ABSTRACT Objective Compare cognitive and hippocampal volume (HCV) trajectories in asymptomatic middle-aged and older adults with positive cerebrospinal fluid (CSF) markers of β-amyloid (Aβ) or tau to adults without an AD-associated biomarker profile. Method 392 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 two biennial or annual neuropsychological evaluations. Cutoffs for Aβ 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) and mixed-effects regression analyses tested linear and quadratic interactions of biomarker group × age at each visit on cognitive and HCV outcomes. Results 215 participants (69%) were biomarker negative (preclinical AD Stage 0), 46 (15%) were Aβ+ only (preclinical AD Stage 1), 25 (8%) were Aβ+ 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 non-linear 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 Aβ (with or without elevated tau) was associated with greater rates of cognitive decline, with the specific pattern of decline varying across cognitive measures.

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