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

ABSTRACT: ?-amyloid (A?) 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?1-42 (A?42). Here we tested the hypothesis that baseline levels of CSF proteins involved in microglia activity, synaptic function and A? metabolism predict the development of A? plaques, assessed by longitudinal CSF A?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?42 from a mean concentration of 211-195 pg ml(-1) after 4 years. Linear mixed-effects models using longitudinal A?42 as the response variable, and baseline proteins as explanatory variables (n=69 proteins potentially relevant for A? metabolism, microglia or synaptic/neuronal function), identified 10 proteins with significant effects on longitudinal A?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?42 (largely overlapping with the proteins identified by linear mixed-effects models). Several proteins (including ACE, CgA and AXL) were associated with A?42 reduction only in subjects with normal baseline A?42, and not in subjects with reduced baseline A?42. We conclude that baseline CSF proteins related to A? metabolism, microglia activity or synapses predict longitudinal A?42 reduction in cognitively healthy elders. The finding that some proteins only predict A?42 reduction in subjects with normal baseline A?42 suggest that they predict future development of the brain A? pathology at the earliest stages of AD, prior to widespread development of A? plaques.

SUBMITTER: Mattsson N 

PROVIDER: S-EPMC3756294 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature