Anticholinergic Activity and Alzheimer's Disease.

AA cascade in AD’ or ‘progression of AD by its own mechanism’. Although there are AA-inducing factors other than downregulation of ACh (e.g. drugs, febrile illness or mental stress), upregulation of ACh is possible if the ACh system is not depressed or overloaded. Thus, upregulation of the ACh system can inhibit AA even in the presence of other factors ( fig. 1 ). The appearance of AA would then suggest that the ACh system is impaired in some way or that disease other than AD is responsible for the AA. Third, downregulation of ACh in the central nervous system (CNS) causes upregulation of inflammation in the CNS and other organ systems. It is, therefore, conceivable that AD, a disease of the CNS, and diabetes mellitus, a disease that affects the peripheral nervous system, have some aspects of pathogenesis in common. Moreover, downregulation of the ACh system seems to be responsible for the simultaneous appearance of AA in the CNS and other organ systems. A correlation between AA in both systems can be explained, then, not only by the permeability of AA through the blood-brain barrier, but also by this simultaneous appearance of AA in both systems. Dr. Tomioka, MD, PhD, Dr. Hachisu, PhD, and Dr. Hori, MD, PhD, conceived the contents of this special issue. We are extremely grateful to all authors for their As members of the Showa University Dementia Study Group (Wade Study Group), we greatly appreciate the opportunities we have to write about the relationship between anticholinergic activity (AA) and neuropsychiatric disorders, and Alzheimer’s disease (AD) in particular. In this special issue, we review our previous articles concerning the endogenous hypothesis of AA in AD that we originally proposed and here extend the hypothesis to various neurocognitive disorders such as Lewy body disease (LBD), delirium and neuropsychiatric disorders including depression and schizophrenia. In this issue, we emphasize the following 3 points with regard to our hypothesis. First, AA not only depresses the acetylcholine (ACh) system through antagonization of ACh receptors, but also accelerates the accumulation of insoluble amyloids in the brain. The resulting dysfunction of the ACh system is not always reversible. Second, downregulation of ACh can also induce AA by way of inflammation. Therefore, the relationships between AA and this dysfunction of the ACh system are bidirectional. Given that downregulation of the ACh system is an essential feature of AD, we consider that endogenous AA accelerates AD pathology. We refer to these bidirectional effects of AA and downregulation of ACh as either the ‘hypothesis of endogenous AA in AD’, ‘the endogenous Published online: June 30, 2015