Abstract

In our functional dissection of the CD33 Alzheimer's disease susceptibility locus, we found that the rs3865444C risk allele was associated with greater cell surface expression of CD33 in the monocytes (t50 = 10.06, Pjoint = 1.3 × 10−13) of young and older individuals. It was also associated with diminished internalization of amyloid-β 42 peptide, accumulation of neuritic amyloid pathology and fibrillar amyloid on in vivo imaging, and increased numbers of activated human microglia.

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Acknowledgements

The authors are grateful to the participants of the ROS, MAP, CHAP, Harvard Aging Brain Study (HAB) and Alzheimer's Disease Neuroimaging Initiative (ADNI) studies. Data used in preparation of this article were obtained from the ADNI database (http://adni.loni.ucla.edu/). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. We also thank the participants of the Brigham and Women's PhenoGenetic Project. This work is supported by the US National Institutes of Health (grants R01 AG031553, R01 AG30146, R01 AG17917, R01 AG15819, P30 AG10161 and R01 AG11101) and the Illinois Department of Public Health. This work was supported by grants R01 NS067305, RC2 GM093080 and R01 AG043617. E.M.B. receives support from the JDRF, American Diabetes Association, Boston Area Diabetes and Endocrinology Research Center and the Harvard NeuroDiscovery Center.

Author information

Affiliations

  1. Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Elizabeth M Bradshaw
    • , Lori B Chibnik
    • , Brendan T Keenan
    • , Linda Ottoboni
    • , Towfique Raj
    • , Anna Tang
    • , Laura L Rosenkrantz
    • , Selina Imboywa
    • , Michelle Lee
    • , Alina Von Korff
    •  & Philip L De Jager
  2. Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Elizabeth M Bradshaw
    • , Lori B Chibnik
    • , Brendan T Keenan
    • , Linda Ottoboni
    • , Towfique Raj
    • , Anna Tang
    • , Laura L Rosenkrantz
    • , Selina Imboywa
    • , Michelle Lee
    •  & Alina Von Korff
  3. Harvard Medical School, Boston, Massachusetts, USA.

    • Elizabeth M Bradshaw
    • , Lori B Chibnik
    • , Linda Ottoboni
    • , Towfique Raj
    • , Keith Johnson
    •  & Reisa A Sperling
  4. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

    • Elizabeth M Bradshaw
    • , Lori B Chibnik
    • , Brendan T Keenan
    • , Linda Ottoboni
    • , Towfique Raj
    • , Anna Tang
    • , Laura L Rosenkrantz
    • , Selina Imboywa
    •  & Philip L De Jager
  5. Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.

    • Martha C Morris
    • , Julie A Schneider
    •  & David A Bennett
  6. Rush Institute for Healthy Aging, Rush University Medical Center, Chicago, Illinois, USA.

    • Denis A Evans
  7. Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Keith Johnson
    •  & Reisa A Sperling
  8. Department of Neurology, Center for Alzheimer's Research and Treatment, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Reisa A Sperling
  9. The Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Keith Johnson
    •  & Reisa A Sperling

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  1. The Alzheimer Disease Neuroimaging Initiative

    A full list of members is available at http://adni.loni.ucla.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

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Contributions

E.M.B. and P.L.D. designed and implemented the study. E.M.B. developed the experimental methods using peripheral blood mononuclear cells (PBMCs). E.M.B., L.O., A.T., L.L.R. and S.I. isolated PBMCs from the PhenoGenetic cohort and analyzed monocyte CD33 expression. E.M.B., A.T. and L.L.R. analyzed the uptake ability of monocytes. T.R., B.T.K. and L.B.C. performed the statistical analyses and assisted with the interpretation and communication of results. A.V.K., M.L. and P.L.D. coordinated the collection of blood from the PhenoGenetic cohort. R.A.S., K.J. and ADNI provided the PiB imaging data and reviewed the manuscript. R.A.S. provided the HAB blood samples. M.C.M. contributed post-mortem data on brain microglia and reviewed the manuscript. D.A.E. provided clinical data and biospecimens. J.A.S. was responsible for the microglia and Alzheimer's disease pathology data collection from the brains of deceased MAP participants and revised the manuscript. D.A.B. contributed ante-mortem biospecimens, clinical and post-mortem data, and revised the manuscript. P.L.D. conceived the study, coordinated access to all of the cohorts and wrote the manuscript with E.M.B.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Philip L De Jager.

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DOI

https://doi.org/10.1038/nn.3435