Abstract
BACKGROUND: Integrating non-invasive measures to estimate abnormal amyloid beta accumulation (Aβ+) is key to developing a screening tool for preclinical Alzheimer's disease (AD). The predictive capability of standard neuropsychological tests in estimating Aβ+ has not been quantified. METHODS: We constructed machine learning models using six cognitive measurements alongside demographic and genetic risk factors to predict Aβ status. Data were drawn from three cohorts: Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4), Alzheimer's Disease Neuroimaging Initiative (ADNI), and Australian Imaging, Biomarker & Lifestyle (AIBL) study. Internal validation was conducted within A4 with external validations in ADNI and AIBL to assess model generalizability. RESULTS: The highest area under the curve (AUC) for predicting Aβ+ was observed with demographic, genetic, and cognitive variables in A4 (median AUC = 0.745), but this was not significantly different from models without cognitive variables. External validation showed no improvement in ADNI and a slight decrease in AIBL. DISCUSSION: Standard neuropsychological tests do not significantly enhance Aβ+ prediction in cognitively unimpaired adults beyond demographic and genetic information. HIGHLIGHTS: Standard neuropsychological tests do not significantly improve the prediction of amyloid beta positivity (Aβ+) in cognitively unimpaired older adults beyond demographic and genetic information alone. Across three well-characterized cohorts, machine learning models incorporating cognitive measures failed to significantly improve Aβ+ prediction, indicating the limited relationship between cognitive performance on these tests and the risk of pre-clinical Alzheimer's disease (AD). These findings challenge assumptions about cognitive symptoms preceding Aβ+ screening and emphasize the need for developing more sensitive cognitive tests for early AD detection.