SORL1 genetic variants and Alzheimer disease risk: a literature review and meta-analysis of sequencing data
Abstract
Massive parallel sequencing recently allowed the identification of three genes carrying a higher burden of rare, protein-truncating and missense predicted damaging variants in Alzheimer disease (AD) cases as compared to controls: TREM2, SORL1, and ABCA7. SORL1 encodes SorLA, a key protein involved in the processing of the amyloid-beta (Aβ) precursor protein (APP) and the secretion of the Aβ peptide, the aggregation of which triggers AD pathophysiology. Common SORL1 single nucleotide polymorphisms had originally been associated with AD with modest odds ratios (ORs). The association of AD with rare SORL1 coding variants has been demonstrated at the gene level by aggregating protein-truncating (PTV) and rare predicted damaging missense variants. In addition to the loss of SorLA function induced by PTVs, a few missense variants were studied in vitro, showing diverse degrees of decreased SorLA function and leading to increased Aβ secretion. However, the exact functional consequences of most of the missense variants remain to be determined as well as corresponding levels of AD risk. Hereby we review the evidence of the association of SORL1 common and rare variants with AD risk and conduct a meta-analysis of published data on SORL1 rare variants in five large sequencing studies. We observe a significant enrichment in PTVs with ORs of 12.29 (95% confidence interval = [4.22-35.78]) among all AD cases and 27.50 [7.38-102.42] among early-onset cases. Rare [minor allele frequency (MAF) -…
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Several genetic loci with relevance to AD pathogenesis (e.g., PICALM, SORL1, BIN1) encode proteins found in the ER and/or Golgi compartments of cells.
“Second, several genetic loci with relevance to AD pathogenesis (e.g., PICALM, SORL1, BIN1) encode proteins found in the ER and/or Golgi compartments of cells.52, 53”
From ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis (2025) · cites this paper as [53]
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- Authors
- Campion, D., Charbonnier, C., & Nicolas, G.
- Affiliations
- Inserm (FR)
- Corresponding author
- Campion, Dominique
- Nicolas, Gaël
- Venue
- Acta Neuropathologica
- Published
- 2019-03-25
- Volume
- 138
- Issue
- 2
- Pages
- 173-186
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- OpenAlex
- W2941381527
- Cited by
- 124
- References
- 12
- Citations by year
- 2026: 10 · 2025: 18 · 2024: 15 · 2023: 16 · 2022: 27 · 2021: 21 · 2020: 13 · 2019: 3
- FWCI
- 1.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Acta Neuropathologica (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fondation pour la Recherche Médicale (DEQ20170336711)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- SORL1, SorLA, Alzheimer's disease, rare variants, truncating mutations, missense mutations, amyloid-beta secretion, amyloid precursor protein, early-onset Alzheimer's disease, genetic risk, fibronectin type III domain, TREM2, ABCA7
- MeSH terms
- Protein Domains, Whole Genome Sequencing, Alzheimer Disease, Codon, Female, Gene Frequency, Genes, Dominant, Humans, Male, Pedigree, Risk, Case-Control Studies, Sequence Analysis, DNA, ATP-Binding Cassette Transporters, Genetic Predisposition to Disease, Mutation, Missense, Polymorphism, Single Nucleotide, LDL-Receptor Related Proteins, Membrane Transport Proteins, Apolipoprotein E4, Genome-Wide Association Study
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