Regional tau Burden and Multidomain Cognitive Function in Clinically Unimpaired Older Adults: Evidence from the A4 Study

Methods:In this cross-sectional study, 447 participants in the A4 study (anti-amyloid treatment in asymptomatic AD) underwent tau-positron emission tomography-standardized uptake value ratio evaluations.Cognitive abilities were assessed using the Preclinical Alzheimer's Cognitive Composite (PACC).Depression, anxiety, and lifestyle factors were analyzed using t-tests, chi-square tests, and multiple linear regression models.Results: The tau-positive cohort was notably older (p=0.002) and significantly more likely to carry APOE4 (p<0.001).Tau-positive groups demonstrated poorer cognitive performance.Negative correlations between tau accumulation and cognitive performance for PACC and its components, with tauMTL/tauNEO associated with worse outcomes.Females were associated with better objective performance but worse informant-reported function, suggesting an early loss of self-awareness.Higher education was protective; depression was linked to decreased memory and executive function, whereas anxiety showed no association.Conclusion: Regional tau pathology is robustly associated with functional decline detectable by informants prior to clinical emergence.The significant interaction between tau and modifiable factors such as depressive symptoms underscores the importance of multifaceted, informant-based assessments in preclinical AD screening.