Over the last 10 years, genetic and pathological analysis has allowed the dissection of the major pathways to cell death in Alzheimer's disease, Pick's disease and Lewy body disease. The central findings are these.

First, the pathology of Alzheimer's disease consists of plaques, made of the Aβ peptide, derived from the APP protein, and neurofibrillary tangles made of the tau protein: Lewy bodies, made of the synuclein protein, are a frequent, but not invariant pathology of Alzheimer's disease (Hansen & Samuel, 1997).

Second, all pathogenic mutations in the APP and presenilin genes alter APP metabolism such that more of the peptide, Aβ42, is produced (Hardy & Selkoe, 2002). These data suggest that Aβ is the primary molecule in the pathogenic cascade for Alzheimer's disease and that tau dysfunction and tangle formation are a necessary downstream event in disease pathogenesis and that α-synuclein dysfunction and Lewy body formation are an occasional downstream event in disease pathogenesis.

Third, mutations in the tau gene causes some frontal temporal dementias and other entities in which tau is deposited (Hutton et al., 1998). In some sporadic tangle disorders, the tau haplotype is a risk factor for disease (Baker et al., 1999). These data suggest that cell death and dementia are a consequence of tau dysfunction and tangle formation (Hardy et al., 1998).

Fourth, mutations in the α-synuclein gene cause Parkinson's disease and other entities in which α-synuclein is deposited (Polymeropoulos et al., 1997).