Immunological mechanisms and the spectrum of psychiatric syndromes in Alzheimer's disease

Pathological, genetic and epidemiological studies support the opinion that inflammatory mechanisms are involved in the pathogenesis of Alzheimer's disease (AD). Recent pathological and neuroradiological (PET) data show that activation of microglia is an early pathogenic event that precedes the process of severe neuropil destruction in AD brains. In this paper we review the evidence that inflammatory mediators can play a pathogenic role in some behavioural disorders frequently encountered during the clinical course in AD patients. Motivational disturbances are the most striking of the depressive symptoms in AD and can be present in a preclinical stage of the disease. Experimental animal studies and clinical trials in humans have shown that cytokines can induce similar symptoms which were described as 'sickness behaviour' or 'depressive-like' state. Delirious states are frequently observed in more advanced stages of dementia. Delirium is generally considered the result of an imbalance in neurotransmitter systems with severe deficits of the cholinergic systems. Animal studies show that pro-inflammatory cytokines, such as interleukin-1, induce a reduced activity of the cholinergic system. In AD, the release of cytokines would exacerbate any already existing disturbances in the cholinergic neurotransmission. This could explain the susceptibility of demented patients to delirium provoked by a wide variety of trivial incidents that are accompanied by an acute phase response. The data reviewed in this paper suggest that it could be worthwhile employing a neuroimmunological approach to study at molecular level the pathogenesis of a broad spectrum of behavioural disturbances common in the clinical course of AD patients. (C) 2002 Elsevier Science Ltd. All rights reserved.