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  1. This is a very thoughtful minireview of presenilin gene action and its significance for AD pathogenesis and therapy, as would be expected from Bart De Strooper and his colleagues. I certainly agree that we need research initiatives that reflect thinking "out of the box." The collective progress on APP metabolism has been marvelous, but we need to pursue ideas for what these authors refer to as "second hits" to understand the common late onset dementias of the Alzheimer type. I would argue for a multiplicity of "hits", perhaps with varying patterns in different individuals,certainly including poorly understood underlying processes of aging.

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