Reduced neuronal activity and reactivation in Alzheimer's disease.

1. Alzheimer's disease is a multifactorial disease in which age and APOE-epsilon 4 are important risk factors. Various mutations and even viral infections such as herpes simplex (Itzhaki et al., 1997) may play an additional role. 2. The neuropathological hallmarks of Alzheimer's disease (AD), i.e. amorphous plaques, neuritic plaques (NPs), pretangles, neurofibrillary tangles (NFT) and cell death are not part of a single pathogenetic cascade but are basically independent phenomena. 3. Pretangles can occur in neurons from which the metabolic rate is not altered. However, in brain areas where classical AD changes, i.e. NPs and NFTs, are present, such as the CA1 area of the hippocampus, the nucleus basalis of Meynert and the tuberomamillary nucleus, a decreased metabolic rate is found. Decreased metabolic rate appears to be an independent phenomenon in Alzheimer's disease. It is not induced by the presence of pretangles, NFT or NPs. 4. Decreased metabolic rate may precede cognitive impairment and is thus an early occurring hallmark of Alzheimer's disease, which, in principle, may be reversible. The observation that the administration of glucose or insulin enhances memory in Alzheimer patients also supports the view that Alzheimer's disease is basically a metabolic disease. Moreover, several observations indicate that activated neurons are better able to withstand aging and AD, a phenomenon paraphrased by us as "use it or lose it". It is, therefore, attractive to direct the development of therapeutic strategies towards restimulation of neuronal metabolic rate in order to improve cognition and other symptoms in Alzheimer's disease. A number of pharmacological and non-pharmacological studies support the concept that activation of the brain indeed has beneficial effects on several aspects of cognition and other central functions.