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distinction is difficult to make clinically). From a original studies provided a landmark description of
research perspective, these imaging techniques allow the natural history of Aβ deposition in living sub-
us to study relationships among amyloid, cognitive jects and were later confirmed by additional studies
function, and neurodegenerative processes across using PiB in AD patients and cognitively normal
the continuum from normal aging to AD and to subjects (4,8,10-12,24,32,34,39,43,44,52,69). A recent
monitor the biological effects of anti-Aβ drugs and meta-analysis among participants with dementia
relate them to effects on neurodegeneration and cog- demonstrated that amyloid positivity was associated
nition. In particular, understanding biomarkers such with clinical diagnosis (i.e., AD), age, and APOE
as PiB in relation to normal aging has become critical genotype. Additionally, similar associations of age
given that we have entered the era of “prevention” and APOE ε4 with amyloid positivity were observed
trials in AD with two studies targeting autosomal in participants with AD dementia at autopsy (41)
dominant AD (DIAN and API), one study targeting (Figure 1).
homozygous APOE*4 carriers (API), and one study
targeting typical late-onset disease (A4). All of these AMYLOID IMAGING IN AUTOSOMAL DOMINANT
studies rely heavily on biomarkers in general and on AD
Aβ biomarkers in particular. A key concept underly- Roughly 1% of all AD cases are caused by single
ing these trials is the NIA-Alzheimer’s Association gene mutations that are transmitted in an autoso-
research criteria for preclinical AD, which argues mal dominant pattern with nearly 100% penetrance.
that Aβ deposition in individuals without cognitive Familial AD has been linked to mutations in prese-
impairments is, in fact, a preclinical stage of AD (55). nilin-1 (PS1, chromosome 14, the most commonly
These criteria have been operationalized by Jack et involved gene), amyloid precursor protein (APP,
al. (19) and suggest amyloid biomarkers, including chromosome 21), or presenilin-2 (PS2, chromosome
PiB-PET, become abnormal first and are followed 1). All these mutations are thought to cause early-on-
by biomarkers of neuronal injury and degeneration, set familial AD (eoFAD) by promoting the cleavage
including FDG-PET, closer to the time when cog- of APP to the pro-aggregatory Aβ1-42 peptide (17).
nitive symptoms appear (19). The present review In order to explore the natural history of preclin-
focuses on use of PiB-PET across the spectrum of ical amyloid deposition in people at high risk for
AD. AD, individuals with eoFAD have been evaluated in
several studies. In the first PiB-PET study, subjects
EARLY PiB STUDIES with two different PS1 mutations were explored (27).
The earliest studies with PiB in AD patients The PS1 mutation carriers, independent of cogni-
showed marked increases in PiB retention in brain tive status, showed a strikingly similar focal amyloid
areas known to contain high levels of amyloid plaques deposition that appeared to begin in the striatum, in
when compared to cognitively normal subjects. PiB contrast to early deposition of amyloid in non-mu-
retention in AD patients was generally most promi- tation carriers, typically in the frontal cortex and
nent in cortical areas and lower in white matter areas, the precuneus/posterior cingulate region but not in
consistent with post-mortem studies of Aβ plaques in striatum (34).
the AD brain (58). PiB retention was observed at high These data have been extended to autosomal
levels in frontal cortex in AD but also was observed in dominant dementia and frequent cerebral amyloid
precuneus/posterior cingulate, temporal, and parietal angiopathy and intracerebral hemorrhages due to an
cortices. The occipital cortex and lateral temporal APP locus duplication (47,50). Similar to previous
cortex were also significantly affected with a rela- findings, PiB retention was highest in the striatum (up
tive sparing of the mesial temporal areas. Significant to 280% of the control mean), and the overall pattern
striatal PiB retention also was observed, consistent of increased PiB retention was different from that
with previous reports of extensive Aβ deposition seen in sporadic AD (48). Theuns et al. (59) reported
in the striatum of AD patients (6,7,57,66). These widespread retention of PiB, typical of that observed