Cerebrospinal Fluid Amyloid and Tau Biomarker Changes Across the Alzheimer Disease Clinical Spectrum

IMPORTANCE The trajectories of core Alzheimer disease (AD) cerebrospinal fluid (CSF) biomarkers and the concurrent cognitive changes across the clinical spectrum remain unclear yet are important for clinical trial design. OBJECTIVE To map longitudinal CSF amyloid, tau, and cognitive trajectories along the clinical spectrum of AD and amyloid-negative controls. DESIGN, SETTING, AND PARTICIPANTS This longitudinal cohort study included participants with a minimum of 2 CSF samples from Alzheimer Centrum Amsterdam cohorts across the AD clinical spectrum (ie, abnormal amyloid levels at first visit, in different clinical stages) and cognitively normal controls with initially normal CSF markers from November 2003 to July 2019. The maximum follow-up period was 19.5 years (median [IQR], 2 [0-3] years). Data were analyzed from March 2024 to May 2025. EXPOSURES AD biomarkers (ß-amyloid [Aß]1-42 to Aß1-40 ratio, total tau [t-tau], and phosphorylated tau [p-tau]) detected in serially collected CSF. MAIN OUTCOMES AND MEASURES CSF AD biomarkers were measured with Lumipulse G600II. Cognition was measured using the Mini-Mental State Examination (MMSE) and delayed memory recall component of the of the Rey Auditory Verbal Learning Test. Analysis was conducted using linear mixed models, including random intercepts and slopes, adjusting for age, education level, and sex. Each model included an interaction term of time and clinical stage to study stage-specific slopes. Biomarker conversion rates per clinical stage were studied by comparing biomarker status between visits. RESULTS The sample included 197 individuals (103 male [52.3%]), including 83 controls (mean [SD] age, 63 [8] years), 31 individuals with amyloid positivity who were cognitively unimpaired (mean [SD] age, 67 [9] years), 30 individuals with amyloid-positive mild cognitive impairment (MCI; mean [SD] age, 67 [7] years), and 53 individuals with amyloid-positive dementia (mean [SD] age, 65 [8] years). Aβ1-42/1-40 ratios decreased in controls (β [SE] = −8.55 × 10 −4 [1.87 × ...