Down syndrome individuals with Alzheimer's disease have a distinct neuroinflammatory phenotype compared to sporadic Alzheimer's disease

Donna M. Wilcock, Jennifer Hurban, Alex M. Helman, Tiffany L. Sudduth, Katie L. McCarty, Tina L. Beckett, Joshua C. Ferrell, M. Paul Murphy, Erin L. Abner, Frederick A. Schmitt, Elizabeth Head

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63 Scopus citations


Down syndrome (DS) is the most common genetic cause of intellectual disability and is primarily caused by the triplication of chromosome 21. The overexpression of amyloid precursor protein gene may be sufficient to drive Alzheimer's disease (AD) neuropathology that is observed in virtually all individuals with DS by the age of 40years. There is relatively little information about inflammation in the DS brain and how the genetics of DS may alter inflammatory responses and modify the course of AD pathogenesis in this disorder. Using the macrophage classification system of M1, M2a, M2b, and M2c inflammatory phenotypes, we have shown that the early stages of AD are associated with a bias toward an M1 or M2a phenotype. In later stages of AD, markers of M1, M2a and M2c are elevated. We now report the inflammatory phenotype in a DS autopsy series to compare this with the progression in sporadic AD. Tissue from young DS cases (under 40years of age, pre-AD) show a bias toward M1 and M2b states with little M2a or M2c observed. Older DS cases (over 40 with AD pathology) show a distinct bias toward an M2b phenotype. Importantly, this is distinct from sporadic AD where the M2b phenotype has been rarely, if ever observed in postmortem studies. Stimulated by immune complex activation of microglial cells and toll-like receptor activation, the M2b phenotype represents a unique neuroinflammatory state in diseased brain and may have significant implications for therapeutic intervention for persons with DS.

Original languageEnglish
Pages (from-to)2468-2474
Number of pages7
JournalNeurobiology of Aging
Issue number9
StatePublished - Sep 1 2015

Bibliographical note

Funding Information:
Research reported in this manuscript was supported by Alzheimer's Association Grant DSADNIP-13-282631 , Eunice Kennedy Shriver National Institute of Child Health and Development of the National Institutes of Health under award number R01HD064993 to Elizabeth Head and Frederick A. Schmitt. The authors are grateful to the UCI-ADRC and Ira T. Lott of UCI for providing some of the tissue for the study (R01HD065160 and R01AG16573 to ITL; P50AG16573 to UCI-ADRC). Other autopsy tissue was obtained from UK ADC (P30AG28383) and from the NICHD Brain and Tissue Bank for Developmental Disorders of the University of Maryland, Baltimore, MD, contract HHSN275200900011C (N01HD90011). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2015 Elsevier Inc.


  • Alzheimer's disease
  • Cytokines
  • Dementia
  • Down syndrome
  • Inflammation
  • Microglia

ASJC Scopus subject areas

  • Neuroscience (all)
  • Aging
  • Developmental Biology
  • Clinical Neurology
  • Geriatrics and Gerontology


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