CSF protein biomarkers predicting longitudinal reduction of CSF β-amyloid42 in cognitively healthy elders

beta-amyloid (A beta) plaque accumulation is a hallmark of Alzheimer's disease (AD). It is believed to start many years prior to symptoms and is reflected by reduced cerebrospinal fluid (CSF) levels of the peptide A beta 1-42 (A beta 42). Here we tested the hypothesis that baseline levels of CSF proteins involved in microglia activity, synaptic function and A beta metabolism predict the development of A beta plaques, assessed by longitudinal CSF A beta 42 decrease in cognitively healthy people. Forty-six healthy people with three to four serial CSF samples were included (mean follow-up 3 years, range 2-4 years). There was an overall reduction in A beta 42 from a mean concentration of 211-195 pg ml(-1) after 4 years. Linear mixed-effects models using longitudinal A beta 42 as the response variable, and baseline proteins as explanatory variables (n = 69 proteins potentially relevant for A beta metabolism, microglia or synaptic/neuronal function), identified 10 proteins with significant effects on longitudinal A beta 42. The most significant proteins were angiotensin-converting enzyme (ACE, P = 0.009), Chromogranin A (CgA, P = 0.009) and Axl receptor tyrosine kinase (AXL, P = 0.009). Receiver-operating characteristic analysis identified 11 proteins with significant effects on longitudinal A beta 42 (largely overlapping with the proteins identified by linear mixed-effects models). Several proteins (including ACE, CgA and AXL) were associated with A beta 42 reduction only in subjects with normal baseline A beta 42, and not in subjects with reduced baseline A beta 42. We conclude that baseline CSF proteins related to Ab metabolism, microglia activity or synapses predict longitudinal A beta 42 reduction in cognitively healthy elders. The finding that some proteins only predict A beta 42 reduction in subjects with normal baseline A beta 42 suggest that they predict future development of the brain Ab pathology at the earliest stages of AD, prior to widespread development of Ab plaques.