Alzheimer's disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons
Open accessAbstract
Alzheimer's disease (AD) is associated with regional reductions in fluorodeoxyglucose positron emission tomography (FDG PET) measurements of the cerebral metabolic rate for glucose, which may begin long before the onset of histopathological or clinical features, especially in carriers of a common AD susceptibility gene. Molecular evaluation of cells from metabolically affected brain regions could provide new information about the pathogenesis of AD and new targets at which to aim disease-slowing and prevention therapies. Data from a genome-wide transcriptomic study were used to compare the expression of 80 metabolically relevant nuclear genes from laser-capture microdissected non-tangle-bearing neurons from autopsy brains of AD cases and normal controls in posterior cingulate cortex, which is metabolically affected in the earliest stages; other brain regions metabolically affected in PET studies of AD or normal aging; and visual cortex, which is relatively spared. Compared with controls, AD cases had significantly lower expression of 70% of the nuclear genes encoding subunits of the mitochondrial electron transport chain in posterior cingulate cortex, 65% of those in the middle temporal gyrus, 61% of those in hippocampal CA1, 23% of those in entorhinal cortex, 16% of those in visual cortex, and 5% of those in the superior frontal gyrus. Western blots confirmed underexpression of those complex I–V subunits assessed at the protein level. Cerebral metabolic rate for glucose abnormalities in FDG PET studies of AD may be associated with reduced neuronal expression of nuclear genes encoding subunits of the mitochondrial electron transport chain.
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Compelling evidence links neurodegeneration to altered brain metabolism and mitochondrial dysfunction, both of which are early hallmarks of Alzheimer's disease.
“Compelling evidence links neurodegeneration to altered brain metabolism and mitochondrial dysfunction, both of which are early hallmarks of AD [21–28].”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [24]
PET studies suggest marked cerebral glucose hypometabolism in brain tissue from LOAD patients decades before symptoms, correlated with decreased neuronal expression of Cx I-V subunits of mitochondrial electron transport chain in total brain extracts and specific brain areas including hippocampus and entorhinal cortex.
“PET studies have suggested a marked cerebral glucose hypometabolism in brain tissue from LOAD patients decades before the symptoms arise, which was correlated with the decreased neuronal expression of Cx I-V subunits of the mitochondrial electron transport chain, in total brain extracts and in samples from specific brain areas, including the hippocampus and entorhinal cortex [60].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [60]
Infection led to mitochondrial dysfunction evident by downregulation of Ndufa5 and Atp5j2.
“At a sub-cellular level, infection led to mitochondrial dysfunction evident by downregulation of Ndufa5 (a structural subunit of complex I)85 and Atp5j286.”
From Chlamydia pneumoniae can infect the central nervous system via the olfactory and trigeminal nerves and contributes to Alzheimer’s disease risk (2022) · cites this paper as [86]
Large transcriptomic studies using quantitative severity metrics and differentially vulnerable regions identified pathway-level changes in transcriptional regulation, apoptosis, cell proliferation, energy metabolism, and synaptic transmission in Alzheimer disease.
“Large studies using quantitative metrics of severity140 and differentially vulnerable regions144 have identified pathway-level changes in transcriptional regulation, apoptosis, cell proliferation, energy metabolism and synaptic transmission.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [144]
Reduced expression of genes involved in mitochondrial energy metabolism may become more pronounced in humans with cognitive decline and Alzheimer's disease.
“Furthermore, reduced expression of genes involved in mitochondrial energy metabolism may become more pronounced in humans with cognitive decline and Alzheimer’s disease (20–22).”
From Neural mechanisms of ageing and cognitive decline (2010) · cites this paper as [21]
The expression of genes and proteins encoding subunits of the mitochondrial electron transport chain (ETC) in mitochondrial metabolic pathways was reduced in brain tissues of patients with AD.
“Also, the expression of genes and proteins encoding subunits of the mitochondrial electron transport chain (ETC) in mitochondrial metabolic pathways was reduced in brain tissues of patients with AD [41].”
Mitochondrial dysfunction has been suggested to occur early in the progression to AD and continues into later stages of AD.
“Mitochondrial dysfunction has been suggested to occur early in the progression to AD and continues into later stages of AD31–34.”
From Large-scale proteomic analysis of human brain identifies proteins associated with cognitive trajectory in advanced age (2019) · cites this paper as [33]
A transcriptomic study of post-mortem brain of AD cases and controls in the PCC and other brain regions found that nuclear genes encoding the mitochondrial electron transport chain subunits had decreased expression in AD cases compared to controls.
“This study found that the nuclear genes encoding the mitochondrial electron transport chain subunits had decreased expression in AD cases compared to controls in PCC and other brain regions33.”
From Large-scale proteomic analysis of human brain identifies proteins associated with cognitive trajectory in advanced age (2019) · cites this paper as [33]
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An inherited variable poly-T repeat genotype in TOMM40 in Alzheimer disease
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Alzheimer’s disease risk polymorphisms regulate gene expression in the ZCWPW1 and the CELF1 loci
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“For this analysis, we used three publicly available datasets (syn5550404 [32], GSE5281 [33], and GSE44770 [34]) that include gene expression data analyzed in nine human brain tissues (prefrontal cortex, temporal cortex, visual cortex, entorhinal cortex, hippocampus, medial temporal gyrus, posterior cingulate, superior…”
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A novel lysosome‐to‐mitochondria signaling pathway disrupted by amyloid‐β oligomers
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AlzBase: An Integrative Database for Gene Dysregulation in Alzheimer’s Disease
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Mitochondria and Cellular Redox State on the Route from Ageing to Alzheimer's Disease
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- Authors
- Liang, W. S., Reiman, E. M., Valla, J., Dunckley, T., Beach, T. G., Grover, A., Niedzielko, T. L., Schneider, L. E., Mastroeni, D., Caselli, R., Kukull, W., Morris, J. C., Hulette, C. M., Schmechel, D., Rogers, J., & Stephan, D. A.
- Affiliations
- Translational Genomics Research Institute (US)
- Barrow Neurological Institute (US)
- Banner Sun Health Research Institute (US)
- Mayo Clinic (US)
- National Alzheimer's Coordinating Center (US)
- Washington University in St. Louis (US)
- Duke Medical Center (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-03-18
- Volume
- 105
- Issue
- 11
- Pages
- 4441-4446
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2393743
- OpenAlex
- W2102117809
- Cited by
- 585
- References
- 57
- Citations by year
- 2026: 21 · 2025: 39 · 2024: 32 · 2023: 26 · 2022: 44 · 2021: 42 · 2020: 40 · 2019: 39 · 2018: 37 · 2017: 33 · 2016: 36 · 2015: 27 · 2014: 20 · 2013: 32 · 2012: 31
- FWCI
- 19.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Barrow Neurological Foundation
- National Alzheimer's Coordinating Center (U01AG016976)
- National Institutes of Health (1k01ag024079-01a2)
- National Institute on Aging (P30-AG-19610, AG05 128, R01AG023193, 1-RO1-AG023193, AG03991, U01AG016976, K01-AG-024079, AG-19610, P50AG005128, AG 05681, P 50 AG05681, P50AG005681, P30AG019610, P01 AG0 3991, P01AG003991)
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- Alzheimer's disease, energy metabolism genes, mitochondrial electron transport chain, posterior cingulate cortex, cerebral metabolic rate of glucose, FDG-PET, gene expression, neuronal transcriptome, middle temporal gyrus, hippocampal CA1, entorhinal cortex, visual cortex, normal aging, pathogenesis
- MeSH terms
- Aged, Alzheimer Disease, Brain, Energy Metabolism, Female, Gene Expression Regulation, Humans, Male, Neurons
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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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