The pathogenesis of Alzheimer disease: an alternative to the amyloid hypothesis.

This paper attempts to put together in the form of a flow sheet (Fig. 1) the several known alterations, both chemical and structural, of brain tissue in Alzheimer disease, which ultimately result in dementia. While most investigators in the field believe strongly that amyloid deposition is at the core of the disease, this writer finds that a more coherent, and thus more satisfying, schema can be based on the centrality of cytoskeletal abnormality. Not only do all four identified genes interact one way or another with the cytoskeleton, but abnormality of the latter leads to alterations of the Golgi apparatus with effects on protein processing, and on axoplasmic flow such that one can expect loss of synapses and subsequent loss of neurons with consequent disconnection and loss of neurotransmitters. Dementia is the result.