Longitudinal tau accumulation interacts with cortical thinning to predict steeper memory decline in cognitively normal older adults

Background Cross‐sectional measures of tau pathology, a hallmark of Alzheimer’s disease (AD), have been associated with brain structure and memory performance in cognitively normal older adults (OA). Fewer studies have explored the downstream effects of longitudinal tau accumulation in OA. Here, we investigated relationships between tau accumulation, atrophy, and memory performance change over time. Method Seventy cognitively normal OA (age = 77 ± 5 years; Table1) underwent longitudinal flortaucipir (FTP) PET, structural MRI scanning, and neuropsychological assessment. Annual change slopes for entorhinal cortex (EC) and a temporal meta‐ROI partial‐volume corrected FTP, cortical thickness, and an episodic memory (EM) composite were estimated using linear mixed effects models. Linear methods (Pearson correlation, multiple regression, mixed effects models) were used to relate regional tau slopes to atrophy and EM change. We used elastic net regression to select the best predictors of EM slope, including all FTP and structural ROIs, age, education, beta‐amyloid burden, and sex. Voxel‐wise FTP slope images were also generated to explore associations with atrophy and EM slope across the cortex. Result Higher FTP slope in EC and meta‐ROI significantly predicted EM decline (β= ‐.26 p=.03 & β= ‐.38 p=.001, respectively; Fig.1). FTP slope did not significantly predict longitudinal atrophy in EC or meta‐ROI (ps>.10). A multiple regression with predictors selected via an elastic net model (Table2) showed a significant interaction between meta‐ROI FTP slope and EC cortical thickness slope such that tau accumulation and EM decline were more strongly related in OA with a higher rate of entorhinal cortical thinning (β=.23 p=.02; Fig.2). Voxel‐wise models with tau slope and memory showed interesting findings in the temporal lobe but clusters did not reach statistical significance. A one‐sample t‐test showed significant tau accumulation in frontal, parietal, and temporal lobe regions (Fig.3). Conclusion EC and meta‐ROI tau accumulation predicts memory decline in cognitively normal OA. EC atrophy moderated the effect of meta‐ROI tau accumulation on memory decline, suggesting a synergic effect of tau pathology and structural atrophy on memory decline in early AD. These novel findings provide insights into mechanisms of memory decline in typical aging and early AD.