Down syndrome individuals with Alzheimer's disease have a distinct neuroinflammatory phenotype compared to sporadic Alzheimer's disease
Open accessAbstract
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 40 years. 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 40 years 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.
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DSAD has changes to neuroimmune biology compared with AD in the general population.
“changes to neuroimmune biology [46, 51, 67]”
From Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome–Alzheimer’s disease (2025) · cites this paper as [67]
The raised levels of APOE are consistent with a growing body of data indicating that the neuroimmune system differs in people with DS.
“The raised levels of APOE are consistent with a growing body of data indicating that the neuroimmune system differs in people with DS [15, 34, 46, 51, 53, 66, 67].”
From Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome–Alzheimer’s disease (2025) · cites this paper as [67]
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“These include a faster development of tau pathology in relation to amyloid-β [72], changes to neuroimmune biology [46, 51, 67], and increased incidence of seizures [2].”
Self-citation
- Authors
- Wilcock, D. M., Hurban, J., Helman, A. M., Sudduth, T. L., McCarty, K. L., Beckett, T. L., Ferrell, J. C., Murphy, M. P., Abner, E. L., Schmitt, F. A., & Head, E.
- Affiliations
- University of Kentucky (US)
- Corresponding author
- Wilcock, Donna M.
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2015-09
- Volume
- 36
- Issue
- 9
- Pages
- 2468-2474
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC4602365
- OpenAlex
- W1949395222
- Cited by
- 110
- References
- 4
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 17 · 2023: 9 · 2022: 11 · 2021: 16 · 2020: 12 · 2019: 7 · 2018: 6 · 2017: 4 · 2016: 8 · 2015: 1
- FWCI
- 3.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Alzheimer's Association (DSADNIP-13-282631)
- National Institute of Child Health and Development (R01HD064993)
- National Institutes of Health
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Keywords
- Down syndrome, Alzheimer's disease, neuroinflammation, macrophage polarization, M1 macrophage phenotype, amyloid precursor protein overexpression, microglia, Toll-like receptor activation, sporadic Alzheimer's disease, disease progression, autopsy brain tissue
- MeSH terms
- Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Alzheimer Disease, Brain, Down Syndrome, Encephalitis, Female, HLA-DR Antigens, Humans, Macrophages, Male, Middle Aged, Peptide Fragments, Phenotype, Case-Control Studies, Cytokines, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Disease Progression, Young Adult
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