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USE OF PiB FOR PET IMAGING OF AD 55

AMYLOID IMAGING IN NORMAL COGNITION carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3
Several studies have now demonstrated PiB reten- carriers, and 95 years for ε2ε3 carriers, suggesting a
tion in cognitively normal controls. Depending on 20- to 30-year interval between first development of
the site, reports have ranged from a proportion of amyloid positivity and onset of dementia (22).
10-30% of normal elderly subjects with significant PiB
retention (i.e., PiB(+))(1,20,23,26,34-36,43,46,51,64). CONCLUSIONS
PiB-PET studies have also demonstrated that ApoE4 The use of amyloid imaging, alone or in conjunc-
genotype is associated with higher PiB retention in tion with other biomarkers, will likely be critical to
cognitively normal elderly in a dose-dependent man- the identification of subjects at risk for AD and future
ner (37,46,51), and ApoE4 carriers are more than decline, as has been suggested in the new diagnostic
twice as likely to convert from PiB(-) to PiB(+) over criteria for preclinical, prodromal, and clinical AD
time (46). Conversely, ApoE2 has been associated (55). One aspect of Ab pathology that has become
with lower PiB retention in normal elderly (37). This clear from amyloid imaging studies is how early in the
wide range likely depends on such factors as the age spectrum of AD the full burden of amyloid plaques
of the cohort, proportion of subjects carrying the begins to develop. Therefore, major challenges for
ApoE4 allele, definition of “cognitively normal,” and amyloid imaging will be: 1) how to determine the
the threshold for defining amyloid-positivity. earliest signs of amyloid accumulation; 2) the associa-
The relationship between increased PiB reten- tions of amyloid accumulation with cognitive impair-
tion and cognition in the normal elderly has been ments; and, ultimately, 3) whether or not this early
difficult to define, as significant plaque load is not amyloid deposition will invariably lead to clinical
related to broad differences in cognitive function dementia in a high percentage of individuals. This
(1,20,34,38,51). However, in other studies, an increase will likely require the field to continue to focus on
in PiB retention has been associated with poorer per- cognitively normal elderly and detection of the ear-
formance on episodic memory tests (23,35,36,43,64). liest signs of amyloid deposition, along with markers
Additionally, a recent study of a community-based of neurodegeneration such as MRI and FDG-PET,
sample demonstrated that elevated amyloid levels in order to determine the clinical significance of
at baseline were associated with worse cognition pre-symptomatic pathology. Further, as anti-amy-
and AD-like imaging biomarkers at baseline and loid clinical trials begin in asymptomatic individuals,
with greater clinical decline and neurodegeneration. it will be critical to effectively identify the earliest
Further, this study demonstrated the increased amy- changes in amyloid deposition and the significance
loid was associated with clinical conversion to MCI of such changes on downstream neurodegenerative
(42). In support of this finding, longitudinal studies processes.
have found that cognitively normal individuals with
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