MedicalResearch.com Interview with:
Gregory Carter, PhD
Associate Professor at The Jackson Laboratory
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Late-onset Alzheimer’s disease (LOAD) is the most common form of the disease and the major cause of dementia in the aging population. To date, the complex genetic architecture of LOAD has hampered both our ability to predict disease outcome and to establish research models that effectively replicate human disease pathology.
Therefore, most basic research into Alzheimer’s disease has focused on early-onset forms caused by mutations in specific genes, which has provided key biological insights but to date has not translated to effective disease preventatives or cures.
Our study analyzes both common and rare human genetic variants to identify those significantly associated with .late-onset Alzheimer’s disease, beginning with a large data set from the Alzheimer’s Disease Sequencing Project. We also analyzed RNA sequencing data from post-mortem human and mouse model samples to prioritize candidate genes.
We found a new common coding variant significantly associated with disease, in addition to those in genes previously associated with late-onset Alzheimer’s disease. We also found five candidate genes conferring a significant rare variant burden.
MedicalResearch.com: What should readers take away from your report?
Response: Our results highlight that both common and rare coding genetic variants are likely to play important roles in late-onset Alzheimer’s disease pathology, indicating a “multiple hit” model for disease that affects cognitive decline. Furthermore, we identified new candidate genes in interacting biological pathways, expanding our understanding of the polygenic nature of late-onset Alzheimer’s disease.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: Two of the pathways in which we identified an excess of rare, deleterious coding variants involved serotonin function and negative regulation of amyloid-beta pathways. A link between these two pathways indicates that impaired serotonin regulation may impair amyloid-beta clearance, and that restoring serotonin balance in the aging brain could provide a promising therapeutic strategy. More research in this area is certainly merited to understand the pathobiology that drives late-onset Alzheimer’s disease.
Novel Models of Late-Onset Alzheimer’s Disease Based on GWAS
presented at AAIC 2018
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