Age-accelerated cognitive decline in asymptomatic adults with CSF beta-amyloid

Objective Compare cognitive and hippocampal volume trajectories in asymptomatic middle-aged and older adults with positive CSF markers of beta-amyloid (A beta) or tau to adults without an Alzheimer disease (AD)-associated biomarker profile. Methods Three hundred ninety-two adults enrolled in a longitudinal cohort study (Wisconsin Registry for Alzheimer's Prevention or Wisconsin Alzheimer's Disease Research Center) completed a lumbar puncture and at least 2 biennial or annual neuropsychological evaluations. Cutoffs for A beta 42, total tau, and phosphorylated tau were developed via receiver operating characteristic curve analyses on a sample of 78 participants (38 dementia, 40 controls). These cutoffs were applied to a separate sample of 314 cognitively healthy adults (mean age at CSF collection = 61.5 years), and mixed-effects regression analyses tested linear and quadratic interactions of biomarker group x age at each visit on cognitive and hippocampal volume outcomes. Results Two hundred fifteen participants (69%) were biomarker negative (preclinical AD stage 0), 46 (15%) were A beta+ only (preclinical AD stage 1), 25 (8%) were A beta+ and tau+ (preclinical AD stage 2), and 28 (9%) were tau+ only. Both stage 1 and stage 2 groups exhibited greater rates of linear decline on story memory and processing speed measures, and nonlinear decline on list-learning and set-shifting measures compared to stage 0. The tau+ only group did not significantly differ from stage 0 in rates of cognitive decline. Conclusion In an asymptomatic at-risk cohort, elevated CSF A beta (with or without elevated tau) was associated with greater rates of cognitive decline, with the specific pattern of decline varying across cognitive measures.