ArticleJournal of Alzheimer's disease : JAD2017
Rare Genetic Variant in SORL1 May Increase Penetrance of Alzheimer's Disease in a Family with Several Generations of APOE-ɛ4 Homozygosity.
Article in Journal of Alzheimer's disease : JAD, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers, 1 of them a synthesis that pooled it.
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Who cites it
23 citing papers in PubMed, 1 synthesis or guideline pooled it, 38 citations in OpenAlex.
- Finding memo: versatile interactions of the VPS10p-Domain receptors in Alzheimer's disease.Molecular neurodegeneration · 2022Pooled it
- SORLA up-regulation suppresses pathological effects in aged tauopathy mouse brain.Science advances · 2026Article
- Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer's disease.Molecular neurodegeneration · 2025Article
- Brain DNA Methylation Atlas of AppAging cell · 2025Article
- Beyond Transgenic Mice: Emerging Models and Translational Strategies in Alzheimer's Disease.International journal of molecular sciences · 2025Review
- TheProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Human brain glycoform coregulation network and glycan modification alterations in Alzheimer's disease.Science advances · 2024Article
- Genetic Phenotypes of Alzheimer's Disease: Mechanisms and Potential Therapy.Phenomics (Cham, Switzerland) · 2023Review
- Golgi fragmentation - One of the earliest organelle phenotypes in Alzheimer's disease neurons.Frontiers in neuroscience · 2023Article
- Mapping the genetic landscape of early-onset Alzheimer's disease in a cohort of 36 families.Alzheimer's research & therapy · 2022Article
- Heterozygous and Homozygous Variants inInternational journal of molecular sciences · 2022Article
- Mutations in SORL1 and MTHFDL1 possibly contribute to the development of Alzheimer's disease in a multigenerational Colombian Family.PloS one · 2022Article
- Symptomatic, Genetic, and Mechanistic Overlaps between Autism and Alzheimer's Disease.Biomolecules · 2021Review
- Article
- Insights Into the Proteomic Profiling of Extracellular Vesicles for the Identification of Early Biomarkers of Neurodegeneration.Frontiers in neurology · 2020Review
- Genome sequencing for early-onset or atypical dementia: high diagnostic yield and frequent observation of multiple contributory alleles.Cold Spring Harbor molecular case studies · 2019Article
- Genetic and epigenetic study of an Alzheimer's disease family with monozygotic triplets.Brain : a journal of neurology · 2019Article
- The Contribution of Genetic Factors to Cognitive Impairment and Dementia: Apolipoprotein E Gene, Gene Interactions, and Polygenic Risk.International journal of molecular sciences · 2019Review
- Cerebral Small Vessel Disease (CSVD) - Lessons From the Animal Models.Frontiers in physiology · 2019Review
- SORLA attenuates EphA4 signaling and amyloid β-induced neurodegeneration.The Journal of experimental medicine · 2017Article
Corrections and comments
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Authors and funding
14 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe major genetic risk factor for late onset Alzheimer's disease (AD) is the APOE-ɛ4 allele. However, APOE-ɛ4 homozygosity is not fully penetrant, suggesting co-occurrence of additional genetic variants.
objectiveTo identify genetic factors that, next to APOE-ɛ4 homozygosity, contribute to the development of AD.
methodsWe identified a family with nine AD patients spanning four generations, with an inheritance pattern suggestive of autosomal dominant AD, with no variants in PSEN1, PSEN2, or APP. We collected DNA from four affected and seven unaffected family members and performed exome sequencing on DNA from three affected and one unaffected family members.
resultsAll affected family members were homozygous for the APOE-ɛ4 allele. Statistical analysis revealed that AD onset in this family was significantly earlier than could be expected based on APOE genotype and gender. Next to APOE-ɛ4 homozygosity, we found that all four affected family members carried a rare variant in the VPS10 domain of the SORL1 gene, associated with AβPP processing and AD risk. Furthermore, three of four affected family members carried a rare variant in the TSHZ3 gene, also associated with AβPP processing. Affected family members presented between 61 and 74 years, with variable presence of microbleeds/cerebral amyloid angiopathy and electroencephalographic abnormalities.
conclusionWe hypothesize that next to APOE-ɛ4 homozygosity, impaired SORL1 protein function, and possibly impaired TSHZ3 function, further disturbed Aβ processing. The convergence of these genetic factors over several generations might clarify the increased AD penetrance and the autosomal dominant-like inheritance pattern of AD as observed in this family.
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