Alzheimer’s disease (AD) is the most common cause of dementia, affecting over 40 million people and is projected to triple by 2050. Currently, the methods available to diagnose AD is costly and/or invasive. Therefore, there is a need for highly accessible and cost-effective non-invasive tests for AD diagnosis. Furthermore, the lack of accessible non-invasive tools to examine the molecular alterations occurring in the brain limits our understanding of the causes and progression of this heterogeneous disease, as well as the identification of therapeutic strategies. Blood-based liquid biopsies have recently emerged as an alternative for non-invasive examination of molecular alterations. In particular, circulating cell free-mRNA (cf-mRNA) has been shown to contain transcripts derived from multiple organs, including the brain. We have previously demonstrated the utility of cell free messenger RNA (cf-mRNA) profiling using next generation sequencing platform to develop non-invasive Alzheimer’s disease (AD) diagnostic biomarker using gene-expression alterations that are distinct to AD. While findings of our proof-of-principle AD study were promising, in order to develop robust AD cf-mRNA diagnostic classifiers, well-characterized clinical cohorts are required, and the diagnostic classifiers must undergo rigorous tests. In addition, disease-specificity of the classifiers must be tested against other neurodegenerative diseases. Here we propose a biomarker development study where we aim to establish and validate cf-mRNA-based AD diagnostic classifiers using circulating whole-transcriptome sequencing in well characterized clinical cohorts.