Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer's disease
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Epidemiological, neuropathological, and functional neuroimaging evidence implicates global and regional disruptions in brain metabolism and energetics in the pathogenesis of cognitive impairment. Nerve cell microcircuits are modified by excitatory and inhibitory synaptic activity and neurotrophic factors. Ageing and Alzheimer's disease cause perturbations in cellular energy metabolism, level of excitation or inhibition, and neurotrophic factor release, which overwhelm compensatory mechanisms and result in dysfunction of neuronal microcircuits and brain networks. A prolonged positive energy balance impairs the ability of neurons to adapt to oxidative and metabolic stress. Results from experimental studies in animals show how disruptions caused by chronic positive energy balance, such as diabetes, lead to accelerated cognitive ageing and Alzheimer's disease. Therapeutic interventions to allay cognitive dysfunction that target energy metabolism and adaptive stress responses (such as neurotrophin signalling) have been effective in animal models and in preliminary studies in humans.
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Observations in AD-afflicted brains of regionally reduced glucose metabolism and alterations in several mitochondrial enzyme activities suggest mitochondrial dysfunction.
“Observations in AD-afflicted brains of regionally reduced glucose metabolism and alterations in several mitochondrial enzyme activities suggest mitochondrial dysfunction.284”
From Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies. (2024) · cites this paper as [284]
Both insulin and insulin-like growth factor 1 can influence brain energy homeostasis, neuronal survival, and learning and memory processes.
“Accordingly, it is now clear that both insulin and its analogue, the insulin-like growth factor 1 (IGF-1), can influence brain energy homeostasis, neuronal survival, and learning and memory processes (Kapogiannis and Mattson, 2011).”
From Exploring the Therapeutic Potential of Phytochemicals in Alzheimer’s Disease: Focus on Polyphenols and Monoterpenes (2022) · cites this paper as Kapogiannis and Mattson, 2011
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“284 This is primarily manifested by defects in energy metabolism, increased oxidative stress, calcium ion imbalance, and abnormal mitochondrial dynamics, all potentially leading to neuronal dysfunction and even apoptosis, exacerbating the neurodegenerative changes in AD.”
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“Conversely, in the context of AD, mitochondrial dysfunction is intimately tied to synaptic dysfunction and cognitive impairment (Kapogiannis and Mattson, 2011; Khacho et al, 2017).”
- Authors
- Kapogiannis, D., & Mattson, M. P.
- Affiliations
- National Institute on Aging (US)
- Corresponding author
- Mattson, Mark P
- Venue
- The Lancet Neurology
- Publisher
- Elsevier BV
- Published
- 2011-02
- Volume
- 10
- Issue
- 2
- Pages
- 187-198
- ISSN
- 1474-4422 (ISSN-L)
- PMC
- PMC3026092
- OpenAlex
- W2168489336
- Cited by
- 594
- References
- 138
- Citations by year
- 2026: 47 · 2025: 38 · 2024: 35 · 2023: 42 · 2022: 56 · 2021: 43 · 2020: 44 · 2019: 37 · 2018: 38 · 2017: 35 · 2016: 29 · 2015: 24 · 2014: 35 · 2013: 30 · 2012: 42
- FWCI
- 2.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (Z99 AG999999, Z01 AG000332)
- National Institute on Aging (ZIAAG000313, Z01AG000312, ZIAAG000330, ZIAAG000331, Z01AG000313, Z01AG000327, Z01AG000317, ZIAAG000312, Z01AG000315, ZIAAG000975, Z01AG000314)
- 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 › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Alzheimer's disease, cognitive impairment, brain energy metabolism, excitation-inhibition balance, neurotrophic factors, neurotrophin signaling, oxidative stress, metabolic stress, positive energy balance, diabetes mellitus, cognitive aging, brain networks
- MeSH terms
- Alzheimer Disease, Animals, Brain, Cognition Disorders, Energy Metabolism, Humans, Nerve Net
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