PLAQUES AND TANGLES: SEARCHING FOR PRIMARY EVENTS IN A FOREST OF DATA

PHILOSOPHICALLY, the continuing controversy over plaques and tangles, b-amyloid and tau, is surprising. Consider two people in a forest. One sees an individual tree and wonders how a tree grows; the other sees patterns among the trees and seeks to understand how trees affect one another. Plaques and tangles are the leaves and branches that together make a forest and are merely convenient tombstones in the study of Alzheimer’s disease (AD). Can these markers provide evidence that b-amyloid or tau are central to the disease process itself? Are they inter-related? The wide range in views may simply be due to the sheer number of researchers roaming the forest. In just the last 5 years, more than 70 studies have examined the progression or contribution of these hallmarks to dementia and AD. However, using postmortem tissue from individuals who may have had a disease for 10 to 15 years makes investigating initiating events inherently difficult, if not impossible. In a Herculean effort, Braak and Braak (5) have extended their studies of neurofibrillary staging in the human population to include an evaluation of 2661 individuals ranging in age from 26 to 95 years. Although I have concerns regarding the evaluation of b-amyloid deposition in this study (see below), this research still contributes to our understanding of the development and progression of neurofibrillary pathology. Of particular interest are several novel discoveries that could only be addressed using such a large data set. For example, essentially all individuals older than the age of 80 have some neocortical NFTs (.99.0%). Cases exhibiting solely “ghost” tangles were not observed, suggesting that once NFT pathology begins, there is no remission. The primary conclusion of the Braaks’ study, however, is that neurofibrillary pathology precedes amyloid deposition by more than a decade. This runs counter to the prevalent “belief” that Ab deposition occurs prior to NFT formation (9,15,16,32); this issue warrants further consideration. Open Peer Commentaries are meant to “stimulate scholarly debate and new thinking.” As suggested above, all human postmortem studies suffer from inherent difficulties and confounding variables (see Reference 9 and commentaries). Hopefully, my peers will comment on the cortical spread of neurofibrillary pathology, questions of incidence versus prevalence, pathology in myelinated versus nonmyelinated regions, and other interesting issues raised by the Braaks’ work. My commentary will focus on the effects of staining sensitivity on the detection of plaques and tangles, an issue that is central to the present study and affects the interpretation of all AD research. How can one account for such a large discrepancy between so many studies supporting the hypothesis that Ab deposition and plaque formation precede neurofibrillary tangle formation in AD, and Braak and Braaks’ findings suggesting that plaques generally appear long after the presence of neurofibrillary pathology? I will examine three possibilities in order of increasing likelihood: A) Is the relationship between plaques and tangles the same in the “general” population as it is in AD? B) Does the operational definition of a “plaque” vary across studies? C) Could differential sensitivity in the detection of plaques and NFTs influence the results? In the following discussion, I suggest that Braak and Braak’s approach and analysis is highly suited for the detection and study of neurofibrillary pathology but is limited in its ability to detect and hence to investigate plaques. Because this issue underlies so many studies of AD neuropathology, the initial, early appearance and overall contribution of plaques to the degenerative process may be underappreciated among AD researchers.