Neuropathology and treatment of Alzheimer disease: did we lose the forest for the trees?

Abstract

Although amyloid-β-containing senile plaques and phospho-tau containing neurofibrillary tangles are hallmark lesions of Alzheimer disease (AD), neither is specific for AD, nor even a marker of AD. Rather, they are empirical lesions that require close correlation with age and clinical signs for optimal interpretation. In essence, these lesions represent the effect rather than the cause of disease. In this review, we discuss diagnostic criteria for AD, the relationship between pathology, pathogenesis and multiple treatment approaches that have so far been disappointing, including those that presume to address pathological lesions. An acceptance that lesion-based therapies do not address etiology or rate-limiting pathogenic factors is probably necessary for the best chance of significant advances that have thus far been elusive.

Keywords::

• Alzheimer disease
• amyloid
• cholinergic
• oxidative stress
• phosphorylation
• tau
• therapeutic

Acknowledgements

Rudy J Castellani and Mark A Smith are both available for correspondence regarding this article, for contact details see ‘Affiliations’. Work in the authors’ laboratories is supported by the NIH, the Alzheimer’s Association, Philip Morris USA Inc. and Philip Morris International. Mark Smith and George Perry are, or were, compensated consultants to Voyager Pharmaceutical Corp. and own equity. Mark Smith is a compensated consultant and owns equity in NeuroPharm Ltd.