Idiopathic normal pressure hydrocephalus (iNPH) is a neurological disorder of aging that is characterized by enlarged cerebral ventricles, gait difficulty, incontinence and dementia. It is a common disorder that occurs almost exclusively after the age of 60. About 1.3% of patients over the age of 65 and 9-14% of nursing home residents are thought to have iNPH. Unfortunately, more than 90% of these patients remain misdiagnosed or undiagnosed, in part because the symptoms of iNPH resemble the symptoms of other neurodegenerative diseases, and in part because many health care practitioners are unfamiliar with this disorder. The etiology of iNPH is not known. Scattered reports of familial cases of iNPH suggest a genetic origin, but the genes involved are unknown. To investigate this matter, we have used exome sequencing to look for genetic factors associated with iNPH. We find recurrent heterozygous mutations in 10 genes, nearly all of which show increased expression in the ciliated ventricular epithelium and/or choroid plexus. Many have previously been associated with the function of cilia. siRNA-mediated knockdown of several of these genes increased ventricular size in vivo, and knockdown of one of these was also shown to decrease cilia number and length in vivo. Importantly, we and others find that ventricular volume increases with age in humans and in mice, and we observed that cilia number and length decreases with age in mice. This proposal will use whole exome sequencing and in vitro and in vivo mouse models to test the hypothesis that heterozygous mutations that compromise the function of motile cilia, combined with age-related declines in ciliated ependymal cell function, lead to iNPH. If successful, the findings may lead to improved understanding, diagnosis or treatment of iNPH.