The rare families with early-onset Alzheimer disease (AD) and autosomal dominant inheritance have been important in elucidating mutations in the presenilin 1 (PS1) and 2 genes and in the amyloid precursor protein gene that cause disease.1 These 3 gene mutations underscore the critical importance of normal amyloid precursor protein processing and the fact that a 50% increase in the amount of amyloid-β peptide (Aβ42) produced as a result of these mutations is sufficient to cause increased accumulation of Aβ42, which in part causes the early and severe dementia. Abnormal amyloidogenesis is the predominant hypothesis to explain increased Aβ42 burden in the brain of patients with AD and the resultant dementia.1 Another major unresolved issue in understanding the genetic and molecular basis of AD is the role of Lewy bodies, composed mainly of α-synuclein. Brains affected by AD may contain significant levels of Lewy bodies diffusely in neocortical and subcortical structures; these cases are referred to as the Lewy body variant of AD.2,3 Neocortical Lewy body neuropathology may be the predominant feature of a dementing, degenerative disorder without the appreciable AD abnormalities of amyloid-containing plaques and neurofibrillary tangles, and is referred to as diffuse Lewy body disease. There is a spectrum of Lewy body neuropathology, from occasional Lewy body pathology with Parkinson disease within the substantia nigra, to Parkinson disease with diffuse Lewy body neuropathology in neocortical and subcortical areas without dementia, to AD pathology with Lewy bodies (AD Lewy body variant), to dementia with Lewy bodies but without appreciable amyloid plaques and tangles.