Blood Biomarkers for Memory: Towards Early Detection of Risk for Alzheimer Disease, Pharmacogenomics, and Repurposed Drugs

Short-memory dysfunction is a key early feature of Alzheimer Disease. Psychiatric patients may be at higher risk for memory dysfunction and subsequent Alzheimer due to the negative effects of stress and depression on the brain. We carried out longitudinal within-subject studies in male and female psychiatric patients to identify blood gene expression biomarkers that track short term memory as measured by the retention measure in the Hopkins Verbal Learning Test. These biomarkers were prioritized with a convergent functional genomics approach using previous evidence in the field implicating them in Alzheimer Disease. The top candidate biomarkers were tested in an independent cohort for ability to predict state short-term memory, and trait future positive neuropsychological testing for cognitive impairment Alzheimer disease (AD) is a clear and present danger to older adults, and has a profound socio-economic impact (refs). Existing therapies are limited in efficacy (refs). Early identification of individuals at risk may open the door to preventive approaches. Short-term memory dysfunction is a key early feature of AD. We proposed to identify blood biomarkers that track a relevant related quantitative phenotype for short-term memory, the retention measure of recall in Hopkins Verbal Learning Test (HVLT) (Figure S1). Previous work by our group has identified blood gene 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) (Le-Niculescu et al. Molecular Psychiatry 2013, Niculescu et al. Molecular Psychiatry 2015) (Levey et al. Molecular Psychiatry 2016) (Niculescu et al. Molecular Psychiatry 2017). Those biomarkers were also useful in pharmacogenomic and drug repurposing analyses. We endeavored to use a similar approach to identify biomarkers for short-term memory. We conducted our longitudinal studies in psychiatric disorder subjects, a population enriched in memory retention abnormalities, and which may be at increased risk of AD and other aging-related disorders, due to the effects of stress and depression (Nho et al. 2015, Rangaraju et al. 2016, al refs). The subjects had blood gene expression data at multiple testing visits, and were phenotyped at each visit, including with HVLT. They also had electronic medical records for long term follow-up of subsequent outcomes, including future neuropsychological testing as part of standard clinical care. Diagnoses: SZ - Schizophrenia SZA - schizoaffective disorder BP - Bipolar Disorder MOOD - Mood PSYCH - Psychotic Disorder NOS MDD - Major Depressive Disorder PTSD - Posttraumatic Stress Disorder