Ketones block amyloid entry and improve cognition in an Alzheimer's model
Abstract
Sporadic Alzheimer's disease (AD) is responsible for 60%-80% of dementia cases, and the most opportune time for preventive intervention is in the earliest stage of its preclinical phase. As traditional mitochondrial energy substrates, ketone bodies (ketones, for short), beta-hydroxybutyrate, and acetoacetate, have been reported to provide symptomatic improvement and disease-modifying activity in epilepsy and neurodegenerative disorders. Recently, ketones are thought as more than just metabolites and also as endogenous factors protecting against AD. In this study, we discovered a novel neuroprotective mechanism of ketones in which they blocked amyloid-β 42, a pathologic hallmark protein of AD, entry into neurons. The suppression of intracellular amyloid-β 42 accumulation rescued mitochondrial complex I activity, reduced oxidative stress, and improved synaptic plasticity. Most importantly, we show that peripheral administration of ketones significantly reduced amyloid burden and greatly improved learning and memory ability in a symptomatic mouse model of AD. These observations provide us insights to understand and to establish a novel therapeutic use of ketones in AD prevention.
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Several clinical studies have shown a positive effect of a ketogenic diet on patients with AD or mild cognitive impairment (MCI), consistent with preclinical results.
“Several clinical studies have shown a positive effect of a ketogenic diet on patients with AD or mild cognitive impairment (MCI), consistent with preclinical results [87–91] (Table 1).”
From Role of diet and its effects on the gut microbiome in the pathophysiology of mental disorders (2022) · cites this paper as [91]
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- Authors
- Yin, J. X., Maalouf, M., Han, P., Zhao, M., Gao, M., Dharshaun, T., Ryan, C., Whitelegge, J., Wu, J., Eisenberg, D., Reiman, E. M., Schweizer, F. E., & Shi, J.
- Affiliations
- Barrow Neurological Institute (US)
- Howard Hughes Medical Institute (US)
- University of California, Los Angeles (US)
- Banner Alzheimer’s Institute (US)
- Corresponding author
- Schweizer, Felix E.
- Shi, Jiong
- ORCID
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 39
- Pages
- 25-37
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W2189973196
- Cited by
- 151
- References
- 66
- Citations by year
- 2026: 11 · 2025: 16 · 2024: 13 · 2023: 17 · 2022: 21 · 2021: 16 · 2020: 17 · 2019: 14 · 2018: 18 · 2017: 5 · 2016: 3
- FWCI
- 6.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Mary S. Easton Center for Alzheimer's Disease Research at UCLA
- Arizona Alzheimer's Disease Consortium (AG019610)
- Barrow Neurological Foundation (3031880)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Physiology › Diet and metabolism studies
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- ketone bodies, Alzheimer's disease, amyloid-beta 42, mitochondrial complex I, oxidative stress, synaptic plasticity, learning and memory, neuroprotection, beta-hydroxybutyrate, acetoacetate, peripheral administration, preclinical Alzheimer's disease
- MeSH terms
- Acetoacetates, Alzheimer Disease, Animals, Cognition, Depression, Chemical, Disease Models, Animal, Ketone Bodies, Learning, Memory, Mice, Transgenic, NADH Dehydrogenase, Neuronal Plasticity, Neurons, Peptide Fragments, Stimulation, Chemical, Amyloid beta-Peptides, Oxidative Stress, Neuroprotective Agents, 3-Hydroxybutyric Acid
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