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Factors affecting Aβ plasma levels and their utility as biomarkers in ADNI

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Abstract

Previous studies of Aβ plasma as a biomarker for Alzheimer’s disease (AD) obtained conflicting results. We here included 715 subjects with baseline Aβ1-40 and Aβ1-42 plasma measurement (50% with 4 serial annual measurements): 205 cognitively normal controls (CN), 348 patients mild cognitive impairment (MCI) and 162 with AD. We assessed the factors that modified their concentrations and correlated these values with PIB PET, MRI and tau and Aβ1-42 measures in cerebrospinal fluid (CSF). Association between Aβ and diagnosis (baseline and prospective) was assessed. A number of health conditions were associated with altered concentrations of plasma Aβ. The effect of age differed according to AD stage. Plasma Aβ1-42 showed mild correlation with other biomarkers of Aβ pathology and were associated with infarctions in MRI. Longitudinal measurements of Aβ1-40 and Aβ1-42 plasma levels showed modest value as a prognostic factor for clinical progression. Our longitudinal study of complementary measures of Aβ pathology (PIB, CSF and plasma Aβ) and other biomarkers in a cohort with an extensive neuropsychological battery is significant because it shows that plasma Aβ measurements have limited value for disease classification and modest value as prognostic factors over the 3-year follow-up. However, with longer follow-up, within subject plasma Aβ measurements could be used as a simple and minimally invasive screen to identify those at increased risk for AD. Our study emphasizes the need for a better understanding of the biology and dynamics of plasma Aβ as well as the need for longer term studies to determine the clinical utility of measuring plasma Aβ.

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Acknowledgments

We thank our ADNI colleagues for their contributions to the work summarized here which has been supported mainly by the ADNI U01 AG024904. ADNI is funded by the National Institute of Aging, the National Institute of Biomedical Imaging and Bioengineering (NIBIB), and the Foundation for the National Institutes of Health, through generous contributions from the following companies and organizations: Pfizer Inc., Wyeth Research, Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Merck & Co. Inc., AstraZeneca AB, Novartis Pharmaceuticals Corporation, the Alzheimer’s Association, Eisai Global Clinical Development, Elan Corporation plc, Forest Laboratories, and the Institute for the Study of Aging (ISOA), with participation from the U.S. Food and Drug Administration. Other support has come from AG10124 and the Marian S. Ware Alzheimer Program. VMYL is the John H. Ware 3rd Professor for Alzheimer’s Disease Research and JQT is the William Maul Measy-Truman G. Schnabel Jr. M.D. Professor of Geriatric Medicine and Gerontology. We thank the ADNI Biomarker Core for the analyses. We thank Donald Baldwin and the Molecular Diagnosis Genotyping Facility at the University of Pennsylvania Medical Center for provision of the APOε genotyping data. J.B.T.’s work was supported by a grant from the Alfonso Martín Escudero foundation. L.S.’s, C.J.’s and M.W.’s work is partially supported by NIH.

Conflict of interest

J.Q.T., V.M.Y.L., A.W.T., S.X.X., E.T., M.F., M.W., C.J., P.A., W.J. and J.B.T. have no conflicts of interest. L.S. belongs to the advisory board of Innogenetics Technical. H.V. works at INNX-Fujirebio.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, HUP, Maloney 3rd (JQT) or 7th (LMS) Floor, 36th and Spruce Streets, Philadelphia, PA, 19104-4283, USA

    Jon B. Toledo, Michal Figurski, Virginia M.-Y. Lee, John Q. Trojanowski & Leslie M. Shaw

  2. Department of Diagnostic Development, Innogenetics NV, Ghent, Belgium

    Hugo Vanderstichele

  3. University of California at San Diego, San Diego, CA, 92093, USA

    Paul S. Aisen

  4. Mayo Clinic College of Medicine, Rochester, MN, 55905, USA

    Ronald C. Petersen

  5. Department of Radiology Medicine and Psychiatry, University of California at San Francisco, San Francisco, CA, USA

    Michael W. Weiner

  6. Mayo Clinic, Rochester, MN, USA

    Clifford R. Jack Jr

  7. Helen Wills Neuroscience Institute University of California, Berkeley, CA, USA

    William Jagust

  8. Department of Neurology, University of California, Sacramento, CA, USA

    Charles Decarli

  9. Laboratory of Neuro Imaging, Department of Neurology, University of California at Los Angeles School of Medicine, Los Angeles, CA, USA

    Arthur W. Toga

  10. Department of Preventive Medicine and Public Health, Medical School, Clinica Universidad de Navarra, University of Navarra, Pamplona, Spain

    Estefanía Toledo

  11. Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA

    Sharon X. Xie

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  1. Jon B. Toledo
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Correspondence to John Q. Trojanowski or Leslie M. Shaw.

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Toledo, J.B., Vanderstichele, H., Figurski, M. et al. Factors affecting Aβ plasma levels and their utility as biomarkers in ADNI. Acta Neuropathol 122, 401–413 (2011). https://doi.org/10.1007/s00401-011-0861-8

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  • DOI: https://doi.org/10.1007/s00401-011-0861-8

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