DISTRIBUTION OF AMYLOID DEPOSITS ACROSS THE RETINA IN ASSOCIATION WITH ALZHEIMER’S DISEASE AS A FUNCTION OF DISEASE SEVERITY

expression biomarkers that track suicidal ideation using longitudinal within-subject designs, validated them in suicide completers, and tested them in independent cohorts for ability to assess state (suicidal ideation), and ability to predict trait (future hospitalizations for suicidality (Niculescu et al. Molecular Psychiatry 2015, 2017). We used a similar approach to identify biomarkers for the memory measure of retention. We conducted our studies in a longitudinal cohort of psychiatric patients, a population enriched in memory retention abnormalities followed for over a decade. In Step 1 Discovery, we identified blood biomarkers that track memory using a powerful within –subject design in a cohort of subjects who displayed at least a 20% change in the measure between different visits (n1⁄4 159). In Step 2 Prioritization, we used a Convergent Functional Genomics approach to prioritize the candidate biomarkers in Step 1, using published literature evidence (genetic, gene expression and proteomic) for involvement in AD. In Step 3 Testing, we examined in an independent cohort (n1⁄4 138) from the one used for discovery whether the top biomarkers prioritized in Aim 2 are predictive of retention measure (state), and of future positive neuropsychological testing results for MCI, ADRD, or other dementias. Results: We identified gene expression biomarkers that were predictive of memory state, and of future positive neuropsychological testing. Over half of the biomarkers had prior evidence of involvement in other psychiatric disorders, particularly depression and stress, providing a molecular underpinning for the precursor effects of these disorders in AD. Some of the biomarkers are targets of existing drugs, and the gene expression signatures yielded new drug candidates and natural compounds upon bioinformatics drug repurposing analyses. Conclusions: Our work may lead to improved early diagnosis of risk and preventive treatment for memory disorders in general, and AD in particular.