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Ferritin levels in the cerebrospinal fluid predict Alzheimer's disease outcomes and are regulated by APOE.

Abstract

Brain iron elevation is implicated in Alzheimer's disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body; by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We show that baseline CSF ferritin levels were negatively associated with cognitive performance over 7 years in 91 cognitively normal, 144 mild cognitive impairment (MCI) and 67 AD subjects, and predicted MCI conversion to AD. Ferritin was strongly associated with CSF apolipoprotein E levels and was elevated by the Alzheimer's risk allele, APOE-ɛ4. These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-ɛ4 being the major genetic risk factor for AD.

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  • Authors+Show Affiliations

    ,

    Oxidation Biology Unit, The Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3052, Australia.

    ,

    1] Bioinformatics Core, The Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3052, Australia [2] Cooperative Research Center for Mental Health, Parkville, Victoria 3052, Australia.

    ,

    1] Oxidation Biology Unit, The Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3052, Australia [2] Cooperative Research Center for Mental Health, Parkville, Victoria 3052, Australia.

    Source

    Nature communications 6: 2015 pg 6760

    MeSH

    Aged
    Aged, 80 and over
    Alzheimer Disease
    Apolipoproteins E
    Atrophy
    Brain
    Cognition
    Cognition Disorders
    Cohort Studies
    Databases, Factual
    Female
    Ferritins
    Gene Expression Regulation
    Genotype
    Humans
    Iron
    Longitudinal Studies
    Magnetic Resonance Imaging
    Male
    Middle Aged
    Risk Factors
    Treatment Outcome

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't
    Research Support, U.S. Gov't, Non-P.H.S.

    Language

    eng

    PubMed ID

    25988319

    Citation

    TY - JOUR T1 - Ferritin levels in the cerebrospinal fluid predict Alzheimer's disease outcomes and are regulated by APOE. AU - Ayton,Scott, AU - Faux,Noel G, AU - Bush,Ashley I, AU - ,, Y1 - 2015/05/19/ PY - 2014/10/31/received PY - 2015/2/25/accepted PY - 2015/5/20/entrez PY - 2015/5/20/pubmed PY - 2016/3/26/medline SP - 6760 EP - 6760 JF - Nature communications JO - Nat Commun VL - 6 N2 - Brain iron elevation is implicated in Alzheimer's disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body; by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We show that baseline CSF ferritin levels were negatively associated with cognitive performance over 7 years in 91 cognitively normal, 144 mild cognitive impairment (MCI) and 67 AD subjects, and predicted MCI conversion to AD. Ferritin was strongly associated with CSF apolipoprotein E levels and was elevated by the Alzheimer's risk allele, APOE-ɛ4. These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-ɛ4 being the major genetic risk factor for AD. SN - 2041-1723 UR - https://www.unboundmedicine.com/medline/citation/25988319/full_citation L2 - http://dx.doi.org/10.1038/ncomms7760 ER -