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.