SORL1 – Alzheimer disease

SORL1 encodes the sortilin‐related receptor (SORLA), a key trafficking protein that regulates amyloid precursor protein (APP) processing. Rare coding variants in SORL1 have been repeatedly observed in families with early‐onset Alzheimer disease (AD) and in case–control cohorts, establishing SORL1 as a strong risk gene for AD.

Inheritance in multiple pedigrees follows an apparent autosomal dominant pattern with heterozygous SORL1 variants segregating with disease across generations. Notably, a missense variant c.2857C>T (p.Arg953Cys) was identified in five of six affected members in a five‐generation family ([PMID:38244079]).

Case reports and sequencing studies have described over 20 distinct rare SORL1 variants in AD cases, including missense, nonsense, frameshift, and splice‐site changes. In early‐onset dementia series, SORL1 protein‐truncating variants (PTVs) such as p.Arg866Ter and p.Arg744Ter were found exclusively in patients, while missense alterations predicted to disrupt key domains also co‐segregated with AD ([PMID:30009200]; [PMID:27026413]).

Population‐based sequencing of 6,965 AD cases and 13,252 controls revealed a significant enrichment of ultra‐rare SORL1 loss‐of‐function variants (19 cases vs 1 control; OR 36.2; P 2.17×10⁻⁸) indicating a strong contribution of SORL1 PTVs to AD risk ([PMID:30009200]).

Functional assays demonstrate that pathogenic SORL1 variants impair SORLA maturation and intracellular trafficking, leading to increased APP at the cell surface, elevated Aβ₄₀/₄₂ secretion, and endolysosome dysfunction. For example, R332W and R654W variants cause endoplasmic reticulum retention and Aβ increase in neuronal cells ([PMID:34922638]; [PMID:25382023]).

In summary, heterozygous rare coding variants in SORL1 confer a strong genetic risk for AD via haploinsufficiency and dominant‐negative effects on SORLA function, resulting in dysregulated APP processing. SORL1 testing can inform diagnostic evaluation and genetic counseling in familial and sporadic early‐onset AD.

Key Take-home: Rare loss‐of‐function and domain‐disrupting SORL1 variants are strong risk factors for autosomal dominant‐like Alzheimer disease and underpin clinical genetic screening.

References

• Annals of clinical and translational neurology • 2018 • Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease. PMID:30009200
• Acta neuropathologica communications • 2021 • Impaired SorLA maturation and trafficking as a new mechanism for SORL1 missense variants in Alzheimer disease. PMID:34922638
• Annals of neurology • 2015 • Coding mutations in SORL1 and Alzheimer disease. PMID:25382023
• Acta neuropathologica • 2024 • A familial missense variant in the Alzheimer's Disease gene SORL1 impairs its maturation and endosomal sorting. PMID:38244079

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