We investigated the distinctive neuropsychological features of Aβ + CN elderlies in a carefully phenotyped, CN cohort that underwent detailed neuropsychological tests, MRI, and amyloid PET scans with the standardized protocols. Accordingly, there were several significant neuropsychological findings in this study. First, the MIMIC model found a difference in the latent mean between the Aβ + and Aβ- groups in the domains of verbal memory, visual memory, and executive functions. Furthermore, MANCOVA showed that the Aβ + group performed worse in the RCFT delayed recall, SVLT-E delayed recall, COWAT animal, and K-CWST color reading within the three cognitive domains. Lastly, based on our results and clinical significance, we developed the PASC with the RCFT delayed recall, SVLT-E delayed recall, COWAT animal, K-CWST color reading, and K-MMSE that were found to be critical for amyloid deposition and global cognition. Hence, the PASC can be used to develop a composite score for detecting Aβ positivity in CN individuals, which can eventually help with early intervention of AD.
The demographic profile of our participants was extremely close to that of the previously reported Asian society profile. The CN Aβ + percentage in Asian countries is known to be lower than that in western countries. The percentage of CN amyloid positivity in the Asian population ranged between 18% and 25% according to the Korean Brain Aging Study for the Elderly Diagnosis and Prediction of Alzheimer’s disease (KBASE) and J-ADNI [18, 19]. On the other hand, the western population, represented by ADNI, was reported to range approximately from 25 to 45% Aβ positivity rate [20, 21]. Our study exhibited approximately 18% Aβ positivity in the 423 CN individuals, which was in line with that in the Asian population. The discrepancy between our results and that of the western society may be explained by the differences in the frequency of APOE ε4 and the age of the study participants. Our cohort seemed to have a lower percentage of APOE ε4 (23%) than that reported by ADNI (27%) [22]. Moreover, the younger age of our cohort (mean, 69.9 years) compared to that of the ADNI CN individuals (mean, 75.8 years) may have affected the lower rate of amyloid positivity [22]. Regardless of these disparities, the APOE ε4 rate and age of our cohort were still at comparable levels to J-ADNI’s APOE ε4 rate (24%) and CN individuals’ ages (mean, 67.9) [18].
Our major finding was that the Aβ + CN individuals presented a lower performance in verbal memory, visual memory, and executive functions compared to Aβ- CN, which was generally consistent with the findings of previous meta-analyses. In terms of memory, there has been a consensus that episodic memory has a strong association with Aβ burden [23–25]. Unlike episodic memory, the results regarding executive functions in the previous studies are not entirely consistent. A recent meta-analysis suggested a significant difference in executive function [24], while two others showed either a small effect size or a weak association with Aβ burden [23, 25]. This may be because the previous studies did not consider the effects of measurement errors that could impact the individual test scores. However, applying a factor analysis with the latent variables, we controlled for the measurement errors from each test score for more precise measurement of the corresponding cognitive function.
In the present study, we developed the PASC to predict amyloid positivity using the SVLT-E delayed recall, the RCFT delayed recall, the COWAT animal, and the CWST color reading from the three cognitive domains, and the K-MMSE. We included the K-MMSE in the PASC because the Mini-Mental State Exam (MMSE) is a practical neuropsychological test to examine individual cognitive function holistically [26]. The PASC seems similar to the Preclinical Alzheimer Cognitive Composite (PACC) [27]. However, the PACC was not developed for differentiation of preclinical AD, but rather has been used in prevention trials for preclinical AD [1, 27].
There are a few reasons why we tried to observe cognitive differences in CN individuals with a unidimensional outcome. First, there is a need to create a novel and reliable measure to holistically assess cognitive domains specific to preclinical AD. AD pathology progression involves the deterioration of multiple cognitive domains instead of a single cognitive function. Currently, the MMSE [26] and the Clinical Dementia Rating (CDR) [28] are commonly used to assess individual cognitive function holistically. However, they often display ceiling effects in CN individuals [29, 30]. Therefore, they are not sensitive measures for CN individuals. Furthermore, the ratings of the CDR primarily rely on clinicians’ judgments following patient and caregiver interviews. Thus, bias is rarely avoidable. Another advantage of obtaining a composite model is that a single factor model allows for a more precise differentiation of distinct groups. Compared to multi-outcomes, a primary outcome usually yields lower background noise in the measurement, which derives a lower risk of Type-I error [8, 31]. Therefore, a primary outcome has better reliability and sensitivity in terms of detecting subtle cognitive differences.
The strength of our study is the large sample size of the CN cohort who underwent amyloid PET. In spite of this strength, there are a few limitations to our study, as well. First, our composite model was not cross-validated. Future studies are needed to cross-validate this composite model in different patient groups and data sets. Second, the participants went through different types of PET ligands. The variety of the tracers may have affected the visual reads of amyloid deposition. However, this limitation can be somewhat alleviated by the high correlations among the different ligands [32, 33]. Moreover, we did not explore the clinical effects of the PASC. Future studies with clinical impacts of the PASC on other biomarkers like tau or cortical atrophy may be recommended. Lastly, our study was a single-center study with the cohort recruited from a hospital. Since we did not recruit the participants from the general population, the generalizability of our study may be challenging.