A Topographical Pathway by Which Histopathological Lesions Disseminate through the Brain of Patients with Alzheimer's Disease

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Abstract
The strength of earlier suggestions about the site where Alzheimer lesions first appear in the brain has been limited, since either too few brain regions or too few cases have been surveyed. We have therefore quantified the density of neuropathological lesions both in serially sectioned hippocampal and also in 10 neocortical regions from the brains of 45 demented patients dying with Alzheimer''s disease (AD) as well as 12 age-matched normal controls. Multivariate analysis and rank ordering confirm that the hippocampus is affected by Alzheimer changes before any parts of the neocortex. The histopathological effects of the disease then progress through the other temporal gyri, followed by frontoparietal and cingulate regions, and involve the sensorimotor and visual cortices only very late in the disorder. This gradual mode of spread through the brain favors the progressive neurone-to-neurone dissemination of an etiological trigger, such as a reactivated latent viral agent (e.g., Herpes simplex), rather than the simultaneous affliction of the entire central nervous system by a systemically circulating substance, such as a protein (e.g. β-amyloid) entering via a hematogenous route.

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