ABSTRACT The effective causative therapies for Alzheimer’s Disease (AD) and related dementias (ADRDs) remain elusive because the patients are often diagnosed at an advanced state of molecular pathology. Clinically difficult differential diagnosis of early AD is Frontotemporal Dementia (FTD), a progressive neurodegenerative syndrome associated with Frontotemporal Lobar Degeneration disorders (FTLDs). The development of diagnostic tools and therapies for AD and ADRDs has been focused on the part of the human genome that encodes proteins. Most of the genome (97%), however, consists of non-coding RNAs (ncRNAs) which are increasingly recognized as pivotal regulators of cellular processes. ncRNAs have recently emerged as key regulators of brain functions derailed in AD and ADRDs. ncRNA longer than 200 nucleotides are generally referred to as long-noncoding RNAs (lncRNAs). We hypothesize that lncRNAs expressed in specific cortical cells, become de-regulated in AD and FTLDs, and are eventually released in circulation, making them potentially specific pathology-associated biomarkers and drug targets. However, systematic approaches to study lncRNA expression patterns in the brain and in liquid biopsies in the context of AD and FTLDs are few and there is an urgent need to fill this gap in knowledge. The data we present demonstrate our ability to discover lncRNAs expressed or enriched in specific neural cell-types and deregulated in the vulnerable cell populations in brains of AD and FTLDs patients. We developed functional analysis tools to dissect the role of disease biomarker candidate lncRNAs in relevant model systems. We also obtained material for testing the expression level and the specificity of our lncRNAs biomarker candidates in the unprecedented combination of samples from Alzheimer’s Disease Neuroimaging Initiative (ADNI), Framingham Heart Study (FHS), and clinical studies at German Center for Neurodegenerative Diseases (DZNE). In Aim 1 we will test the hypothesis that the differential expression of lncRNAs in postmortem dorsolateral prefrontal cortex and hippocampus will discriminate between AD, FTLDs, and control subjects. We have developed a single nucleus RNA sequencing (snRNAseq) protocol to study the full spectrum of lncRNAs and used this technique to measure lncRNAs in all major cortical cell-types. Our preliminary data indicate that our newly discovered, cortical cell-type specific, lncRNAs are deregulated in AD and FTLDs. In Aim 2 we will define the functions of candidate lncRNA biomarkers in vitro and in vivo to determine the roles of disease-biomarker candidate lncRNAs in relevant model systems. In Aim 3 we will test the hypothesis that distinct expression patterns of lncRNAs biomarker candidates in plasma samples of ADNI, FHS, and DZNE studies participants differentiate among cognitively normal elderly adults, individuals with MCI, and dementia patients meeting clinical criteria for AD or FTLDs. Together, the proposed experiments will ...