Abstract
Recently, the focus of Alzheimer’s disease (AD) research has shifted from the clinical stage to the preclinical stage. We, therefore, aimed to develop a cognitive composite score that can detect the subtle cognitive differences between the amyloid positive (Aβ+) and negative (Aβ−) status in cognitively normal (CN) participants. A total of 423 CN participants with Aβ positron emission tomography images were recruited. The multiple-indicators multiple-causes model found the latent mean difference between the Aβ+ and Aβ− groups in the domains of verbal memory, visual memory, and executive functions. The multivariate analysis of covariance (MANCOVA) showed that the Aβ+ group performed worse in tests related to the verbal and visual delayed recall, semantic verbal fluency, and inhibition of cognitive inference within the three cognitive domains. The Preclinical Amyloid Sensitive Composite (PASC) model we developed using the result of MANCOVA and the MMSE presented a good fit with the data. The accuracy of the PASC score when applied with age, sex, education, and APOE ε4 for distinguishing between Aβ+ and Aβ− was adequate (AUC = 0.764; 95% CI = 0.667–0.860) in the external validation set (N = 179). We conclude that the PASC can eventually contribute to facilitating more prevention trials in preclinical AD.
Highlights
With the advancement of amyloid-β (Aβ) positron emission tomography (PET), the focus of research on Alzheimer’s disease (AD) has shifted from the clinical and symptomatic stages to the preclinical and asymptomatic stages of AD1
multivariate analysis of covariance (MANCOVA) showed that the Aβ+ group performed worse in the Seoul Verbal Learning Test-Elderly’s version (SVLT-E) delayed recall, the Rey-Osterrieth Complex Figure Test (RCFT) delayed recall, the Korean-Color Word Stroop test (K-CWST) color reading, and the Controlled Oral Word Association Test (COWAT) animal naming within the three cognitive domains
The Preclinical Amyloid Sensitive Composite (PASC) model that we developed using the result of MANCOVA and the Mini-Mental State Exam (MMSE) presented a good fit with the data
Summary
With the advancement of amyloid-β (Aβ) positron emission tomography (PET), the focus of research on Alzheimer’s disease (AD) has shifted from the clinical and symptomatic stages to the preclinical and asymptomatic stages of AD1. Approximately 20–30% of cognitively normal (CN) elderly population appear to be CN individuals with Aβ positivity[2,3,4] These CN individuals with elevated amyloidosis are considered to be more vulnerable to AD progression. A large lifespan study of CN adults found association of amyloid deposition with executive functions, but not with memory burden[10] This discrepancy may be because not many previous studies considered the effects of measurement errors, there is always a possibility for the presence of measurement errors in psychometrics[11]. We developed the Preclinical Amyloid Sensitive Composite (PASC) model, a composite model that precisely distinguishes cognitive differences between Aβ+ and Aβ− in CN individuals. Considering that subtle deficits in episodic memory and executive functions appear to be critical in preclinical AD due to their strong association with AD p rogression[12], we hypothesized that the PASC score consisting of memory and executive functions might differentiate Aβ+ CN from Aβ− CN with adequate accuracy
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