Brain gene expression patterns differentiate mild cognitive impairment from normal aged and Alzheimer’s disease
Open accessAbstract
Mild cognitive impairment (MCI) represents a cognitive state intermediate between normal aging and early Alzheimer's disease (AD). To investigate if the molecular signature of MCI parallels the clinical picture, we use microarrays to extensively profile gene expression in 4 cortical brain regions (entorhinal cortex, hippocampus, superior frontal gyrus, post-central gyrus) using the postmortem tissue from cognitively normal aged controls, MCI, and AD cases. Our data reveal that gene expression patterns in MCI are not an extension of aging, and for the most part, are not intermediate between aged controls and AD. Functional enrichment analysis of significant genes revealed prominent upregulation in MCI brains of genes associated with anabolic and biosynthetic pathways (notably transcription, protein biosynthesis, protein trafficking, and turnover) as well as mitochondrial energy generation. In addition, many synaptic genes showed altered expression in MCI, predominantly upregulation, including genes for central components of the vesicle fusion machinery at the synapse, synaptic vesicle trafficking, neurotransmitter receptors, and synaptic structure and stabilization. These data suggest that there is a rebalancing of synaptic transmission in the MCI brain. To investigate if synaptic gene expression levels in MCI were related to cognitive function, Pearson correlation coefficient between the Mini Mental State Examination (MMSE) and region-specific messenger RNA expression were computed for MCI cases. A number of synaptic genes showed strong significant correlations (r > 0.8, p < 0.01) most notably in the entorhinal cortex, with fewer in the hippocampus, and very few in neocortical regions. The synaptic genes with highly significant correlations were predominantly related to synaptic transmission and plasticity, and myelin composition. Unexpectedly, we found that gene expression changes that facilitate synaptic excitability and plasticity were overwhelmingly associated with poorer MMSE, and conversely that gene expression changes that inhibit plasticity were positively associated with MMSE. These data suggest that there are excessive excitability and apparent plasticity in limbic brain regions in MCI, that is associated with impaired synaptic and cognitive function. Such changes would be predicted to contribute to increased excitability, in turn leading to greater metabolic demand and ultimately progressive degeneration and AD, if not controlled.
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This analysis identified differential gene expression changes between normal aging and pathological astrocytes, providing a resource to distinguish between astrocytes in healthy aging and disease.
“This analysis identified differential gene expression changes between normal aging and pathological astrocytes, providing a resource to distinguish between astrocytes in healthy aging and disease (Berchtold et al., 2014; Sekar et al., 2015).”
From The aging astrocyte transcriptome from multiple regions of the mouse brain. (2018) · cites this paper as Berchtold et al., 2014
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The aging astrocyte transcriptome from multiple regions of the mouse brain.
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- Authors
- Berchtold, N. C., Sabbagh, M. N., Beach, T. G., Kim, R. C., Cribbs, D. H., & Cotman, C. W.
- Affiliations
- University of California, Irvine (US)
- Banner Sun Health Research Institute (US)
- Corresponding author
- Berchtold, Nicole C.
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2014-09
- Volume
- 35
- Issue
- 9
- Pages
- 1961-1972
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC4067010
- OpenAlex
- W2074509666
- Cited by
- 124
- References
- 75
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 7 · 2023: 9 · 2022: 11 · 2021: 15 · 2020: 12 · 2019: 13 · 2018: 14 · 2017: 7 · 2016: 10 · 2015: 11 · 2014: 4
- FWCI
- 8.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- University of Pennsylvania
- National Institutes of Health
- National Institute on Aging (P01AG000538, R01AG034667, AG 16573, AG-000538, P50AG016573, AG034667)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- mild cognitive impairment, Alzheimer's disease, gene expression profiling, synaptic genes, synaptic plasticity, synaptic excitability, entorhinal cortex, hippocampus, postmortem brain, cognitive function, Mini-Mental State Examination, mitochondrial bioenergetics, protein synthesis, myelin, cognitive aging
- MeSH terms
- Aged, Aged, 80 and over, Aging, Alzheimer Disease, Brain, Energy Metabolism, Female, Humans, Male, Metabolism, Mitochondria, Myelin Sheath, Synaptic Transmission, Neuronal Plasticity, Neuropsychological Tests, Transcription, Genetic, Protein Biosynthesis, Gene Expression, Gene Expression Profiling, Protein Transport, Microarray Analysis, Cognitive Dysfunction
About these checks
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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