A consensus regarding the precise nature and causes of neuropathology accompanying Alzheimer’s disease (AD) has yet to emerge (5). Nevertheless, there is broad agreement that accumulation of b-amyloid containing plaques and neurofibrillary changes both are involved in pathogenesis of AD and dementia. Braak and Braak (2) have described the characteristics of amyloid deposits and neurofibrillary changes in a series of 2661 unselected brains. This large sample, with its broad range in age at death (25–95 years of age), provides a truly unique opportunity to evaluate the possible relationships among age, amyloid-deposition, and neurofibrillary changes. Individual cases were classified based on their age at death and the development of b-amyloid and neurofibrillary pathology by employing the staging developed previously by Braak and Braak (1). Briefly, b-amyloid pathology, when present, can be subcategorized into three ordinal levels (stages A–C), and neurofibrillary changes can be subcategorized into six ordinal levels (stages I–VI), with progression defined largely on the basis of topographic expansion in lesion distributions. [In their data presentation, the six stages of neurofibrillary changes were collapsed into three (I and II, III and IV, and V and VI)]. It should also be noted that Braak and Braak (1,2) are using a somewhat idiosyncratic nomenclature for describing b-amyloid plaques, and, therefore, it is difficult to interpret their findings with respect to the more generally accepted descriptions of: 1) diffuse, with minimal or no fibrillization, that are thioflavin-S negative or benign, 2) neuritic, with clearly fibrillized substructures that are thioflavin-S positive or malignant, 3) primitive, referring to neuritic plaques lacking a central core or star of amyloid, and 4) classical, referring to neuritic plaques with a central core or star of amyloid (7). In fact, in working with sections of 70 to 100 m, as described by Braak and Braak (2), we have found this type of subclassification of b-amyloid plaques to be extremely difficult and sometimes impossible. As the disector technique is fast becoming the procedural standard, this possible limitation should be recognized. In addition, the importance of categorizing classical and primitive plaques with respect to their PHF immunoreactivity (PHF1 or PHF2) has been demonstrated (7), and this cannot be done using the staining procedures described (2). To stage their cases, Braak and Braak (2) examined only two blocks of tissue, including anteromedial portions of the temporal lobe at the mid-uncal level and portions of the occipital lobe. However, their figures obviously refer to their earlier procedures that included sampling of many additional areas (1). Therefore, although there is some empirical support for making generalizations beyond the two regions sampled, this can introduce some inaccuracy in individual classifications. Staging according to Braak and Braak (1,2) is not based on quantitative criteria, and the schematics of lesion distributions are therefore somewhat oversimplified. In our experience, neurofibrillary and b-amyloid pathology can often be broadly distributed within brains, although at low densities, even during neurofibrillary stages I and II and b-amyloid stage A. Further, we have observed evidence for quantitative progression of neurofibrillary pathology in advanced cases of AD clearly meeting criteria for stages V and VI. Therefore, it seems likely that the staging system, as described, omits details of case descriptions that may be meaningfully related to clinical progression. Results indicated that neurofibrillary changes localized within transentorhinal and entorhinal cortex (stages I and II) could be found at surprisingly young ages when amyloid deposits were absent (2), suggesting that in the progression of AD, neurofibrillary changes anticipate b-amyloid pathology. However, when these data were examined employing a slightly different strategy, a more complicated picture seemed to emerge. The age distributions of cases in the various Braak and Braak stages were recalculated from their Tables 2 and 3, assuming that every case at a later stage would have also been classified as positive at all earlier stages. The proportion of cases meeting or exceeding stage criteria were then plotted against age to generate the curves illustrated in Figure 1. Several features of these curves are of interest. First, as indicated in Figure 1a, neurofibrillary changes characteristic of stages I–II are indeed observed quite early in lifespan development and well before b-amyloid pathology is a factor. Progression to stages III–IV seems to require a great deal of time, several decades in fact, and further progression to stages V–VI occurs in roughly half that time, or over the course of approximately 15 years. The increase in prevalence of stages III–IV with age have an acceptable correspondence to the age-associated increase in risk for dementia of the Alzheimer type (3), suggesting that there are clear functional