ArticleActa neuropathologica2024
A familial missense variant in the Alzheimer's disease gene SORL1 impairs its maturation and endosomal sorting.
Article in Acta neuropathologica, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 25 citations in OpenAlex.
- The Alzheimer's disease risk gene SORL1 is a regulator of excitatory neuronal function.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- SORL1 variant links endosomal amyloid precursor protein mis-sorting to axonal transport defects and neuronal dysfunction.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- SORLA up-regulation suppresses pathological effects in aged tauopathy mouse brain.Science advances · 2026Article
- Novel Frameshift Variant in SORL1 Gene Identified in a EOAD Family Causes APP Sorting Dysfunction and Endolysosomal Swelling.Molecular neurobiology · 2026Article
- Alzheimer's disease risk single nucleotide polymorphism rs11218343 is linked to functional expression of SORL1 in microglia.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Estradiol ameliorates AD pathology and cognitive deficits by SORLA-mediated APP endosomal trafficking.Alzheimer's research & therapy · 2026Article
- RhoGEF12 regulates endosomal SORL1-retromer and its inhibition is therapeutic in human neuronal models of Alzheimer's disease.bioRxiv : the preprint server for biology · 2026Article
- Immune dysfunction in Alzheimer disease.Nature reviews. Neuroscience · 2026Review
- Shared Neuroinflammatory Mechanisms Across Dementia Types: An Integrative Review.International journal of molecular sciences · 2025Review
- Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer's disease.Molecular neurodegeneration · 2025Article
- Region-specific proteomic analysis of aging rhesus macaques following chronic glutamate-carboxypeptidase-II (GCPII) inhibition elucidates potential treatment strategies for sporadic Alzheimer's disease.bioRxiv : the preprint server for biology · 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
- 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
- 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
- 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
- Limbic-predominant age-related TDP-43 encephalopathy (LATE-NC): Co-pathologies and genetic risk factors provide clues about pathogenesis.Journal of neuropathology and experimental neurology · 2024Review
- Functional characterization ofPhilosophical transactions of the Royal Society of London. Series B, Biological sciences · 2024Article
- Pharmacologic enhancement of retromer rescues endosomal pathology induced by defects in the Alzheimer's gene SORL1.Stem cell reports · 2023Article
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13 authors at 4 institutions in 2 countries.
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Abstract
The SORL1 gene has recently emerged as a strong Alzheimer's Disease (AD) risk gene. Over 500 different variants have been identified in the gene and the contribution of individual variants to AD development and progression is still largely unknown. Here, we describe a family consisting of 2 parents and 5 offspring. Both parents were affected with dementia and one had confirmed AD pathology with an age of onset > 75 years. All offspring were affected with AD with ages at onset ranging from 53 years to 74 years. DNA was available from the parent with confirmed AD and 5 offspring. We identified a coding variant, p.(Arg953Cys), in SORL1 in 5 of 6 individuals affected by AD. Notably, variant carriers had severe AD pathology, and the SORL1 variant segregated with TDP-43 pathology (LATE-NC). We further characterized this variant and show that this Arginine substitution occurs at a critical position in the YWTD-domain of the SORL1 translation product, SORL1. Functional studies further show that the p.R953C variant leads to retention of the SORL1 protein in the endoplasmic reticulum which leads to decreased maturation and shedding of the receptor and prevents its normal endosomal trafficking. Together, our analysis suggests that p.R953C is a pathogenic variant of SORL1 and sheds light on mechanisms of how missense SORL1 variants may lead to AD.
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