This project represents a continuation of Project 2 from the previous grant period of our ADRC. At the outset of that project, data from postmortem studies available on the rare group of individuals who carry mutations that cause early-onset familial Alzheimer's disease (eFAD) indicated that amyloid deposition in these carriers shared a final common pathway with late-onset sporadic Alzheimer's disease (LOAD). The unique advantage of in vivo amyloid imaging, is that it allows longitudinal studies on individuals beginning in the very earliest stages of the disease. By exploiting this capability, we demonstrated a dramatic difference in the timing and regional distribution of PiB retention in many subjects with several distinct eFAD mutations. At the earliest, presymptomatic stages, many mutation carriers show intense, focal Pittsburgh Compound-B (PiB) retention in the striatum and relatively little neocortical PiB retention. Furthermore, our unpublished data suggests that the amount of striatal amyloid may recede in the later stages of eFAD. It is important to fully understand the similarities and differences in the natural history of eFAD and LOAD. In this project, we propose to continue the first-ever amyloid imaging studies in presymptomatic eFAD and extend these studies to help understand the mechanistic and functional underpinnings of the striatal findings. First, we will take advantage of the valuable cohort of eFAD subjects we have assembled, to continue to document the natural history of amyloid deposition and begin to look for functional correlates by adding a measure of blood flow (arterial spin labeling or ASL) that we will be applying in separate LOAD studies. Second, we will recruit subjects between 21 and 30 years of age to determine how early this process may begin. Third, we will utilize neuropsychological tests chosen specifically to challenge striatal circuits in an attempt to uncover correlates of striatal amyloid in the otherwise asymptomatic mutation carriers. Fourth, we will perform detailed histological studies on a postmortem brain from a parent of one of the larger, extended PS1 families currently in our study to determine if the unusual pattern of PiB retention in this kindred is based on an atypical distribution of typical AB or on a typical distribution of atypical tertiary structures of AB.
Answers to the questions posed by this study will help us understand the significance of amyloid deposition in non-demented individuals. If it becomes clear that pre-clinical amyloid depositions progresses to clinical AD with high frequency, then it will become important to identify and treat non-demented, amyloid-positive individuals. It will be important to identify the optimal time point to begin treatment, i.e. prior to the onset of clinical symptoms. It is at this early stage that anti-amyloid therapies will likely be most effective.
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