Background: Limited availability of longitudinal amyloid PET measurements has made it difficult to examine the pattern of amyloid deposition over the entire course of disease. Of particular importance is determining the early period during which amyloid accumulates up to a maximum. This period is a critical window for disease-modifying treatments. PiB-PET studies have begun to model trajectories of longitudinal amyloid change, but it is unclear how these models generalize to other amyloid PET tracers, such as florbetapir, and other methodological factors such as reference region.
      Methods: We used longitudinal florbetapir PET measurements obtained at a two year interval in cognitively normal (N=68), Early MCI (N=84), Late MCI (N=28), and AD participants (N=15; 195 total) from the Alzheimer's Disease Neuroimaging Initiative. In particular, we focused on examining characteristics of normal individuals with subthreshold florbetapir retention. We also examined the influence of several methodological factors such as reference region selection on estimated trajectories across the entire range of amyloid measurements.
      Results: Average annual absolute florbetapir change was consistent across diagnostic groups (1-2%) but was highly variable across individuals (SD=1%). Of cognitively normal individuals, 52/68 (76%) were florbetapir negative at baseline. Of this group, 21 (40%) decreased during followup (-1 +/- 1% annual SUVR decrease), indicating absence of AD-related pathology. The remaining 60% had a 2 +/- 1% annual SUVR increase), suggesting that some of these individuals are on a trajectory to AD. Of the 16/68 normals (24%) who were amyloid positive at baseline, 13 increased at approximately the same rate as the amyloid negative normals (2 +/- 2%). Plotting florbetapir change as a function of baseline status in accumulating normal and the patient groups resulted in an inverted-U shaped function. This allowed us to estimate a 6-7 year window of accumulation between the threshold for amyloid positivity and the peak of amyloid deposition.
      Conclusions: Longitudinal florbetapir measurements are highly variable in subthreshold individuals. Amyloid deposition that occurs between the positivity threshold and the peak of accumulation may represent an optimal window for therapeutic intervention.