CRH-IR is significantly reduced in the cerebral cortex of individuals with AD, PD and PSP. Furthermore, we report that the decreases in CRH-IR in AD are accompanied by reciprocal increases in CRH receptors in affected cortical areas. The changes in pre- and postsynaptic markers for CRH are significantly correlated with decrements in ChAT activity. The demonstration of an up regulation of CRH receptors following a decrease in CRH-IR indicates a physiological relevance of the receptor site and is consistent with the concept that CRH acts as a neurotransmitter in normal cortical functions and that disease of this peptidergic systems may be important in certain clinical manifestations of dementia. While the clinical consequences of the changes in CRH in these various disorders are unclear, future therapies directed at increasing CRH levels in brain may prove useful for treatment.