Alzheimer's disease and the pivotal role of the hypothalamus and the intrinsic opioid system.

Although the "cholinergic hypothesis" of the pathophysiology of Alzheimer's disease has received great attention during the past years, it has recently come under increasing criticism specifically owing to failure of therapeutic endeavors based on this premise. As the potential broad role of the intrinsic opioids in the neurochemical modulation of diverse brain functions emerges, the realization that these data may be reconciled to a unifying hypothesis underlying the nature of some chronic dementing diseases (including Alzheimer's disease, Korsakoff disease and Parkinson's disease) occurs. Certain specific characteristics of the known pathologic changes and neurotransmitter deficits of Alzheimer's disease may be explained based on an early vulnerability of the hypothalamus combined with derangements of endorphinergic functions which follow. The latter may be implicated in the subsequent degeneration of structures receiving projections from the arcuate nucleus of the hypothalamus. This is based on the known role of endorphins in the modulation of central neurotransmitters and specifically acetylcholine activity. In addition, the reciprocal neuroendocrine and neuroimmunologic interactions mediated through the hypothalamus, may be of further importance in the evolution of Alzheimer's disease.