ArticleActa neuropathologica2017
Deleterious ABCA7 mutations and transcript rescue mechanisms in early onset Alzheimer's disease.
Article in Acta neuropathologica, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers, 1 of them a synthesis that pooled it.
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Who cites it
49 citing papers in PubMed, 1 synthesis or guideline pooled it, 73 citations in OpenAlex.
- Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.Nature genetics · 2019Pooled it
- Advancements in the Study of Missense Mutations in ABCA7 in Alzheimer's Disease.Journal of molecular neuroscience : MN · 2026Review
- Article
- The first description of CTNNB1 syndrome in the Tunisian population: clinical investigation, molecular docking and molecular dynamics simulation of β-catenin/E-cadherin complex.Molecular biology reports · 2025Article
- ABCA7 Loss-of-Function Variants Impact Phosphatidylcholine Metabolism in the Human Brain.bioRxiv : the preprint server for biology · 2025Article
- Long-read RNA sequencing: A transformative technology for exploring transcriptome complexity in human diseases.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Neuronal ABCA7 deficiency aggravates mitochondrial dysfunction and neurodegeneration in Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- The impact of rare genetic variants on Alzheimer disease.Nature reviews. Neurology · 2025Review
- Cellular insights into transposable elements in Alzheimer's disease.Frontiers in molecular biosciences · 2025Article
- Association of common and rare variants with Alzheimer's disease in more than 13,000 diverse individuals with whole-genome sequencing from the Alzheimer's Disease Sequencing Project.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Article
- Very low levels of ABCA7 in the cerebrum and Alzheimer's disease onset between the ages of 60 and 80 independently of APOE.Journal of neuropathology and experimental neurology · 2024Article
- Article
- The Abca7Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Article
- Brain cholesterol and Alzheimer's disease: challenges and opportunities in probe and drug development.Brain : a journal of neurology · 2024Review
- The ABC's of Alzheimer risk gene ABCA7.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Review
- Long-read sequencing for brain tumors.Frontiers in oncology · 2024Review
- CSF biomarker analysis of ABCA7 mutation carriers suggests altered APP processing and reduced inflammatory response.Alzheimer's research & therapy · 2023Article
- The Early-Onset Alzheimer's Disease Whole-Genome Sequencing Project: Study design and methodology.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2023Article
- Beyond the exome: What's next in diagnostic testing for Mendelian conditions.American journal of human genetics · 2023Review
- PSEN2 and ABCA7 variants causing early-onset preclinical pathological changes in Alzheimer's disease: a case report and literature review.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2023Review
Corrections and comments
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Authors and funding
45 authors at 16 institutions in 8 countries.
Funding
Abstract
Premature termination codon (PTC) mutations in the ATP-Binding Cassette, Sub-Family A, Member 7 gene (ABCA7) have recently been identified as intermediate-to-high penetrant risk factor for late-onset Alzheimer's disease (LOAD). High variability, however, is observed in downstream ABCA7 mRNA and protein expression, disease penetrance, and onset age, indicative of unknown modifying factors. Here, we investigated the prevalence and disease penetrance of ABCA7 PTC mutations in a large early onset AD (EOAD)-control cohort, and examined the effect on transcript level with comprehensive third-generation long-read sequencing. We characterized the ABCA7 coding sequence with next-generation sequencing in 928 EOAD patients and 980 matched control individuals. With MetaSKAT rare variant association analysis, we observed a fivefold enrichment (p = 0.0004) of PTC mutations in EOAD patients (3%) versus controls (0.6%). Ten novel PTC mutations were only observed in patients, and PTC mutation carriers in general had an increased familial AD load. In addition, we observed nominal risk reducing trends for three common coding variants. Seven PTC mutations were further analyzed using targeted long-read cDNA sequencing on an Oxford Nanopore MinION platform. PTC-containing transcripts for each investigated PTC mutation were observed at varying proportion (5-41% of the total read count), implying incomplete nonsense-mediated mRNA decay (NMD). Furthermore, we distinguished and phased several previously unknown alternative splicing events (up to 30% of transcripts). In conjunction with PTC mutations, several of these novel ABCA7 isoforms have the potential to rescue deleterious PTC effects. In conclusion, ABCA7 PTC mutations play a substantial role in EOAD, warranting genetic screening of ABCA7 in genetically unexplained patients. Long-read cDNA sequencing revealed both varying degrees of NMD and transcript-modifying events, which may influence ABCA7 dosage, disease severity, and may create opportunities for therapeutic interventions in AD.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.