Imaging with the radioligand [¹¹C]Pittsburgh Compound-B (PiB) has provided strong evidence of group differences between cognitively impaired (AD and MCI) and normal (CN) older adults in global as well as regional measures of Aβ deposition (for review, see [14]). It is noteworthy that the level of Aβ in MCI individuals who are PiB-positive approaches the level in AD, suggesting either a plateau [15] or a low rate [16] of Aβ accumulation after the appearance of clinical symptoms. Frontal, lateral temporal, and parietal regions show consistent patterns of elevated Aβ in those with cognitive impairment compared with healthy older adults, with more variable findings with respect to group differences in the occipital and striatal regions (for review, see [14]). These global and regional patterns of differences between impaired and CN individuals are generally consistent across a variety of PET amyloid radiotracers. The majority of studies to date have used PiB, but a number of [¹⁸F] radiotracers for amyloid imaging recently have become available and have been applied in imaging studies of AD. These include Florbetaben (BAY94-9172), Flutemetamol (GE067) and Florbetapir (AV-45), and all show differences between AD patients and controls that are similar in distribution to group differences using PiB [17–19]. Additional studies are required to provide information on long-term predictive utility of these amyloid imaging tracers, especially in the case of MCI and preclinical AD in asymptomatic individuals. However, the availability of [¹⁸F] ligands, which have a 110-minute half-life and can be produced for regional distribution, will allow more widespread research and potential clinical applications compared to [¹¹C] ligands, which have a 20-minute half-life requiring on-site radiopharmaceutical production.

Another PET radiotracer that has been used to evaluate AD pathology is [¹⁸F]FDDNP. [¹⁸F]FDDNP differs from the other amyloid imaging compounds in several ways. It labels plaques and tangles, as well as alpha-synuclein [20]. Furthermore, the radioactivity signal from this tracer is lower than the signal achieved with more specific Aβ radiotracers, leading to difficulties in quantification [21]. However, an interesting application of this tracer is the potential use of subtraction measures to highlight non-amyloid pathology [22]. By using multiple radiotracers, [¹⁸F]FDDNP shows additional binding in the hippocampal formation compared to PiB, perhaps reflecting neurofibrillary tangle pathology [22].

Despite consistent group differences between impaired and CN individuals, amyloid imaging compounds show varying levels of elevated Aβ across individuals. In studies with PiB, attempts have been made to define values for a PiB positive study indicating elevated Aβ burden. A variety of cut-points have been used (for review, see [14]), but these are dependent on the specific method used for quantification - for example, standard uptake value ratio (SUVR) versus dynamic modeling of the time course of radioactivity in brain. Both cut-points and approaches that examine Aβ as a continuous measure have been used to determine relationships with cognitive status.

Amyloid imaging may be especially useful in distinguishing between individuals with MCI who will progress to dementia and AD versus those who will not progress to dementia [23–25]. MCI represents a heterogeneous group, with individuals showing either AD-like levels of Aβ deposition or CN-like levels of Aβ deposition [25–28]. Approximately one-half of individuals with amnestic MCI [25, 29], characterized by memory impairment, have elevated Aβ on imaging and have an increased risk of conversion to AD (see below). MCI individuals without elevated Aβ have a lower likelihood of progression to AD [24, 25]. These individuals may be cases of misdiagnosis, may have different conditions that interfere with cognitive function, or may be false negatives on imaging due to the fact that current radiotracers do not label all Aβ isoforms [30].

Variability in imaging-assessed amyloid burden is also apparent in older cognitively healthy adults. As noted above, the proportion of PiB-positive individuals has ranged from 20% in a study by Mintun and colleagues [5] to 47% in the multicenter study performed through the Alzheimer's Disease Neuroimaging Initiative [4]. Cognitively healthy PiB-positive individuals show a range of values of PiB that are clearly detectable on imaging but are typically below those observed in AD. To date, the primary factors associated with increased Aβ burden in CN individuals are older age and Apolipoprotein E (APOE) ε4 genotype [7, 31]. For example, in the Australian Imaging, Biomarker, and Lifestyle (AIBL) study of 177 healthy controls, 33% of healthy controls were PiB-positive, with a rate of 65% in individuals older than 80 years compared with 18% in individuals aged 60 to 69 years [7, 31]. Moreover, the rate of elevated PiB binding was more than double in APOE ε4 gene carriers (49%) compared with noncarriers (21%) [7]. Cognitively healthy individuals with elevated amyloid burden likely represent a heterogeneous group with respect to long-term outcome. While some of these individuals will progress to cognitive impairment and AD, others will remain resilient in the face of pathology. The latter group may parallel the group we have called asymptomatic AD at autopsy (and others have called high pathology controls or preclinical AD), because they do not show accelerated cognitive decline despite substantial amyloid pathology [11]. Some investigators attribute this resilience to 'cognitive reserve' [32–34], implying greater neural complexity or plasticity at baseline, but the resilience may also reflect a more general capacity to regain homeostasis across body systems in the face of a variety of age-associated insults, including Aβ deposition.

Investigations of the associations between in vivo measurement of amyloid burden and cognition are necessary to determine the extent and conditions under which elevated amyloid burden is associated with cognitive decline. When data are combined across groups of individuals with AD, MCI and CN older adults, higher Aβ burden is correlated with lower episodic memory performance [21, 28, 35, 36]. These associations are also evident in analyses pooling MCI and AD together [37] and in studies pooling CN and AD together [33, 38]. Correlations between Aβ burden and performance in non-memory cognitive domains also have been identified in analyses pooling groups of impaired and unimpaired individuals [33, 38]. In one study, correlations across diagnostic groups suggested that increased frontal PiB is associated with lower memory whereas increased parietal PiB is associated with lower performance on non-memory functions [36].

Associations between in vivo neuropathology and cognitive performance across combined groups of impaired and unimpaired individuals also have been reported using [¹⁸F]FDDNP as the radiotracer [20, 39]. In addition to inverse associations between [¹⁸F]FDDNP binding and verbal paired associate memory when CN and MCI individuals were combined, [¹⁸F]FDDNP was also inversely associated with performance on other cognitive measures, including mental status and digit recall, across all groups [20]. Spatial associations of [¹⁸F]FDDNP binding with lower performance on tests of episodic memory and frontal lobe function across groups localized to entorhinal, lateral temporal, parietal, orbitofrontal and dorsolateral prefrontal cortex [39]. Mesial temporal associations with [¹⁸F]FDDNP may reflect sensitivity to neurofibrillary tangles in these regions.

Associations between Aβ and cognitive performance are even more variable in studies of CN individuals. Table 2 summarizes findings from cross-sectional studies of CN older adults. Several investigations have shown negative cross-sectional correlations between PiB retention and measures of episodic memory [19, 41, 42], and one study indicated that cognitive reserve, measured by the National Adult Reading Test, may modify this association [33]. However, the largest study of 177 CN adults found no significant cross-sectional correlations with episodic memory [7], suggesting that a few PiB-positive individuals may have a large influence on findings in smaller samples. The varied results across studies highlight the complexity of the relationship between cognitive performance and amyloid deposition at the earliest stages of cognitive decline.

The few longitudinal investigations of cognitive change in relation to Aβ burden have more consistently shown associations for cognitively healthy individuals (Table 2). For example, Villemagne and colleagues [43] reported that greater decline in word list recall was associated with higher Aβ deposition in nondemented elderly who ultimately progressed to MCI/AD but not in individuals who remained cognitively normal [43]. Storandt and colleagues [42] found that elevated Aβ burden was associated with greater longitudinal decline in episodic and working memory, as well as visuospatial ability, and we [6] reported that higher Aβ was associated with greater longitudinal decline in verbal memory (Figure 1b), executive function and mental status, but not visual memory. Our observations of significant relationships between higher PiB retention and greater cognitive decline in cognitively healthy individuals appear at first glance to conflict with our autopsy findings [11] showing similar longitudinal cognitive trajectories in older adults with and without AD pathology (Figure 1a, b). However, participants in imaging studies are younger and have not passed fully through the risk period for cognitive decline. Thus, cognitively healthy individuals with elevated Aβ on imaging include those who are in a preclinical phase of AD as well as those who will be resilient and maintain cognitive health.

In MCI, Aβ burden assessed by PiB PET has been helpful in distinguishing between individuals who will convert to AD and those who will remain stable [23–25] or develop other forms of dementia. Rates of conversion to AD in MCI individuals with a positive amyloid imaging scan are substantially higher than those with a negative PiB scan, with the latter showing less than 10% rates of conversion over 3 years [24, 25]. As described in Table 3, MCI converters may also have different patterns of PiB amyloid deposition compared to MCI non-converters [24], with higher PiB retention in posterior cingulate [23, 44] and frontal [44] regions. Okello and colleagues [24] identified a subset of PiB-positive MCI individuals who rapidly progressed to AD. Compared to PiB-positive slower MCI converters and nonconverters, the rapid converters had higher PiB retention in anterior cingulate, frontal, and lateral temporal cortices. In addition, the presence of the APOE ε4 allele in PiB-positive MCI individuals was associated with higher rates of conversion to AD [24].

In CN adults, consideration of Aβ burden alone showed that risk for AD in PiB-positive individuals was 4.8 times that in PiB-negative CN individuals over a 2.4-year follow-up [45] (Table 3). However, no studies to date have combined PET measures of Aβ burden with cognitive performance for prediction of AD risk in CN individuals. In our concluding comments, we operationalize the way that cognitive performance, especially on episodic memory tests, can be used in combination with Aβ burden to further increase prediction of CN individuals who are likely to develop AD versus remain healthy.

The ability to image brain Aβ in vivo is advancing our understanding of the neurobiology of cognitive impairment and holds promise as a tool that will contribute to the detection of early pathological changes and prediction of who will ultimately develop AD and who will maintain cognitive health. From a number of studies, it is clear that PET amyloid imaging shows robust differences in Aβ levels among groups of AD, MCI and CN individuals. When groups are combined, associations between higher Aβ and lower cognitive performance, especially episodic memory, emerge consistently across studies. Within diagnostic groups, correlations between Aβ burden and cognitive performance are less clear in cross-sectional investigations (summarized in Tables 1 and 2). The few longitudinal studies to date that included measures of change in cognitive performance over time provide more convincing evidence that increased Aβ correlates with greater decline in verbal memory, and perhaps other cognitive measures, such as executive function and mental status.

The potential utility of Aβ imaging as a clinical tool for early diagnosis of preclinical AD remains limited by its lower specificity due to the high proportion of PiB-positive CN individuals [3, 5, 28, 31, 35]. Additional challenges in interpreting a positive amyloid scan are the presence of amyloid plaques in other forms of dementia, for example, Lewy body disease [28], and the fact that Aβ also binds to intravascular amyloid, as is the case with cerebral amyloid angiopathogy [46]. Further, current radiotracers for Aβ imaging label predominantly fibrillar Aβ and do not measure soluble forms, providing only a partial quantification of Aβ burden. Despite these limitations, Aβ imaging in combination with information on cognitive function can help inform early detection and diagnosis of AD.

In addition to its contributing role in early identification of individuals at greatest risk for AD, amyloid imaging is also aiding in drug development and elucidating the regional distribution and temporal course of the neuro-biological changes leading to memory loss and AD. Amyloid imaging informs the selection of participants in therapeutic trials - for example, for anti-Aβ treatments - and may be useful in monitoring therapeutic response. In one recent trial, an 8.5% decline in Aβ level was detected in response to an anti-Aβ treatment [48]. PET amyloid imaging is also being used in combination with CSF and MRI measures to track the temporal course and regional brain changes preceding memory loss. Amyloid deposition is hypothesized to be an early stage of the disease process, with functional and structural brain changes, including hippocampal volume loss, occurring closer to the manifestation of clinical symptoms [49]. Imaging tools provide information throughout the brain, directing attention to the regions showing the earliest amyloid deposition and volumetric changes. In some cases, such as early amyloid deposition in precuneus/posterior cingulate, these imaging findings are focusing more detailed investigation on brain regions that were not included previously in laborious neuropathological evaluations [50, 51]. Amyloid imaging also provides the opportunity for prospective assessment of amyloid deposition in relation to changes in cognitive performance and regional brain volumes [47, 52]. The ability to track pathology over time using both amyloid imaging and CSF measures of Aβ [53] will enhance understanding of the temporal sequence of events in parallel and subsequent to amyloid deposition. Such studies may reveal whether there is some threshold beyond which memory impairment is evident and may identify factors that either render some individuals with substantial pathology resilient to disease or promote a delayed onset of clinical symptoms.

This article is part of a review series on Amyloid Imaging. Other articles in the series can be found online at http://alzres.com/series/amyloidimaging