Understanding the natural history of amyloid deposition is of great importance for advancing our knowledge of the pathophysiology of Alzheimer's disease—both during the clinically apparent phase as well as during the antecedent pre-clinical phase (Goldman et al ., 2001). Awareness of the natural history of amyloid deposition also will be necessary to interpret experimental anti-amyloid drug studies that might extend over a year or more. Post-mortem studies cannot, of course, directly assess the progression of amyloid deposition in an individual over time and attempts to deduce the natural history by comparing a series of post-mortem cases with different clinical severities and amyloid loads have significant limitations (Hyman and Gomez-Isla, 1997). Nevertheless, several very extensive post-mortem studies have provided useful information (Braak and Braak, 1997). For example, although some degree of correlation has been reported between plaque load (Cummings et al ., 1996) or Aβ levels (Naslund et al ., 2000) and measures of cognition, it is generally believed that neither the number nor the total area of neocortical plaques correlate well with cognitive deficits before death (Terry et al ., 1991; Braak and Braak, 1998). It is with this backdrop that we must interpret the manuscript by Engler et al . (2006) in which they report the first longitudinal study of Aβ amyloid deposition in living subjects. The original cohort was scanned in 2002–2003 and was the subject of the initial report on amyloid imaging using the positron emission tomography (PET) tracer, PIB (Pittsburgh Compound-B) (Klunk et al ., 2004). Remarkably, Engler and co-workers succeeded in re-scanning all 16 of the original subjects who had a clinical diagnosis of Alzheimer's disease 1.5–2.5 years after the baseline PIB scan. They also re-scanned the one control who showed evidence of high PIB retention in the baseline study. As has been shown …