Association of item-level responses to cognitive function index with tau pathology and hippocampal volume in the A4 Study

INTRODUCTION: Alzheimer's disease (AD) has a long preclinical phase in which individuals may accumulate amyloid beta (Aβ) and tau pathology without noticeable cognitive impairment. Subjective cognitive impairment reports can provide early insights into cognitive decline. METHODS: In the A4 Study, 339 cognitively unimpaired, Aβ-positive individuals underwent tau positron emission tomography imaging. Tau status was classified based on medial temporal lobe tau standardized uptake value ratios (tau_MTL). Participants and study partners assessed cognitive changes using the 15-item Cognitive Function Index (CFI) questionnaire. We explored the relationship among tau_MTL, hippocampal volume (HVa), and CFI reports. RESULTS: Higher tau_MTL was associated with participant-reported concerns about memory and navigation, and with study partner–reported difficulty remembering appointments. Lower HVa showed a marginal association with participant-reported driving difficulty. DISCUSSION: These findings support the utility of participant- and study partner–reported concerns as early indicators of preclinical AD pathology, with potential value for early detection and trial enrichment strategies. Highlights: Higher tau in the medial temporal lobe (tau_MTL) was linked to participant-reported memory and orientation decline such as needing reminders or getting lost. Higher tau_MTL was associated with increased memory-related concerns, such as needing help with appointments and asking repetitive questions. Lower hippocampal volume was associated with spatial memory and navigation such as driving difficulties and greater memory decline as reported by study partners.