Project Abstract Primary cilia are mechano- and chemo-sensory organelles with diverse functions. Abnormal function or structure of primary cilia cause a list of diseases, termed ciliopathies. Although ciliopathies include expanding spectrum of kidney, liver, and cardiovascular disorders, it is yet to be investigated whether or not cilia are associated with Alzheimer’s disease (AD) and/or its related dementias. In this Administrative Supplement proposal, we combine expertise from two laboratories of the neighboring institutions. This multi-PI proposal includes Dr. Amal Alachkar (the University of California, Irvine), whose research group has strong expertise in neurological degeneration including Alzheimer, and Dr. Surya Nauli (Chapman University), whose laboratory has strong records in interrogating primary cilia functions. The overall goal of this proposal is to examine the alterations of cilia structure and functions in early- and late-stage AD in 3xTg mice brains. The role of cilia will also be evaluated using conditional inducible IFT88 knockout mice that do not possess cilia. IFT88 mouse will be put into the 3xTg-AD mouse background. Our first aim is therefore to test the hypothesis that cilia structure/length is altered in early- and/or late-stage 3xTg-AD mice. The second aim is to test the hypothesis that genetic and pharmacological manipulations of cilia alter behavioral changes in AD. The outcomes of these limited studies offer new knowledge if genetic elimination of cilia exacerbates behavioral deficits in 3xTg-AD mouse and if cilia-targeted therapy improves the behavioral deficits in 3xTg-AD mice.