The DOI matches its Crossref record; 145 of the 145 references it cites were found in a registry or an index.
The Alzheimer’s Disease Mitochondrial Cascade Hypothesis
Open accessAbstract
We first proposed the mitochondrial cascade hypothesis of sporadic Alzheimer's disease (AD) in 2004. Our core assumptions were a person's genes determine baseline mitochondrial function and durability, this durability determines how mitochondria change with advancing age, and critical changes in mitochondrial function initiate other pathologies characteristic of AD. Since then several lines of investigation report data consistent with or supportive of our hypothesis. In particular, AD endophenotype studies suggest a strong maternal genetic contribution, and links between mitochondrial function, tau phosphorylation, and amyloid-beta (Abeta) amyloidosis are increasingly recognized. As predicted, AD therapies designed to reduce Abeta thus far have had at best very limited clinical benefits; our hypothesis identifies alternative therapeutic targets. While placing mitochondria at the apex of an AD cascade certainly remains controversial, it is increasingly accepted by the AD research community that mitochondria play an important role in the late-onset forms of the disease. Even if the mitochondrial cascade hypothesis proves incorrect, considering its assumptions could potentially advance our understanding of sporadic, late-onset AD.
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In the citing paper
“Models based on early-onset, autosomal dominant AD may therefore provide limited insight into late-onset, non-autosomal dominant AD.”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [146]
In the citing paper
“In other words, toxic cascades in AD are not initiated by Aβ, but by mitochondria.”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [146]
In the citing paper
“If correct, the mitochondrial cascade hypothesis has several inconvenient implications. The main implication is that early-onset, autosomal dominant and late-onset, non-autosomal dominant AD cases do not share a common etiology.”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [146]
In the citing paper
“According to the hypothesis Aβ is not an “upstream” biomarker of AD, but is instead a “downstream” marker of evolving mitochondrial dysfunction.”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [146]
In the citing paper
“Accordingly, Aβ deposition within an aging brain simply indicates critical age-related changes are occurring.”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [146]
In the citing paper
“According to the mitochondrial cascade hypothesis, mitochondrial function constitutes the crucial link between brain aging and AD.”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [146]
In the citing paper
“It deviates from the amyloid cascade hypothesis by predicting age-related changes in mitochondrial function, rather than mutations or polymorphisms in APP or Aβ processing genes, primarily account for age-associated brain Aβ changes.”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [146]
In the citing paper
“When mitochondrial decline surpasses a threshold compensatory mechanisms fail and late-onset AD ensues.”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [146]
In the citing paper
“The mitochondrial cascade hypothesis proposes mitochondrial function declines with age, and this decline promotes some features of brain aging including Aβ accumulation.”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [146]
In the citing paper
“In contrast to the amyloid cascade hypothesis, which views Aβ as the primary upstream AD biomarker, the mitochondrial cascade hypothesis in general sees Aβ more as a downstream biomarker of brain aging.”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [146]
In the citing paper
“The mitochondrial cascade hypothesis proposes mitochondrial function declines with age, and this decline promotes some features of brain aging including Aβ accumulation.”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [146]
In the citing paper
“In this explanation, the mitochondrial function declines with age and leads to increased production of ROS [65,66].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [66]
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Citations
Cites
The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics
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Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
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Hardy, J. A., & Higgins, G. A. (1992) · Science · doi:10.1126/science.1566067 · Cited by 7,484 · cited 1×
“For almost twenty years the amyloid cascade hypothesis has dominated Alzheimer’s disease (AD) thinking, modeling, and therapeutic development efforts [1].”
BackgroundGoate, A., Chartier-Harlin, M.-C., Mullan, M., Brown, J., Crawford, F., Fidani, L., Giuffra, L., Haynes, A., Irving, N., James, L., et al. (1991) · Nature · doi:10.1038/349704a0 · Cited by 4,659 · cited 1×
“The amyloid cascade hypothesis was formulated after an AβPP mutation was reported in a family with autosomal dominant amyloid angiopathy, dementia, and AD-typical histology [4].”
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“Two other genes, presenilin 1 and 2, also contain mutations in autosomal dominant AD and the presenilin proteins are reportedly part of the gamma secretase complex that processes APP [5,6,7,8].”
BackgroundPremature ageing in mice expressing defective mitochondrial DNA polymerase
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“This has led some investigators to speculate somatic mtDNA mutation contributes to age-related declines in mitochondrial function, and available data support this view [38, 50].”
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“In autosomal dominant AD, mutations in each of these proteins are believed to shift APP processing towards Aβ42 [9].”
BackgroundCandidate gene for the chromosome 1 familial Alzheimer’s disease locus
Levy-Lahad, E., Wasco, W., Poorkaj, P., Romano, D. M., Oshima, J., Pettingell, W. H., Yu, C.-E., Jondro, P. D., Schmidt, S. D., Wang, K., et al. (1995) · Science · doi:10.1126/science.7638622 · Cited by 2,577
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Cited by
Sorted by citations
Oxidative Stress: A Key Modulator in Neurodegenerative Diseases
Singh, A., Kukreti, R., Saso, L., & Kukreti, S. (2019) · Molecules · doi:10.3390/molecules24081583 · Cited by 2,398
Mitochondria and Mitochondrial Cascades in Alzheimer’s disease
Swerdlow, R. H. (2018) · Journal of Alzheimer’s Disease · doi:10.3233/jad-170585 · Cited by 850
Self-citationMitochondrial Dysfunction in Neurodegenerative Diseases
Johri, A., & Beal, M. F. (2012) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.112.192138 · Cited by 806
“It has been proposed that in sporadic AD mitochondrial dysfunction is the primary event that causes A deposition, synaptic degeneration, and formation of neurofibrillary tangles (Swerdlow et al., 2010).”
BackgroundThe Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives
Swerdlow, R. H., Burns, J. M., & Khan, S. M. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.09.010 · Cited by 786
“This review will discuss recent AD biomarker data, diagnostic criteria, and clinical trial results from the perspective of a different AD hypothesis, the “mitochondrial cascade hypothesis” [21-27].”
BackgroundCalkins, M. J., Manczak, M., Mao, P., Shirendeb, U., & Reddy, P. H. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr381 · Cited by 646
“AD is also associated with inflammatory responses, synaptic damage and mitochondrial structural and functional abnormalities (3-10).”
Background
Metadata
- Authors
- Swerdlow, R. H., Burns, J. M., & Khan, S. M.
- Affiliations
- University of Kansas (US)
- Gencia (United States) (US)
- Corresponding author
- Swerdlow, Russell H.
- Venue
- Journal of Alzheimer s Disease
- Publisher
- SAGE Publications
- Published
- 2010-06-03
- Volume
- 20
- Issue
- s2
- Pages
- S265-S279
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- PMC
- PMC2883665
- OpenAlex
- W1685999671
- Cited by
- 562
- References
- 145
- Citations by year
- 2026: 31 · 2025: 30 · 2024: 26 · 2023: 63 · 2022: 34 · 2021: 37 · 2020: 38 · 2019: 25 · 2018: 36 · 2017: 37 · 2016: 41 · 2015: 31 · 2014: 33 · 2013: 37 · 2012: 28
- FWCI
- 3.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Alzheimer s Disease (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (AG026374, R21AG029615, AG029615, AG022407, R01AG022407, R03AG026374)
- National Eye Institute (R21EY018474, EY018474)
- National Institute of Neurological Disorders and Stroke (K23NS058252)
- National Center for Research Resources (M01RR023940)
- 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
- MeSH terms
- Aging, Alzheimer Disease, Animals, Electron Transport Complex IV, DNA, Mitochondrial, Humans, Mitochondria, Models, Biological, Amyloid beta-Peptides
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