RETROSPECTIVE COGNITIVE DECLINE IS ASSOCIATED WITH NEUROFIBRILLARY TANGLES AND BETA-AMYLOID PLAQUES MEASURED BY [F-18]MK-6240 AND [C-11]PIB IN LATE-MIDDLE AGED PERSONS CLINICALLY UNIMPAIRED AT BASELINE

Abstract

Characterizing contributions of neurofibrillary tangles (NFTs) and beta-amyloid (AB) plaques to cognitive decline, and relationships with other biomarkers during the preclinical phase of Alzheimer's disease (AD) may improve diagnostic and clinical trial outcomes. This work investigated if NFTs and AB plaques measured by PET explained differences in retrospective longitudinal cognitive trajectories of persons recruited from the Wisconsin Registry for Alzheimer's Prevention (WRAP) who were clinically unimpaired at their baseline cognitive assessment. Individuals (N=159; 59±6 years at baseline composite) recruited from WRAP underwent longitudinal cognitive assessments and T1-weighted MR, MK-6240 and PiB PET imaging. A preclinical Alzheimer's cognitive composite (PACC-3: RAVLT Total, WMS-R Logical Memory Delayed Recall, and WAIS-R Digit Symbol) was calculated (mean of Z-scored tests) for each assessment. Four biomarker groups (A+/-, T+/-) were established based on PiB (Global DVR >1.19; Reference Logan, cerebellum GM) and MK-6240 (Entorhinal cortex SUVR>1.27, mean+2SD of PIB(-) group; cerebellum GM, 70–90 min) PET. Differences in PACC-3 trajectories by group were interrogated using a linear mixed effects model with random person-level slopes and intercepts (model in Figure 1). Group differences in demographics, select neuropsychological tests, and biomarkers (PET, hippocampal volume, systolic blood pressure) were also investigated. The linear model indicated a significant group×time interaction (Figure 1); post-hoc pairwise comparisons (Tukey-adjusted) indicated the A+/T+ group had steeper PACC-3 decline compared to all other groups, but other groups did not differ significantly. Groups did not differ by sex, race, or family history of dementia, but did differ in the frequency of APOE-e4 carriers (Table 1). Systolic blood pressure and hippocampal volume did not differ by group at baseline or last assessments. RAVLT Total, WMS-R Logical Memory Delayed Recall, self-reported severity of memory problems, PACC-3 and the frequency of MCI differed by group at last assessment, but MMSE, self- and informant-reported memory problems, and WAIS-R Digit Symbol did not (Table 2).