[Etiologic and pathogenetic heterogeneity of Alzheimer disease]

The present review discusses whether the clinically and pathologically uniform phenotype of Alzheimer's disease (AD) consists of different subtypes with respect to etiopathogenesis. In a minority of patients with AD, the disease is determined by mutations of genes on chromosomes 1, 14, and 21. The amyloid cascade hypothesis provides a conclusive model for etiopathogenesis of these cases. The majority of patients, however, suffer from the sporadic subtype of AD, the etiopathogenesis of which is presently unknown. This subtype's pathogenesis is determined by a cascade of events, among which age, a disturbance of neuronal insulin receptor function leading to a deficit in acetylcholine and available energy, and membrane instability are the most important factors. The effects of these factors are modulated by the presence or absence of apolipoprotein E4. Thus, the development of this form of AD is characterized by dynamic cellular biological changes in the brain which are independent of the metabolism of the amyloid precursor protein and genetic factors. Therefore, the sporadic subtype of AD may be regarded as an age-associated metabolic disease of the brain.