Cerebrospinal Fluid Alzheimer’s Disease Biomarker Patterns of Change Prior to the Onset of Mild Cognitive Impairment

Abstract

Background: Cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) are altered many years before the onset of clinical symptoms of mild cognitive impairment (MCI). Incorporating clinical symptom onset time into biomarker modeling may enhance our understanding of changes preceding MCI. Objective: Using a new analytical approach, we examined patterns of biomarker change prior to MCI symptom onset among individuals who progressed from normal cognition to MCI, stratified based on the age of symptom onset. We also analyzed biomarker patterns of change among participants who remained cognitively normal, and examined potential modifiers of biomarker trajectories, including demographics and apolipoprotein E (APOE) status. Methods: Analyses included 93 participants who progressed from normal cognition to MCI and 186 participants who remained cognitively normal, over an average follow-up period of 16.2 years. CSF biomarkers, including Aβ42, Aβ40, total tau (t-tau), and phosphorylated tau181 (p-tau181), were measured using the fully automated Lumipulse assays. Results: Among participants who progressed to MCI, Aβ42/Aβ40 decreased, and t-tau and p-tau181 increased. For participants who did not progress to MCI, CSF biomarkers showed relatively stable patterns. In both progressors and non-progressors, APOE4 carriers showed lower Aβ 42/Aβ40 levels (compared to non-carriers) at each point of the mean curves. Among non-progressors, APOE4 carriers had higher levels of p-tau181, p-tau181/(Aβ 42/Aβ40), and t-tau/(Aβ 42/Aβ 40). Additionally, among those who did not progress, female sex was associated with higher levels of t-tau, p-tau181, t-tau/(Aβ 42/Aβ 40), and p-tau181/(Aβ 42/Aβ 40). Conclusions: These findings suggest that this analytic approach may provide additional insights into biomarker changes during early phases of AD.