Understanding the molecular mechanisms that contribute to neuropsychiatric symptoms in Alzheimer Disease

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PROJECT SUMMARY Neuropsychiatric symptoms (NPS) are core features of Alzheimer’s disease (AD) and related dementias that are associated with major adverse effects on daily function and quality of life, and accelerate time to institutionalization. Of all the NPS, depression is the most frequently observed symptom in people with mild cognitive impairment and early AD. As the disease progresses, agitation, delusions and hallucinations become more common, whereas apathy is the most persistent and frequent NPS throughout all the stages of AD. AD- NPS share some clinical features with serious mental illnesses (SMIs), such as schizophrenia, bipolar disorder and major depressive disorder, but whether these conditions share similar aethiopathies is unclear. Given that reliable treatments for NPS in the context of AD and other dementias do not exist, a better understanding of the molecular mechanisms and pathways underlying NPS in AD and other neuropsychiatric illnesses is a critical next step to identify reliable biomarkers that could lead to novel therapeutics. The overarching goals of the parent grant are to: (1) identify the molecular mechanisms and neuropathological changes that are associated with the presence of NPS in patients with AD; and (2) examine if the mechanisms of pathology associated with NPS are shared or distinct among AD and SMIs. More specifically, we are currently building gene regulatory networks to integrate phenomics and genomics data (genotypes, single nucleus profiles from dorsolateral prefrontal cortex) from 1,500 autopsy cases. Detailed phenomics data such as well characterized NPS, clinical diagnosis (AD and other neurodegenerative or neuropsychiatric traits), severity of cognitive decline and neuropathology are being utilized. We expect that these models will enable us to assign genotypes and molecular markers to specific NPS within AD and other neuropsychiatric traits at the single-cell level, an unprecedented level of resolution. In addition, we will test the translational potential of the genotype- marker-phenotype models to predict AD-NPS using independent large-scale biobank datasets, in which genotypes and electronic health records are available. This administrative supplement will further enhance these efforts by leveraging human brain single-cell data generated as part of large consortia, including BICAN, SEA-AD, psychENCODE, AMP-PD, and AMP-AD, to validate molecular mechanisms and pathways that are shared or distinct across AD and SMIs. Successful completion of the proposed studies will have immediate utility by generating potential biomarkers for NPS diagnosis and prognosis and by providing predictive models for patient stratification in clinical trials. In the longer term, our models will help us create a blueprint for therapeutic strategies and interventions to treat NPS in AD.