Identifying and treating SORL1-associated Alzheimer’s disease (SORLA - FIX)

SORL1 is an essential component of the retromer, which supports the trafficking of cargo away from the endosome to the Golgi or the cell surface. The functioning of this cellular pathway is essential for brain health. Genetic variants that impair SORL1 function lead to cellular defects underlying neuroinflammation and neurodegeneration, and specifically Alzheimer's Disease.
With the SORLA-FIX consortium, we investigated which of the many genetic mutations in the SORL1 have a risk-increasing or even causative effect on Alzheimer Disease, and we evaluated why specific variants had an impairing effect on its sorting function.

Goal

The aim of this project is to investigate the effect of SORL1-mutations on the production and accumulation of Alzheimer proteins in the patient brain. Second, we will investigate whether we can identify medications that can counteract these harmful effects. With this research we hope to contribute to a selective treatment strategy for SORL1-mutation carriers, in order to postpone or to escape the onset of SORL1-associated AD.

Approach

Using an approach called domain mapping of disease mutations (DMDM), we identified high-risk variants that lead to early onset forms of Alzheimer's disease. Knowing which variants are causative or risk-increasing for AD allows clinical geneticists to identify which AD patients may be affected by impaired SORL1 function. Furthermore, we investigated soluble SORLA levels in CSF, which were decreased in carriers of protein-impairing genetic variants in SORL1. Additionally, we found that brain tissues from SORL1 variant carriers reveal dysregulated pro- and anti-inflammatory cytokines, indicating disrupted inflammatory regulation in SORL1-associated AD.

Results

We have identified mutations in the gene that are predicted to impair SORL1 protein function. We identified three families with early onset AD, in which affected family members carried with the Y1816C variant. Further investigation of the effect of this mutation, which included cloning this variant into iPSCs, indicated that it strongly impaired SORL1 homodimerization in the endosome, leading to decreased trafficking to the cell surface and less sSORLA shedding.
One of the most impactful achievements of the SORLA-FIX consortium is the addition of SORL1 as an Alzheimer gene on Alzforum, and the media coverage around this: https://www.alzforum.org/mutations/sorl1

This database includes all the SORL1 variants known to date, which are annotated according to the pathogenicity as evaluated by the SORLA-FIX consortium.
Together, we provided supporting evidence that specific variants in the SORL1 gene should be considered alongside impairing genetic variants in the established ADAD genes APP, PSEN1, and PSEN2 in AD diagnostics.