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Coding mutations in SORL1 and Alzheimer disease
Badri N Vardarajan1, Yalun Zhang, Joseph H Lee
1Taub Institute for Research on Alzheimer's Disease and the Aging Brain; Gertrude H. Sergievsky Center, Columbia University, New York, NY.
Annals of Neurology
|November 11, 2014
Summary
Genetic variants in the SORL1 gene increase the risk of late-onset Alzheimer disease (LOAD) by altering amyloid precursor protein (APP) processing. This leads to higher levels of amyloid-beta (Aβ) peptides, contributing to disease development.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Single nucleotide polymorphisms in the SORL1 gene are linked to late-onset Alzheimer disease (LOAD).
- The specific causal variants and underlying mechanisms require further elucidation.
Purpose of the Study:
- To identify functional SORL1 mutations in patients diagnosed with LOAD.
- To investigate the impact of these variants on amyloid precursor protein (APP) processing and amyloid-beta (Aβ) secretion.
Main Methods:
- A family- and cohort-based genetic association study involving Caribbean Hispanics and individuals of Northern European origin.
- Targeted resequencing and genotyping of SORL1 coding variants.
- Functional analysis of variants in human embryonic kidney 293 cell lines to assess Aβ40, Aβ42 secretion, and cell surface APP levels.
Main Results:
- Seventeen coding exonic variants in SORL1 were significantly associated with LOAD.
- Two rare variants (E270K, T947M) and one common variant (A528T) were identified as deleterious.
- Transfected cells exhibited increased Aβ40 and Aβ42 secretion and elevated cell surface APP for all identified variants.
Conclusions:
- Both common and rare SORL1 variants increase LOAD risk.
- These variants directly impact APP processing, leading to elevated Aβ40 and Aβ42 secretion.
- Dysfunctional APP processing and subsequent Aβ accumulation are key mechanisms in SORL1-associated LOAD.
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