening of PSEN1, PSEN2, and exons 16 and 17 of APP by Sanger sequencing in the three Chinese EOAD families. We identified two novel mutations of PSEN1 (Y256N and H214R) in samples from these families, and a de novo mutation of PSEN1 (G206V) in a patient with very early-onset sporadic Alzheimer's disease. A combination of bioinformatics tools based on evolutionary, structural and computational methods predicted that the mutations were all deleterious. These findings suggest that PSEN1 Y256N, H214R, and G206V need to be considered as potential causative mutations in EOAD patients. Further functional studies are needed to evaluate the roles of these mutations in the pathogenesis of AD.
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Sanger sequencing
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