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

• β-amyloid (Ab) 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 Aβ1-42 (Aβ42). Here we tested the hypothesis that baseline levels of CSF proteins involved in microglia activity, synaptic function and Ab metabolism predict the development of Ab plaques, assessed by longitudinal CSF Aβ42 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 Aβ42 from a mean concentration of 211-195 pg ml1 after 4 years. Linear mixed-effects models using longitudinal Aβ42 as the response variable, and baseline proteins as explanatory variables (n=69 proteins potentially relevant for Ab metabolism, microglia or synaptic/neuronal function), identified 10 proteins with significant effects on longitudinal Aβ42. The most significant proteins were angiotensinconverting enzyme (ACE, P=0.009), Chromogranin A (CgA, P=0.009) and Axl receptor tyrosine kinase (AXL, P=0.009). Receiveroperating characteristic analysis identified 11 proteins with significant effects on longitudinal Aβ42 (largely overlapping with the proteins identified by linear mixed-effects models). Several proteins (including ACE, CgA and AXL) were associated with Aβ42 reduction only in subjects with normal baseline Aβ42, and not in subjects with reduced baseline Aβ42. We conclude that baseline CSF proteins related to Ab metabolism, microglia activity or synapses predict longitudinal Aβ42 reduction in cognitively healthy elders. The finding that some proteins only predict Aβ42 reduction in subjects with normal baseline Aβ42 suggest that they predict future development of the brain Ab pathology at the earliest stages of AD, prior to widespread development of Aβ plaques. © 2013 Macmillan Publishers Limited All rights reserved.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

Nyckelord

Alzheimer's disease

Beta-amyloid

Biomarker

Cerebrospinal fluid

Longitudinal

Microglia

amyloid beta protein[1-42]

beta 2 microglobulin

CD40 antigen

chromogranin A

clusterin

colony stimulating factor 1

CXCL9 chemokine

dipeptidyl carboxypeptidase

fibrinogen

follitropin

immunoglobulin A

monocyte chemotactic protein 1

osteopontin

plasminogen activator inhibitor 1

protein tyrosine kinase

serum amyloid P

somatomedin binding protein 2

tau protein

tissue inhibitor of metalloproteinase

tumor necrosis factor receptor 2

tumor necrosis factor related apoptosis inducing ligand

von Willebrand factor

aged

Alzheimer disease

amyloid plaque

article

cerebrospinal fluid analysis

controlled study

female

follow up

human

longitudinal study

male

Mini Mental State Examination

normal human

protein cerebrospinal fluid level

protein metabolism

synapse

synaptic potential

Publikations- och innehållstyp

ref (ämneskategori)

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