ArticleGenome medicine2022
Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes.
Article in Genome medicine, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 16 papers.
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16 citing papers in PubMed, 23 citations in OpenAlex.
- Assessing the de novo paradigm in sporadic early-onset Alzheimer disease trios.Molecular psychiatry · 2026Article
- Novel Frameshift Variant in SORL1 Gene Identified in a EOAD Family Causes APP Sorting Dysfunction and Endolysosomal Swelling.Molecular neurobiology · 2026Article
- ACE-Dependent Alzheimer's Disease: Blood ACE Phenotyping of the Most Prevalent and DamagingBiomedicines · 2026Article
- Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer's disease.Molecular neurodegeneration · 2025Article
- Genetic testing of common and rare variants in dementia patients from a memory clinic : Dementia-related genetic testing in memory clinic.Alzheimer's research & therapy · 2025Article
- An International Working Group viewpoint on stratifying risk and prevention of the clinical expression of Alzheimer's disease.Nature aging · 2025Article
- The Biomarker Profile of Alzheimer's Disease for Disease-Modifying Treatment Eligibility: Questions and Debates.International journal of molecular sciences · 2025Review
- Familial Alzheimer's disease mutation identifies novel role of SORLA in release of neurotrophic exosomes.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Article
- Soluble SorLA in CSF, a novel biomarker to explore disrupted trafficking of SorLA protein in Alzheimer disease.Alzheimer's research & therapy · 2025Article
- The impact of rare genetic variants on Alzheimer disease.Nature reviews. Neurology · 2025Review
- Alzheimer Disease as a Clinical-Biological Construct-An International Working Group Recommendation.JAMA neurology · 2024Article
- Haploinsufficiency and Alzheimer's Disease: The Possible Pathogenic and Protective Genetic Factors.International journal of molecular sciences · 2024Review
- TheProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Morphological profiling in human neural progenitor cells classifies hits in a pilot drug screen for Alzheimer's disease.Brain communications · 2024Article
- Publisher Correction: Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes.Genome medicine · 2022Article
Corrections and comments
- Erratum issued
Authors and funding
14 authors at 4 institutions in 1 country.
Funding
Abstract
backgroundAlzheimer disease (AD) is a common complex disorder with a high genetic component. Loss-of-function (LoF) SORL1 variants are one of the strongest AD genetic risk factors. Estimating their age-related penetrance is essential before putative use for genetic counseling or preventive trials. However, relative rarity and co-occurrence with the main AD risk factor, APOE-ε4, make such estimations difficult.
methodsWe proposed to estimate the age-related penetrance of SORL1-LoF variants through a survival framework by estimating the conditional instantaneous risk combining (i) a baseline for non-carriers of SORL1-LoF variants, stratified by APOE-ε4, derived from the Rotterdam study (N = 12,255), and (ii) an age-dependent proportional hazard effect for SORL1-LoF variants estimated from 27 extended pedigrees (including 307 relatives ≥ 40 years old, 45 of them having genotyping information) recruited from the French reference center for young Alzheimer patients. We embedded this model into an expectation-maximization algorithm to accommodate for missing genotypes. To correct for ascertainment bias, proband phenotypes were omitted. Then, we assessed if our penetrance curves were concordant with age distributions of APOE-ε4-stratified SORL1-LoF variant carriers detected among sequencing data of 13,007 cases and 10,182 controls from European and American case-control study consortia.
resultsSORL1-LoF variants penetrance curves reached 100% (95% confidence interval [99-100%]) by age 70 among APOE-ε4ε4 carriers only, compared with 56% [40-72%] and 37% [26-51%] in ε4 heterozygous carriers and ε4 non-carriers, respectively. These estimates were fully consistent with observed age distributions of SORL1-LoF variant carriers in case-control study data.
conclusionsWe conclude that SORL1-LoF variants should be interpreted in light of APOE genotypes for future clinical applications.
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