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Total apolipoprotein E levels and specific isoform composition in cerebrospinal fluid and plasma from Alzheimer’s disease patients and controls

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Abstract

The apolipoprotein E (ApoE) ε4 allele is the strongest risk factor of sporadic Alzheimer’s disease (AD), however, the fluid concentrations of ApoE and its different isoforms (ApoE2, ApoE3 and ApoE4) in AD patients and among APOE genotypes (APOE ε2, ε3, ε4) remain controversial. Using a novel mass spectrometry-based method, we quantified total ApoE and specific ApoE isoform concentrations and potential associations with age, cognitive status, cholesterol levels and established AD biomarkers in cerebrospinal fluid (CSF) from AD patients versus non-AD individuals with different APOE genotypes. We also investigated plasma total ApoE and ApoE isoform composition in a subset of these individuals. In total n = 43 AD and n = 43 non-AD subjects were included. We found that CSF and plasma total ApoE levels did not correlate with age or cognitive status and did not differ between AD and non-AD subjects deeming ApoE as an unfit diagnostic marker for AD. Also, whereas CSF ApoE levels did not vary between APOE genotypes APOE ε4 carriers exhibited significantly decreased plasma ApoE levels attributed to a specific decrease in the ApoE4 isoform concentrations. CSF total ApoE concentrations were positively associated with CSF, total tau, tau phosphorylated at Thr181 and Aβ1-42 of which the latter association was weaker and only present in APOE ε4 carriers indicating a differential involvement of ApoE in tau versus Aβ-linked neuropathological processes. Future studies need to elucidate whether the observed plasma ApoE4 deficiency is a life-long condition in APOE ɛ4 carriers and whether this decrease in plasma ApoE predisposes APOE ɛ4 carriers to AD.

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Abbreviations

Aβ:

Amyloid-β

AD:

Alzheimer’s disease

ApoE:

Apolipoprotein E

BBB:

Blood–brain barrier

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

HDL:

High-density lipoprotein

LDL:

Low-density lipoprotein

MMSE:

Mini-mental state examination

QAlb:

CSF/plasma albumin ratio

SNP:

Single nucleotide polymorphism

T-tau:

Total tau

P-tau:

Tau phosphorylated at Thr181

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Acknowledgments

The authors wish to sincerely thank the participating research subjects for their dedication in furthering our knowledge on the involvement of ApoE in AD. We also want to thank Camilla Orbjörn, Lund University Malmö Sweden, for technical support. The authors wish to acknowledge the regional agreement on medical training and clinical research (A.L.F.) between the Skåne County Council and Lund University for financial support (OH, LM, HMN).

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Authors and Affiliations

  1. Lunenfeld-Tanenbaum Research Institute, Joseph and Wolf Lebovic Health Centre, Mount Sinai Hospital, Toronto, ON, Canada

    Eduardo Martínez-Morillo

  2. Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Memory Clinic at Skåne University Hospital, Lund University, Malmö, Sweden

    Oskar Hansson & Lennart Minthon

  3. Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Yuka Atagi, Guojun Bu & Henrietta M. Nielsen

  4. Molecular Memory Research Unit, Department of Clinical Sciences Malmö, The Wallenberg Laboratory at Skåne University Hospital, Lund University, Malmö, Sweden

    Lennart Minthon & Henrietta M. Nielsen

  5. Department of Clinical Biochemistry, Toronto General Hospital, University Health Network, Toronto, ON, Canada

    Eleftherios P. Diamandis

  6. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

    Eleftherios P. Diamandis

  7. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada

    Eleftherios P. Diamandis

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  1. Eduardo Martínez-Morillo
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  2. Oskar Hansson
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  3. Yuka Atagi
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  4. Guojun Bu
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  6. Eleftherios P. Diamandis
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  7. Henrietta M. Nielsen
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Correspondence to Henrietta M. Nielsen.

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Martínez-Morillo, E., Hansson, O., Atagi, Y. et al. Total apolipoprotein E levels and specific isoform composition in cerebrospinal fluid and plasma from Alzheimer’s disease patients and controls. Acta Neuropathol 127, 633–643 (2014). https://doi.org/10.1007/s00401-014-1266-2

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