Ballard, C. | bioRxiv Science

bioRxiv2019

Identifying Novel Candidates for Re-Purposing as Potential Therapeutic Agents for Alzheimer’s disease

The current paper describes the identification of novel candidate compounds for repositioning as treatments for Alzheimers disease (AD) from the CMAP library. Candidate compounds were identified based on inverse correlation with transcriptome signatures developed from meta-analyses of Alzheimer RNA expression studies using the SPIED platform. The 78 compounds with a significant inverse correlation were taken forward into an in vitro programme using 6 well validated screening assays relevant to potential treatment targets in AD. Nineteen pf the compounds were hits in at least 2 of these assays. A description of each of these compounds is presented.

neuroscience↗

bioRxiv2019

Association between schizophrenia polygenic score and psychotic symptoms in Alzheimer disease: meta-analysis of 10 cohort studies

BackgroundPsychosis (delusions and hallucinations) is common in Alzheimers disease (AD) and associated with worse clinical outcomes including accelerated cognitive decline and shorter time to nursing home admission. Atypical antipsychotics have limited efficacy which, along with emerging genomic research, suggests some overlapping mechanisms with other disorders characterized by psychosis, like schizophrenia. In this study, we tested whether polygenic risk score (PRS) for schizophrenia was associated with psychotic symptoms in AD. MethodsSchizophrenia PRS was calculated using Psychiatric Genomics Consortium data at 10 GWAS p-value thresholds (PT) in 3,173 AD cases from 11 cohort studies. Association between PRS and AD psychosis status was tested by logistic regression in each cohort individually and the results meta-analyzed. ResultsThe schizophrenia PRS was associated with psychosis in AD at an optimum PT of The strongest association was for delusions where a one standard deviation increase in PRS was associated with a 1.17-fold increased risk (95% CI: 1.07-1.3; p=0.001). ConclusionThese new findings point towards psychosis in AD - and particularly delusions - sharing some genetic liability with schizophrenia, and support a transdiagnostic view of psychotic symptoms across the lifespan.

genomics↗