#aaic18

Catherine Kaczorowski, Ph.D. Associate Professor and Evnin Family Chair in Alzheimer's Research Kristen O’Connell, Ph.D., Assistant Professor Amy Dunn, Ph.D., Postdoctoral Associate The Jackson Laboratory MedicalResearch.com: What is the background for this study? What are the main findings?  Dr. Amy Dunn: “Alzheimer's disease is complex, with both genetic and environmental factors determining symptom onset and disease progression, though our current understanding of how genetic and environmental factors interact to influence disease risk is incomplete. We recently developed a panel of genetically diverse mice carrying human familial AD mutations (AD-BXDs) that better model human AD in order to determine how genetics and diet interact to modify disease onset and severity. We fed a high fat diet to AD-BXDs and monitored metabolic and cognitive function over the duration of the HFD feeding.  We observed accelerated working memory decline in most of the AD-BXD mouse strains, however, the impact of high fat diet on memory was dependent on individual genetic differences across the panel, with some AD-BXD strains maintaining cognitive function on high fat diet (resilient strains). Our data suggest that diet and genetic background interact to mediate vulnerability to AD pathogenesis, and that metabolic factors (e.g. obesity, body composition) that may contribute to cognitive decline differentially in normal aging versus AD. “ Dr. Kristen O’Connell: “We also found that sex plays a critical role in determining the impact of high fat diet and body weight on the onset and severity of memory deficits, with females exhibiting more rapid decline, paralleling what has been reported in humans. These data suggest that incorporation of genetic diversity into existing models of AD dramatically enhances their translational relevance and emphasizes the need to include both males and females in preclinical studies. Our panel can now be used to identify the mechanisms underlying how and why certain individuals are more susceptible (or resilient) to developing Alzheimer’s disease based on their genetics and environment.  “ MedicalResearch.com: What should readers take away from your report? Dr. Catherine Kaczorowski: There are individual differences in how vulnerable people are to environmental risk factors for Alzheimer’s disease. Identifying the genetic bases for these differences is difficult to do in humans, so my lab developed the first mouse model of Alzheimer’s disease that will allow us to tease apart these gene-by-environment interactions. Future analyses will identify the genetic and molecular targets contributing to Alzheimer’s disease pathogenesis that may be exploited to delay, prevent or even cure the disease.”  MedicalResearch.com: What recommendations do you have for future research as a result of this work?  Dr. Amy Dunn: “Alzheimer’s disease is a highly complex disease with many contributing genetic and environmental factors. Understanding how these factors interact to determine disease risk and progression will be important in understanding how to best treat the disease in a patient-by-patient manner. By focusing on these individual variations in disease vulnerability in the future, we will improve our ability for individualized therapeutic strategies and multi-scale interventions to better combat Alzheimer’s disease. “   Citation: Gene x Diet Interactions Modify Symptoms of Alzheimer’s Disease (Poster AAIC 2018, Sunday July 22)  The information on MedicalResearch.com is provided for educational purposes only, and is in no way intended to diagnose, cure, or treat any medical or other condition. Always seek the advice of your physician or other qualified health and ask your doctor any questions you may have regarding a medical condition. In addition to all other limitations and disclaimers in this agreement, service provider and its third party providers disclaim any liability or loss in connection with the content provided on this website.   Read the full article

Dr. Carter 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. Citation: Novel Models of Late-Onset Alzheimer’s Disease Based on GWAS presented at AAIC 2018 https://www.alz.org/aaic/overview.asp   The information on MedicalResearch.com is provided for educational purposes only, and is in no way intended to diagnose, cure, or treat any medical or other condition. Always seek the advice of your physician or other qualified health and ask your doctor any questions you may have regarding a medical condition. In addition to all other limitations and disclaimers in this agreement, service provider and its third party providers disclaim any liability or loss in connection with the content provided on this website.    Read the full article

At the Alzheimer’s Association International Conference with JHU Press!