ABSTRACT Patients with Alzheimer's Disease (AD) frequently manifest comorbid neuropsychiatric symptoms (NPS) and related conditions with depression and anxiety being most prevalent. Posttraumatic stress disorder (PTSD) is one neuropsychiatric condition that is highly comorbid with depression and anxiety, and has been shown to increase one's risk for developing dementia. Our central hypothesis is that there are shared genetic etiologies between AD and PTSD and the shared molecular phenotypes between the two conditions will reveal clues for advancing therapeutic interventions that could delay our ultimately prevent the onset of AD. Toward this end, the goal for this proposal is to dissect the genetic, epigenetic and transcriptomic perturbations that are shared between AD and PTSD and to determine the predictive validity of these molecular phenotypes for the development of AD. Comparing and contrasting the corresponding `-omics' profiles between AD and PTSD represents a novel strategy. We will leverage our extensive current `-omics' studies of PTSD in active-duty service members before and after deployment as well as human postmortem samples in PTSD cases and controls and use parallel data in AD from the ROSMAP and ADNI studies. In silico analyses will use existing AD datasets that include phenotypic data for depression and anxiety and extensive high-dimensional molecular data. We will complement the computational analyses with in vivo experimental validations using single-cell analyses in human brain. In Aim 1, we will identify genetic signatures common for AD and PTSD. We will test for genetic overlap for the two phenotypes at baseline and for progression/decline over time using NPS scores. The validity of the signatures will be tested for prediction of conversion from NCog to MCI and AD. Aim 2 will analyze epigenetic changes in AD and PTSD compared to age- sex- APOE- matched control groups and identify overlapping genomic regions that undergo epigenomic modification in AD and PTSD. Epigenome-wide (DNA methylation and histone acetylation (H3K9Ac)) profiles from brain samples for the ROSMAP and PTSD cohorts will be used to test for epigenetic changes associated with AD and PTSD using a similar experimental design as Aim 1. DNA methylation and ATAC-seq in AD and PTSD brains will be used for validation. Aim 3 will characterize differential gene-expression profiles in AD and PTSD compared to the respective age- sex- APOE- matched control groups. RNAseq data will be used to test for gene-expression changes associated with AD and PTSD. Single-cell gene expression profiling will be used to validate specific genes identified. The validity of the identified transcriptomic changes for prediction of conversion from NCog to MCI and AD will be tested. The outcomes of this study will identify specific molecular signatures and build predictive models for AD and PTSD. This knowledge will provide insights regarding actionable targets for development of novel therapies to treat NPS earlier in life in an effort to delay or ultimately prevent the onset of AD.