Acta Neuropathol (2006) 111: 503–509 DOI 10.1007/s00401-006-0071-y REVIEW Rudy J. Castellani · Hyoung-Gon Lee · Xiongwei Zhu Akihiko Nunomura · George Perry · Mark A. Smith Neuropathology of Alzheimer disease: pathognomonic but not pathogenic Received: 28 June 2005 / Revised: 29 March 2006 / Accepted: 29 March 2006 / Published online: 27 April 2006  Springer-Verlag 2006 Abstract Neuropathological changes in subjects with dementia are, by deWnition, end-stage phenomena. While such changes allow case characterization and lend them- selves to disease classiWcation and modeling, the lesions themselves are not etiological. This truth would appear to be self-evident, yet the medical and scientiWc literature suggests otherwise. Indeed it is now customary to view amyloid plaques in Alzheimer disease as primary etiolog- ical, neurotoxic lesions and, hence, removing them (e.g., by immunotherapy) is believed to lead to clinical improvement. The foundation for this line of thinking lies in the existence of rare kindreds with mutations in amyloid-, or mutations believed to be involved in the processing of amyloid-, and then the extrapolation of the inherited condition to sporadic disease. We believe that this overall construct ignores early events that are more critical to onset and progression of sporadic dis- ease. Likewise, we have studied subjects with sporadic Alzheimer disease, as well as early onset familial Alzhei- mer disease and Down’s syndrome, over a spectrum of ages, and have found that markers of oxidative stress precede amyloid deposits in all three conditions. Amyloid and neuroWbrillary pathology in the Alzheimer brain show a decrease in oxidative stress relative to vul- nerable but morphologically intact neurons, suggesting that neurodegenerative lesions are compensatory phe- nomena, and thus manifestations of cellular adaptation. The pathology of neurodegenerative diseases should be viewed as the end-stage consequence, as opposed to cause, of the disease processes, so that early disease pro- cesses that are amenable to intervention can be properly recognized and treated. Keywords Alzheimer disease · Amyloid · Neuropathology · Tau phosphorylation Introduction Neuropathological assessment by light microscopy is regarded as a means of deWnitive diagnosis of patients with dementia, and further establishes benchmarks by which models of neurodegenerative diseases are vali- dated. This being the case, it is axiomatic that the basic pathology of dementia is over-rated in terms of insight into early disease processes. The simple fact, which is not new but rather ignored, is that neuropathological diagnosis, in the setting of neu- rodegenerative diseases, is little more than a “tallying” of lesions at the end of life, be they plaques, tangles, or other inclusion; the key to proper diagnosis rests more in the association of that tally with a clinical phenotype during life than in the identiWcation of a pathogenic pro- cess [28, 38]. Indeed, disease etiology, within the context of dementia brain interpretation, is irrelevant. Yet we are fascinated with lesions—amyloid plaques, neuroWbrillary tangles, Lewy bodies, etc. and study them extensively using every conceivable modality. This is not particularly surprising from the standpoint of the neuro- pathologist, since we rely on those changes that can be visualized and, without them, we are rendered impotent in our ability to assess disease. Nevertheless, the persev- eration on lesions, not only by neuropathologists but Drs. Rudy J. Castellani and Hyoung-gon Lee contributed equally to this work. H. G. Lee · X. Zhu · G. Perry · M. A. Smith (&) Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, OH 44106, USA E-mail: mark.smith@case.edu Tel.: +1-216-3683670 Fax: +1-216-3688964 R. J. Castellani Department of Pathology (Neuropathology), University of Maryland, Baltimore, MD, USA A. Nunomura Department of Psychiatry and Neurology, Asahikawa Medical College, Asahikawa 078-8510, Japan G. Perry College of Sciences, University of Texas at San Antonio, San Antonio, TX, USA