Genes and pathways underlying regional and cell type changes in Alzheimer’s disease
Open accessAbstract
Background: Transcriptional studies suggest Alzheimer's disease (AD) involves dysfunction of many cellular pathways, including synaptic transmission, cytoskeletal dynamics, energetics, and apoptosis. Despite known progression of AD pathologies, it is unclear how such striking regional vulnerability occurs, or which genes play causative roles in disease progression. Methods: To address these issues, we performed a large-scale transcriptional analysis in the CA1 and relatively less vulnerable CA3 brain regions of individuals with advanced AD and nondemented controls. In our study, we assessed differential gene expression across region and disease status, compared our results to previous studies of similar design, and performed an unbiased co-expression analysis using weighted gene co-expression network analysis (WGCNA). Several disease genes were identified and validated using qRT-PCR. Results: We find disease signatures consistent with several previous microarray studies, then extend these results to show a relationship between disease status and brain region. Specifically, genes showing decreased expression with AD progression tend to show enrichment in CA3 (and vice versa), suggesting transcription levels may reflect a region's vulnerability to disease. Additionally, we find several candidate vulnerability (ABCA1, MT1H, PDK4, RHOBTB3) and protection (FAM13A1, LINGO2, UNC13C) genes based on expression patterns. Finally, we use a systems-biology approach based on WGCNA to uncover disease-relevant expression patterns for major cell types, including pathways consistent with a key role for early microglial activation in AD. Conclusions: These results paint a picture of AD as a multifaceted disease involving slight transcriptional changes in many genes between regions, coupled with a systemic immune response, gliosis, and neurodegeneration. Despite this complexity, we find that a consistent picture of gene expression in AD is emerging.
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The expression of SST and KCNIP1 is reduced in the brains of individuals with AD, and downregulation of these two genes has been implicated in mediating the formation of Aβ oligomers.
“The expression of SST (61) and KCNIP1 (62) is reduced in the brains of individuals with AD, and downregulation of these two genes has been implicated in mediating the formation of Aβ oligomers.”
From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [62]
Table 3 in the Results lists KCNIP1 as downregulated with AD in the CA1 hippocampal region (fold change −1.77), supporting the part of the sentence attached to this citation. The paper does not implicate KCNIP1 downregulation in Aβ oligomer formation; SST has a separate citation in the citing sentence. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPurifying cell populations or performing single-cell transcriptional analyses can identify important changes not apparent in whole-tissue transcriptomes.
“Purifying cell populations or carrying out transcriptional analyses on single cells158–163 can identify important changes that are not apparent in whole-tissue transcriptomes141,142.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [141]
Transcriptome networks in AD brain have been examined, but network changes in the AD brain proteome, including early asymptomatic stages, have not been explored.
“While transcriptome networks in AD brain have been examined (Miller et al., 2008; Miller et al., 2013; Zhang et al., 2013), network changes in the AD brain proteome, including those associated with early asymptomatic stages of disease, have not been explored.”
From A Multi-network Approach Identifies Protein-Specific Co-expression in Asymptomatic and Symptomatic Alzheimer’s Disease (2017) · cites this paper as Miller et al., 2013
MAPK1 and MAPK3 are stress-activated kinases previously observed as increased in AD transcriptome studies of hippocampus.
“Key hub proteins in B-M13 included MAPK1 and MAPK3, stress-activated kinases previously observed as increased in AD transcriptome studies of hippocampus (Miller et al., 2013).”
From A Multi-network Approach Identifies Protein-Specific Co-expression in Asymptomatic and Symptomatic Alzheimer’s Disease (2017) · cites this paper as Miller et al., 2013
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“[29]; (7) Myers, signature computed by comparing gene expression between AD and control from the cerebellum region fromWebster et al.”
BackgroundMethod
- Authors
- Miller, J. A., Woltjer, R. L., Goodenbour, J. M., Horvath, S., & Geschwind, D. H.
- Affiliations
- University of California, Los Angeles (US)
- Oregon Health & Science University (US)
- Corresponding author
- Geschwind, Daniel H
- Venue
- Genome Medicine
- Published
- 2013-05-25
- Volume
- 5
- Issue
- 5
- Pages
- 48-48
- ISSN
- 1756-994X (ISSN-L)
- PMC
- PMC3706780
- OpenAlex
- W2158198121
- Cited by
- 275
- References
- 67
- Citations by year
- 2026: 13 · 2025: 23 · 2024: 19 · 2023: 16 · 2022: 26 · 2021: 19 · 2020: 34 · 2019: 24 · 2018: 25 · 2017: 29 · 2016: 18 · 2015: 15 · 2014: 12 · 2013: 1
- FWCI
- 10.68
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Genome Medicine (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs (P30‐AG008017)
- Office of Research and Development
- Multiple Sclerosis Society
- National Institutes of Health (AG008017)
- National Institute on Aging (AG008017, P30AG008017, R01AG026938)
- National Institute of Mental Health
- National Institute of Neurological Disorders and Stroke
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, regional brain vulnerability, CA1, CA3, differential gene expression, gene co-expression network, microglial activation, gliosis, neurodegeneration, disease-associated genes, ABCA1, PDK4, gene expression signatures
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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