CSF beta-amyloid 1-42 - what are we measuring in Alzheimer's disease?

Objective: To characterize biological and technical factors which influence cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarker levels, including the presence of apolipoprotein E (APOE) epsilon 4 allele, AD diagnosis, A beta-binding proteins, sample processing, and preanalytical handling. Methods: CSF was collected from 140 subjects with normal cognition, mild cognitive impairment, AD, and non-AD dementia. CSF levels of beta-amyloid 1-42 (A beta 42), total Tau (t-Tau), and Tau phosphorylated at threonine 181 (p-Tau181) were analyzed following the standard and modified protocols. CSF levels of apoJ, apoE, albumin, and alpha-synuclein were measured in a subgroup (n = 69), and their effects on measured AD biomarker levels were also determined in vitro using human CSF samples. Results: CSF A beta 42 levels measured using the AD Neuro-imaging Initiative (ADNI) protocol (which we call suspended A beta 42 or susA beta) were lower than total measurable CSF A beta 42 in all groups, and on average represents 57% of the latter. Logistic regression analysis showed this proportion (% susA beta) to be directly correlated with CSF A beta 42 and apoJ levels, but inversely correlated with CSF t-Tau levels. Finally, we showed in vitro that increasing apoE and apoJ levels directly increased % susA beta. Conclusion: CSF susA beta levels are influenced by biological and technical factors, and may represent a marker of A beta susceptible to lipoprotein-mediated clearance. Clinical trials should include total measurable A beta 42 and susA beta to better inform outcomes.