Project summary Alzheimer's disease (AD) pathology is characterized by the accumulation of neurofibrillary tangles, dystrophic neurites, and abundant extracellular fibrils of amyloid-β peptide. However, the etiology of typical late onset AD remains elusive. Over 20 genes have been associated with late onset AD, and this heterogeneity complicates the task of discovering disease modifying treatments. The parent application proposed to: (i) identify robust molecular subtypes of AD and their characteristic molecular signatures across different layers of Omics data; (ii) characterize molecular subtypes of AD by molecular signatures, multiscale regulatory networks and key drivers; (iii) evaluate genomic and functional impact of key drivers using human iPSC derived neurons and glia; and (iv) validate key drivers of molecular networks underlying AD subtypes. Recently, efforts by the investigators in the parent grant led to the identification of the VGF gene as a key driver of the network predicted to be altered in AD. However, the molecular mechanism by which VGF modulates the network altered in AD is not well understood. It is possible that receptor systems activated by peptides derived from VGF play a crucial role in this process. Support for this comes from our previous studies of another key driver, PREPL, where we found that decreases in PREPL expression leads to decreases in levels of secreted VGF- derived peptides. Also, several VGF-derived peptides have been detected in the cerebro-spinal fluid of AD subjects and many of these peptides exhibit distinct biological activities. This suggests the existence of receptors for the VGF-derived peptides and an important role for them in AD. To date receptors for the majority of these peptides have not been definitively identified. In this supplement we propose to carry out studies to identify neuronal receptors to 18 VGF-derived peptides using the PRESTO-TANGO® assay system that contains 302 G protein-coupled receptors including 135 listed as “orphan” receptors. Identification of these receptors is a prerequisite to studies investigating the physiological significance of VGF-derived peptides to AD as well as to identifying small molecules targeting these receptors, which could become potential therapeutics for the treatment of AD.