Elucidating Molecular Phenotypes Caused by the SORL1 Alzheimer’s Disease Genetic Risk Factor Using Human Induced Pluripotent Stem Cells

• hIPSC-derived neurons were made from six control individuals and seven SAD patients
• Neurons have SAD risk (R) or protective (P) variants in the SORL1 gene
• P variant neurons increase SORL1 expression and reduce Aβ after BDNF treatment
• The reduction of Aβ in response to BDNF is dependent on SORL1 expression

SummaryPredisposition to sporadic Alzheimer’s disease (SAD) involves interactions between a person’s unique combination of genetic variants and the environment. The molecular effect of these variants may be subtle and difficult to analyze with standard in vitro or in vivo models. Here we used hIPSCs to examine genetic variation in the SORL1 gene and possible contributions to SAD-related phenotypes in human neurons. We found that human neurons carrying SORL1 variants associated with an increased SAD risk show a reduced response to treatment with BDNF, at the level of both SORL1 expression and APP processing. shRNA knockdown of SORL1 demonstrates that the differences in BDNF-induced APP processing between genotypes are dependent on SORL1 expression. We propose that the variation in SORL1 expression induction by BDNF is modulated by common genetic variants and can explain how genetic variation in this one locus can contribute to an individual’s risk of developing SAD.

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