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Corresponding authors: Tel.: 11-215-746-7015; Fax: 11-215-573-3111. E-mail addresses: trojanow@mail.med.upenn.edu (J.Q.T.), lswang@ mail.med.upenn.edu (L.-S.W.)

For acknowledgments, see the full article.

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Research Funding:

This work was sponsored by a collaborative research project between the University of Pennsylvania, the Center for Neurodegenerative Disease Research, and Janssen entity.

This work was also supported by the UPennAG-10124.

J.B.T. was supported by a grant of the Alfonso Martin Escudero Foundation.

This work was supported by a grant to Washington University from Pfizer.

This work was also supported by the National Institutes of Health grants P50 AG05681, P01AG03991, P01 AG026276, P30 NS057105, and the Charles and Joanne Knight Alzheimer Research Initiative.

This publication was made possible by grant number UL1 RR024992 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research.

For additional funding information, see the full article.

Keywords:

  • Alzheimer’s disease
  • Amyloid beta
  • Biomarkers
  • Cerebrospinal fluid
  • Cognitive impairment
  • Dementia

Identifying amyloid pathology-related cerebrospinal fluid biomarkers for Alzheimer's disease in a multicohort study

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Journal Title:

Alzheimer's and Dementia

Volume:

Volume 1, Number 3

Publisher:

, Pages 339-348

Type of Work:

Article | Final Publisher PDF

Abstract:

Introduction: The dynamic range of cerebrospinal fluid (CSF) amyloid β (Aβ1–42) measurement does not parallel to cognitive changes in Alzheimer's disease (AD) and cognitively normal (CN) subjects across different studies. Therefore, identifying novel proteins to characterize symptomatic AD samples is important. Methods: Proteins were profiled using a multianalyte platform by Rules Based Medicine (MAP-RBM). Due to underlying heterogeneity and unbalanced sample size, we combined subjects (344 AD and 325 CN) from three cohorts: Alzheimer's Disease Neuroimaging Initiative, Penn Center for Neurodegenerative Disease Research of the University of Pennsylvania, and Knight Alzheimer's Disease Research Center at Washington University in St. Louis. We focused on samples whose cognitive and amyloid status was consistent. We performed linear regression (accounted for age, gender, number of apolipoprotein E (APOE) e4 alleles, and cohort variable) to identify amyloid-related proteins for symptomatic AD subjects in this largest ever CSF–based MAP-RBM study. ANOVA and Tukey's test were used to evaluate if these proteins were related to cognitive impairment changes as measured by mini-mental state examination (MMSE). Results: Seven proteins were significantly associated with Aβ1–42 levels in the combined cohort (false discovery rate adjusted P < .05), of which lipoprotein a (Lp(a)), prolactin (PRL), resistin, and vascular endothelial growth factor (VEGF) have consistent direction of associations across every individual cohort. VEGF was strongly associated with MMSE scores, followed by pancreatic polypeptide and immunoglobulin A (IgA), suggesting they may be related to staging of AD. Discussion: Lp(a), PRL, IgA, and tissue factor/thromboplastin have never been reported for AD diagnosis in previous individual CSF–based MAP-RBM studies. Although some of our reported analytes are related to AD pathophysiology, other's roles in symptomatic AD samples worth further explorations.

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© 2015 The Authors.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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