Reduced Neuronal Activity as the Major Cause of Dementia in Alzheimer's Disease: Therapeutic Strategies for Reactivation

D.F. Swaab

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Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam ZO, the Netherlands

A long struggle has been going on about the question what is more important for the development of dementia in Alzheimer's disease (AD): cytoskeletal changes, amyloid or cell death. The answer is probably neither. As will be argued in this presentation, reduced neuronal activity most prabably is one of the major characteristics of AD and may underlie the clinical symptoms of dementia.

AD is a multifactorial disease in which age and APOE-e4 are important risk factors. Various mutations also play a role. Studies comparing different brain areas show that the neuropathological hallmarks of AD, i.e. amorphous plaques, neuritic plaques (NPs), pretangles, neurofibrillary tangles (NFTs) and cell death are not part of a single pathogenetic cascade but are basically independent phenomena. In brain areas where classical AD changes, i.e. NPs and NFTs, are present, a decreased metabolic rate is found. Decreased metabolic rate is not induced by the presence of pretangles, NFTs or NPs and may precede cognitive impairment and thus is an early occurring hallmark of AD. The observations that the administration of glucose or insulin enhances memory in Alzheimer patients also support the view that AD is basically a metabolic disease. Moreover, several observations indicate that activated neurons can better withstand aging and AD, a phenomenon paraphrased by us as "use it or lose it". Therapeutic strategies are therefore directed towards restimulation of neuronal metabolic rate. A number of pharamacological and non-pharmacological studies support the concept that activation of the brain indeed has beneficial effects on several cognitive and non-cognitive symptoms of AD.