Examining Differences Across Cognitive Trajectory Profiles in Late Middle‐aged Adults: Results from the Wisconsin Registry for Alzheimer’s Prevention

Cognitive decline in Alzheimer’s disease (AD) and other dementias may accelerate in preclinical phases as brain pathology increases. Here we: 1) developed cognitive trajectory profiles using longitudinally-based random slope and change point (CP) parameter estimates from a cognitive composite; and 2) examined how AD-related biomarkers varied across these cognitive profiles. WRAP participants with > = 3 Preclinical Alzheimer’s Cognitive Composite (PACC3) scores, dementia-free at baseline, were included (n = 1068). Amyloid measures from positron emission tomography (PET) [C-11]Pittsburgh Compound B (PiB; n = 361) scans included Global PiB DVR and proportion PiB+ (Global PiB DVR>1.16). Tau measures included PET MK-6240 regional entorhinal cortex and hippocampal SUVR (n = 321). Neurodegeneration measures included MRI hippocampal volume and global brain atrophy (GBA; n = 581). Plasma measures included pTau217 (n = 166). Posterior median estimate person-level CPs, slopes pre- and post-CP, and intercepts at CP for PACC3 were extracted from Bayesian random CP mixed models (BRCPMM; age = time scale) and used to characterize cognitive trajectory profiles (K-means clustering). We compared demographic, last visit cognitive statuses (cognitively unimpaired-stable (CU-S), CU-declining (CU-D), and MCI/Dementia), amyloid, tau, neurodegenerations and plasma measures across the cognitive trajectory profiles using analysis of variance, chi-square and Fisher’s exact tests. Significant omnibus tests (p<.05) were followed with pairwise comparisons. Mean(sd) last cognitive assessment age was 66.6(6.6) years; PiB, MK, MRI scans and plasma occurred within mean(sd) 1.1(2.7), 1.6(1.4), .6(3) and .09(.7) years of cognitive assessment. Cluster analysis identified 3 groups of performance patterns representing highest to lowest risk of cognitive decline (high: n = 77(7.2%); intermediate: n = 446(41.8%); and low: n = 545(51.0%); Figure 1 & 2). The high risk group was older, had more females, APOE e4 carriers, and MCI/Dementia at last visit (Table 1). The high risk group also had worse PiB-amyloid, MK-tau, pTau217, and MRI-neurogeneration levels than the lower risk groups (Table2; Figure 3). In this initially non-demented sample, differences between cognitive clusters across multiple biomarkers and AD risk factors indicate that within-person PACC3 performance patterns are sensitive to preclinical change. Identifying cognitive trajectory profiles may provide an opportunity for early intervention for high-risk subjects at the right time for treatment and/or enrollment in a clinical trial.