The purpose of this application for a K23 award is to provide additional training to Dr. Sokolow to establish herself as a successful independent investigator in patient-oriented research focusing on the pharmacogenomics (PGX) of Alzheimer's Disease (AD). Dr. Sokolow's academic background includes an advanced degree in pharmacy practice and a doctorate in Biomedical Sciences with specialization in molecular biology and mouse genetics. For the past seven years, her research program at the UCLA School of Nursing has focused on the neurobiology of AD. Her training plan includes a cross-training in bioinformatics, biostatistics and statistical genomics. In addition to her training pla, she has assembled an outstanding mentoring team with expertise in clinical phenomenology of AD, genome-wide association studies (GWAS) and PGX. The collaborative environment of the UCLA School of Nursing, the UCLA Mary S. Easton Center for AD Research and the Institute for Translational Genomics and Population Sciences - Los Angeles Biomedical Research Institute is ideal for developing her new research program focusing on the investigation of genetic factors affecting the response to donepezil (DPZ) in MCI individuals. MCI is a syndrome characterized by a memory deficit which differs from normal age-related changes in memory and dementia. There is no pharmacotherapy approved for the treatment of cognitive symptoms in MCI patients; however DPZ is the most commonly prescribed medication for this disorder. Existing neuropsychological testing and GWAS data collected from 3 previously conducted studies [i.e. Alzheimer's Disease Neuroimaging Initiative study (ADNI); Alzheimer's Disease Cooperative Study (ADCS) trial of MCI and the Imaging and Genetic Biomarkers for Alzheimer's Disease study (ImaGene)] will be used to address 3 complementary specific aims.
In Aim 1, we will impute the existing GWAS against the 1000 genome project and we will perform association studies to test the interactions between DPZ response and candidate genetic polymorphisms associated with AD susceptibility/endopehenotype and/or with DPZ response in AD. DPZ response will first be estimated with existing Clinical Dementia Rating sum of boxes scores. Follow-up of the top PGX markers will be assessed with 5 other measures of cognition and executive function.
In Aim 2, we will use the same resources and we will apply pathway-based association analyses of DPZ response in MCI to identify new PGX markers.
In Aim 3, we expect to validate the associations between DPZ response and the strongest candidate for the actual predisposing SNPs at the top genetic loci discovered in Aims 1&2 using existing Whole-genome sequence (WGS) data from ADNI study. Overall, we expect to demonstrate the usefulness of PGX testing in clinical practice and in clinical trials to identify the individuals who are most liely to benefit from the pharmacotherapy. At the conclusion of this award, Dr. Sokolow will have the necessary skill sets to compete effectively for future NIH support and to propel her to an independent career in AD PGX.
Mild cognitive impairment (MCI) is a syndrome characterized by a memory deficit which differs from normal age-related changes in memory and dementia. The most common treatment for MCI is donepezil, given the inter-patient variability to donepezil response, it is important to identify genetic variations offering the best therapeutic benefits in MCI patients taking DPZ. The discovery of new genetic markers associated with slower cognitive decline and/or slower conversion to Alzheimer's disease provides the opportunity to assess the utility of genetic testing for personalized DPZ therapy in MCI patients.
| Sokolow, Sophie; Li, Xiaohui; Chen, Lucia et al. (2017) Deleterious Effect of Butyrylcholinesterase K-Variant in Donepezil Treatment of Mild Cognitive Impairment. J Alzheimers Dis 56:229-237 |
