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Effect of ApoE isoforms on mitochondria in Alzheimer disease
Open accessAbstract
OBJECTIVE: To test the hypothesis that ApoE isoforms affect mitochondrial structure and function that are related to cognitive impairment in Alzheimer disease (AD), we systematically investigated the effects of ApoE isoforms on mitochondrial biogenesis and dynamics, oxidative stress, synapses, and cognitive performance in AD. METHODS: We obtained postmortem human brain tissues and measured proteins that are responsible for mitochondrial biogenesis (peroxisome proliferator-activated receptor-gamma coactivator-1α [PGC-1α] and sirtuin 3 [SIRT3]), for mitochondrial dynamics (mitofusin 1 [MFN1], mitofusin 2 [MFN2], and dynamin-like protein 1 [DLP1]), for oxidative stress (superoxide dismutase 2 [SOD2] and forkhead-box protein O3a [Foxo3a]), and for synapses (postsynaptic density protein 95 [PSD95] and synapsin1 [Syn1]). A total of 46 cases were enrolled, including ApoE-ɛ4 carriers (n = 21) and noncarriers (n = 25). RESULTS: Levels of these proteins were compared between ApoE-ɛ4 carriers and noncarriers. ApoE-ɛ4 was associated with impaired mitochondrial structure and function, oxidative stress, and synaptic integrity in the human brain. Correlation analysis revealed that mitochondrial proteins and the synaptic protein were strongly associated with cognitive performance. CONCLUSION: ApoE isoforms influence mitochondrial structure and function, which likely leads to alteration in oxidative stress, synapses, and cognitive function. These mitochondria-related proteins may be a harbinger of cognitive decline in ApoE-ɛ4 carriers and provide novel therapeutic targets for prevention and treatment of AD.
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“in both a mouse model and human postmortem brains, APOEε4 is linked to altered expression of proteins involved in mitochondrial fission and fusion, suggesting that an alteration in mitochondrial dynamics might lead to or arise from impaired mitochondrial function147,170.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [170]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“MFN1, MFN2, OPA1, and FIS1 levels were decreased in the brains and neurons of AD patients and APOE4 carriers [37,38], whereas APOE4 N2A cells expressed higher levels of fission and fusion proteins than APOE3 N2A cells [33].”
From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [38]
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“In contrast, APOE-dependent alterations in mitochondrial fusion/fission protein levels have been shown in other studies; however, those were contradictory.”
From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [38]
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“Work from our group and others show that postmortem AD brain from APOE4 carriers display mitochondrial dysfunction and increased oxidative stress markers 15,16 .”
From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [15]
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Cites
Mitochondrial Dysfunction and Oxidative Stress in Neurodegenerative Diseases
Lin, M. T., & Beal, M. F. (2006) · Nature · doi:10.1038/nature05292 · Cited by 6,455
Impaired Balance of Mitochondrial Fission and Fusion in Alzheimer's Disease
Wang, X., Su, B., Lee, H.-G., Li, X., Perry, G., Smith, M. A., & Zhu, X. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.1357-09.2009 · Cited by 1,224
The Alzheimer’s Disease Mitochondrial Cascade Hypothesis
Swerdlow, R. H., Burns, J. M., & Khan, S. M. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-100339 · Cited by 562 · cited 9×
“Since a mitochondrial cascade hypothesis was proposed in 2004,(20) it is increasingly suspected that mitochondrial dysfunction plays a detrimental role in AD.(21) Mitochondrial dysfunction has been identified as an early event in AD pathogenesis,(5) and enhancing mitochondrial function may attenuate pathologic changes…”
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Cited by
Sorted by citations
Multifaceted roles of APOE in Alzheimer disease
Jackson, R. J., Hyman, B. T., & Serrano-Pozo, A. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-024-00988-2 · Cited by 193
ApoE4 attenuates autophagy via FoxO3a repression in the brain
Sohn, H.-Y., Kim, S.-I., Park, J.-Y., Park, S.-H., Koh, Y. H., Kim, J., & Jo, C. (2021) · Scientific Reports · doi:10.1038/s41598-021-97117-6 · Cited by 54
Botchway, B. O., Okoye, F. C., Chen, Y., Arthur, W. E., & Fang, M. (2022) · Aging and disease · doi:10.14336/ad.2021.0616 · Cited by 32
APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons
Budny, V., Knöpfli, Y., Meier, D., Zürcher, K., Bodenmann, C., Peter, S. L., Müller, T., Tardy, M., Cortijo, C., & Tackenberg, C. (2024) · Cells · doi:10.3390/cells13141207 · Cited by 15
APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology
Lysaker, C. R., Johnson, C. N., Csikos, V., Franczak, E., Benson, M., Gilmore, C. A., Birky, C. J., Davis, X., McCoin, C. S., Smith, K. P., et al. (2026) · npj Dementia · doi:10.1038/s44400-026-00105-8 · Cited by 1
Metadata
- Authors
- Yin, J., Reiman, E. M., Beach, T. G., Serrano, G. E., Sabbagh, M. N., Nielsen, M., Caselli, R. J., & Shi, J.
- Affiliations
- Cleveland Clinic (US)
- ORCID
- Venue
- Neurology
- Published
- 2020-06-09
- Volume
- 94
- Issue
- 23
- Pages
- e2404-e2411
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- PMC
- PMC7455369
- OpenAlex
- W3031542208
- Cited by
- 116
- References
- 6
- Citations by year
- 2026: 14 · 2025: 15 · 2024: 24 · 2023: 24 · 2022: 20 · 2021: 14 · 2020: 5
- FWCI
- 9.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P30AG019610)
- National Institute of Neurological Disorders and Stroke (U24NS072026)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, apolipoprotein E isoforms, APOE ε4 carriers, mitochondrial biogenesis, mitochondrial dynamics, oxidative stress, synaptic integrity, cognitive impairment, PGC-1α, SIRT3, mitofusins, Drp1, manganese superoxide dismutase, FOXO3, PSD-95, synapsin-1, postmortem brain
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Mental Status and Dementia Tests, Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Organelle Biogenesis, Brain Chemistry, Female, Humans, Male, Mitochondria, Nerve Tissue Proteins, Neuronal Plasticity, Verbal Learning, Oxidative Stress, Protein Isoforms, Mitochondrial Proteins, Apolipoprotein E4, Sirtuin 3, Mitochondrial Dynamics
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