The present study examined in vivo brain PiB retention in a group of clinically unimpaired elderly persons. Our primary aims were to estimate the prevalence of significant amyloid deposition among clinically unimpaired elderly persons during life, and to characterize the association of amyloid deposition with demographic characteristics and cognitive performance.
Amyloid load and, therefore, PiB retention, is a continuous variable. Even clinically unimpaired elderly persons often have measurable amounts of insoluble Aβ after death. Näslund et al43
have shown that participants who had Clinical Dementia Rating (CDR) scale scores of 0 before death had measurable levels of insoluble Aβ, although these levels were only 4% to 20% of the levels observed among participants with severe AD. That having been said, a dichotomous definition of an amyloid-positive and amyloid-negative state is often useful for group designations in studies such as ours, in which the effect of detectable PiB retention on cognition is being evaluated. Ultimately, the definition of amyloid-positivity will need to be validated by the comparison of in vivo PiB retention with postmortem verification of the presence or absence of significant numbers of Aβ plaques at autopsy. Until then, objective criteria for the definition of amyloid-positivity are needed. Few clear criteria have been posed to define amyloid-positivity. Most studies have defined amyloid-positivity among clinically unimpaired persons or those with MCI either from visual reads of the images (ie, as “AD-like”) or from rough quantitative comparisons of PiB retention among controls with the range of values observed among AD participants (ie, PiB retention above that of the lowest PiB retention value in an AD participant is considered amyloid-positive).7,17,18
Klunk et al7
attempted to provide an objective definition of amyloid-positivity and make it independent of any AD cohort by defining the cutoff point as PiB retention values 1 SD or more above the mean of the entire control group. Pike et al44
have taken a more sophisticated objective approach by using a receiver operating characteristic curve to generate a cutoff point between clinically unimpaired controls and AD participants, although this approach remains dependent on the composition of the AD cohort. Although these 2 objective approaches are an improvement over subjective assessments, they can be disproportionately affected by outliers in either the AD or control groups or by large gaps between the groups.
To remove the contribution of the AD cohort and minimize the impact of controls with high PiB retention on the definition of amyloid-positive cutoff values, we used an iterative outlier removal method and generated an upper- and lower-bound of DVRs for each ROI. Individuals with DVRs above the upper-bound in the ACG or PRC/PCG cortex were considered amyloid-positive. These subjects typically showed a visual pattern of PiB retention that was qualitatively similar to, but quantitatively less than, most AD participants. Individuals with PiB retention below the lower-bound were considered amyloid-negative. Individuals with PiB retention in the ACG or PRC/PCG cortex that was between the lower- and upper-bounds were called intermediate
for the purpose of this study. Of 43 subjects, 9 (21%) were amyloid-positive, 29 (67%) amyloid-negative, and 5 (12%) intermediate. Our observation of significant amyloid deposition in a subset of cognitively unimpaired elderly persons is consistent with previous observations from neuropathological studies45–47
and recent amyloid imaging studies.17,18
Our estimate of 21% is similar to that reported by Mintun et al,17
who used a higher threshold for classifying subjects as amyloid-positive, and Rowe et al18
and matches closely the postmortem observations from Knopman et al,47
who reported that 18% of participants met Consortium to Establish a Registry for Alzheimer’s Disease criteria for possible AD.
It should be stressed that the designation of amyloid-positive in the context of clinically unimpaired elderly persons does not imply that these subjects have AD-like results on a PiB PET scan. On the contrary, the scans of most subjects could be easily distinguished from the PiB PET scans of AD patients. This is quantitatively apparent in the global measure (GBL6) in and visually apparent in . Only 6 of 9 amyloid-positive subjects are globally positive, and even these 6 are clearly distinguishable from all but 1 AD case with unusually low PiB retention. Although data from only our first 9 consecutive AD patients are shown in , we have now studied PiB retention in more than 20 AD participants, and the case shown in is the only one with GBL6 retention that overlaps with that of any amyloid-positive clinically unimpaired participant. This has important implications for the use of amyloid imaging as a diagnostic tool. That is, although subtle amyloid-deposition can be identified by low levels of PiB retention (often focal), it is relatively easy to visually and quantitatively distinguish this type of amyloid deposition from that seen among symptomatic patients with AD.
The degree of PiB retention among amyloid-positive cognitively unimpaired elderly persons also differs from the pattern of PiB retention observed among most participants with MCI. Participants with MCI who also had significant PiB retention typically show a much higher amount of PiB retention than cognitively unimpaired elderly persons, in the range of AD participants.16,40
Most participants with MCI show a dichotomous pattern: 30% to 40% are clearly amyloid-negative, and 50% to 60% have AD-like PiB retention. In the literature, only10% to 15% of participants with MCI fall into the range occupied by the amyloid-positive but clinically unimpaired elderly participants in this study. This has important implications for antiamyloid therapies currently in development, such as that the active phase of Aβ plaque accumulation occurs when a person is asymptomatic. It is likely that antiamyloid therapies will have the highest chance of success during this period. Therefore, if a safe and effective antiamyloid therapy can be developed, it may become critical to identify amyloid-positive individuals at a presymptomatic stage.
Our results strongly suggest that amyloid deposition can be detected at an asymptomatic stage. Similar to the results of several recent neuropathological studies,48,49
we did not find significantly worse cognitive performance among amyloid-positive subjects. In fact, the only significant difference we found between the amyloid-positive and amyloid-negative groups was in a direction opposite to that expected. The amyloid-positive group performed better on the Delayed Word Recall test. It is unclear why this group would show improved performance on a declarative memory task. One speculation is that perhaps subjects with preclinical amyloid deposition who are still clinically unimpaired have particularly high cognitive reserve in areas relatively unaffected by amyloid deposition (ie, medial temporal lobe).
The prevalence estimate of amyloid deposition reported here is based on a very small sample of community volunteers and, therefore, may not reflect the true prevalence in a random sampling of the community. In particular, the sample may be biased by an overrepresentation of more highly educated and motivated volunteers. However, educational level did not differ significantly between amyloid-positive and amyloid-negative groups, so it is unlikely that it would significantly alter the prevalence estimate. In addition, the estimate of 20% to 25% prevalence of amyloid-positivity in this clinically unimpaired cohort with a mean (SD) age of 75(6) years is in keeping with an expected AD prevalence of approximately 25% among people older than 85 years if asymptomatic amyloid deposition invariably leads to AD and if the clinically silent period of amyloid deposition is on the order of 10 years.
Although our primary finding suggests that there is no significant cognitive deficit in the amyloid-positive group compared with the amyloid-negative group, we recognize that this conclusion is based on a relatively small sample of amyloid-positive individuals (n=9) and an even smaller number with complete cognitive data (5 amyloid-positive participants with delayed recall and Rey figure data). Further studies with larger samples are necessary to identify whether subtle differences in cognition may exist among amyloid-positive individuals. Another limitation of this study is that the cognitive testing protocol had only limited executive function assessment and, therefore, it is possible that future studies with more detailed executive function tests may find differences between amyloid-positive and amyloid-negative groups.
In conclusion, to our knowledge, this is one of the first and the largest study to examine in vivo amyloid deposition among clinically unimpaired elderly persons with extensively documented cognitive function. We found that a significant number (21%) of clinically unimpaired elderly persons had amyloid deposition, and the deposition was primarily in regions that ultimately develop heavy amyloid loads in AD patients, especially the ACG and the PRC/PCG cortex. We found mixed results in relating amyloid deposition to demographic and cognitive variables. In particular, we did not find amyloid-positive subjects to have worse cognitive performance than that of the amyloid-negative group, and we did not find any demographic differences between the groups, although there was a suggestion of more frequent amyloid-positivity among those who carry an APOE ε4 allele. Thus, it appears that, in a significant number of elderly, cognitively normal persons, amyloid accumulation does not impair cognitive function.
This study suggests that, among people older than 65 years, amyloid deposition without cognitive sequelae and amyloid deposition accompanied by cognitive impairment in the form of dementia (ie, AD) or MCI have a similar prevalence (approximately 20%). It is possible, but yet unproven, that elderly persons with significant PiB retention may progress to AD and that the preserved cognition observed in this study is owing to compensation. This finding could have profound implications for future prevention strategies, such that it may be possible to predict fairly accurately who will develop AD 5 to 10 years before the onset of symptoms. If compensatory mechanisms are involved in delaying the onset of symptoms, identification of these mechanisms could lead to novel and effective preventative treatment strategies.