Sequential early cognitive changes sensitive to rising beta‐amyloid and tau pathology in preclinical AD

Abstract Background AD clinical trials are increasingly looking towards intervention at the earliest stage of preclinical AD, when beta‐amyloid (Aβ) is emerging and tau pathology remains restricted to MTL. While some evidence suggests subtle cognitive changes start this early stage, it unclear what measures may be most sensitive whether they reflect Aβ, or both. Method 143 clinically‐normal adults with longitudinal PIB‐PET, FTP‐PET data (median follow‐up: 7.68(1.17) years) were included from Harvard Aging Brain Study (HABS). Analyses focused first on those initially PIB‐ (<Centiloid (CL) 20), then expanded <CL 40, approximately where neocortical proliferation accelerates. Linear mixed effects (LME) models assessed PIB slope*time effect each task across full time‐course. FTP was introduced later (∼Year 3), so LME assessing combined PIB+FTP cognition (Year3+) divided into prior (PIB slope‐Year0‐3, Year3‐FTP level) concurrent slope‐Y3+, slope‐Y3+). Both entorhinal (ERC) inferior temporal (IT) tested. ROC curve analyses sensitivity/specificity composite slope. Result In slope time‐course (Fig 1), rising robustly associated declining processing speed (DSST, Trails A) in <CL20 include memory encoding (FCsrt‐FR, SRT‐tr, LM‐immed) <CL40 group. under CL20 2), DSST, FCsrt‐FR, while only between ERC FCsrt‐FR. Expanding up CL40, IT became dominant related tasks, but independent remained for DSST measures. A measure A, demonstrated high sensitivity specificity (SE=.85, SP=.88, Fig 3) slope, performing better than any individual PACC. Conclusion Measures Aβ pathology, help determine anti‐Aβ therapies administered signs might preserve function.