PROFILES OF COGNITIVE DECLINE ASSOCIATED WITH BIOMARKER-DEFINED PRECLINICAL STAGES OF ALZHEIMER’S DISEASE

Understanding the relationship between amyloidosis (Ab), neurodegeneration (ND), and cognition in clinically normal older adults is imperative as the field moves toward earlier identification and earlier intervention in Alzheimer’s disease. Previous research indicates that individuals with both Ab and ND show decline on cognitive composites. In this study, we sought to determine whether clinically normal individuals with Ab and ND show decline on particular neuropsychological measures and/or in a domain-specific manner and whether Ab and ND together or in isolation are associated with different neuropsychological profiles longitudinally. A total of 247 clinically normal older adults (mean age=73.67, 63-90) from the Harvard Aging Brain study completed annual neuropsychological exams (mean= 3.05±0.98 years) and baseline imaging (Pittsburgh compound B-PET, FDG-PET, and structural MRI). Subjects were grouped according to preclinical AD stages: Stage 0 (Ab-/ND-), Stage 1 (Ab+/ND-), Stage 2 (Ab+/ND+), and suspected non-Alzheimer’s associated pathology (SNAP; Ab-/ND+). Linear mixed models controlling for age, sex and education were used to examine cognitive decline across multiple measures and domains including Memory (6-trial SRT, FCSRT), Semantic Processing (BNT, category fluency), Basic Attention/Working Memory (DS, LNS, TMTA), Executive Functioning (TMT B, D-S Coding, FAS), and Visuospatial Skills (VFDT). Pairwise comparisons between preclinical stages were explored. Stage 2 performed consistently worse compared with Stage 0 in Memory (β= -0.21, p<0.0001), Semantic Processing (β= -0.13, p<0.0001), and Executive Functioning (β= -0.10, p<0.0001), but equivalently in Basic Attention/Working Memory and Visuospatial skills. Contrary to previous reports showing no decline in Stage 1, there was diminished practice effect in Semantic Processing (β= -0.07, p<0.01) and Memory (β= -0.07, p<0.05) in this group in comparison with Stage 0. Stage 0 and SNAP remained cognitively stable. The combination of Aβ and ND in clinically normal older adults appears to drive longitudinal decline in a clinical pattern consistent with Alzheimer’s disease. Some changes in semantic processing and memory functions are already observable in Stage 1, while Stage 0 and SNAP are associated with improved to stable cognition, respectively.