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At the recent American Academy of Neurology annual meeting, researchers presented findings on a Peruvian family with Alzheimer's disease carrying a likely pathogenic stop-gain SORL1 variant.

In this exclusive 番茄社区 video, Anthony Griswold, PhD, an assistant professor in the Department of Human Genetics at the University of Miami Miller School of Medicine, and his research collaborator Mario Cornejo-Olivas, MD, the senior researcher at the Neurogenetics Research Center at the National Institute of Neurological Sciences in Lima, Peru, discuss the findings of the and the novel mutation they identified.

Following is a transcript of their remarks:

Griswold: We have a collaboration at the University of Miami with colleagues in Peru, Mario Cornejo-Olivas. And as part of that study, we're trying to identify risk variance for Alzheimer's disease that may be unique to populations across the world, and particularly in Peru.

Cornejo-Olivas: Since 2019, we are working on this genetic association study for Alzheimer's and related dementias. It's a case-control study intended to identify novel variants and to understand better the genetic architecture of Alzheimer's disease and related dementias in Peru or in the Peruvian populations and populations with very high Amerindian ancestry like us.

Griswold: Dr. Cornejo-Olivas had identified a Peruvian family in which there were four Alzheimer's disease cases as well as two individuals with cognitive impairment. So that's six siblings, all with cognitive impairment in a single family.

Cornejo-Olivas: So clearly it was a familial Alzheimer's disease family. And as part of the study, together with the University of Miami, we were able to identify the genetic cause of this disorder in this particular family.

Griswold: As part of our study, we enrolled these individuals. We did whole genome sequencing for all six of these individuals to try to identify any shared variation between them. One of the variants that we identified is in a protein called SORL1, and this causes a change from a tryptophan to a stop codon in this protein. That means that there is, what we believe, only half of the functional protein of SORL1 exists in these individuals.

The reason why this was interesting to us particularly is that SORL1 has been identified as a risk factor for Alzheimer's disease starting in around 2007. The first variants in SORL1 were identified. And SORL1 is a protein that's involved in the trafficking of A [amyloid] beta from cellular membranes to inside the cells for degradation. So it's part of an endosomal pathway. And so when you have misfunctioning SORL1, the thought is that there is more A beta that can accumulate in these amyloid plaques that are a hallmark of Alzheimer's disease. And so having functional SORL1 is very important for the cells in the brain -- the neurons and the astrocytes -- to remove what could be these toxic A beta molecules.

And so in this particular family with this truncation mutation, we expect that they only have half of the amount of SORL1, and so probably a deficit in its function.

Cornejo-Olivas: The reason why, from the genetic perspective, it's quite important to study these populations is because we certainly can find novel variants that are only related to our genetic or ancestry background that may increase or also diminish the risk or somehow modify the risk for many different disorders. In this case, for Alzheimer's disease.

Griswold: This particular mutation is unique. No one has ever seen it before, even in the thousands of genomes that have been sequenced of Alzheimer's cases. And so this is really a novel mutation, and not only is it novel, but it also falls only on the part of the genome that comes from an Amerindian ancestry. And so this really highlights the necessity of recruiting into studies representative populations from all over the world because we believe that there are going to be variants that are being missed if we are not inclusive of all of these individuals.

And so the hope is that as we continue to find more evidence for proteins like SORL1 and this type of mutation, these can then become therapeutic targets because they inform us of the downstream molecular pathways that are involved in the ultimate pathogenesis for Alzheimer's disease.

Cornejo-Olivas: At this point, we are completing the functional analysis on the samples that we gathered from all this family, trying to expand as much as possible the clinical information, and obviously work with the family to try to help them to understand what's going on in this family. We are in contact with them trying to provide as much as information that is going to be relevant for them in terms of healthcare and to prevent the future for them and for their at-risk family members as well.

Griswold: And so we hope to continue this study. We're starting to do functional work on this mutation now. We have some preliminary data that's quite exciting, that it does look that this mutation is inhibiting the SORL1 function. And so we're going to continue to work through this and really try to characterize this variant in more detail from this particular family.

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