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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
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Seddon, A. R., MacArthur, C. P., Hampton, M. B., & Stevens, A. J. (2024) · Redox Report · doi:10.1080/13510002.2024.2428152 · Cited by 11
Alzheimer’s Disease and Its Possible Evolutionary Origin: Hypothesis
Whitfield, J. F., Rennie, K., & Chakravarthy, B. (2023) · Cells · doi:10.3390/cells12121618 · Cited by 11
The concept of FDG-PET endophenotype in Alzheimer’s disease
During, E., Osorio, R. S., Elahi, F. M., Mosconi, L., & de Leon, M. J. (2011) · Neurological Sciences · doi:10.1007/s10072-011-0633-1 · Cited by 14
“(ROS) production, as a consequence of reduced cytochrome oxidase (COX) activity [79, 80], which also may enhance Aß toxicity [81].”
Mastroeni, D., Khdour, O. M., Arce, P. M., Hecht, S. M., & Coleman, P. D. (2015) · ACS Chemical Neuroscience · doi:10.1021/cn500323q · Cited by 11
Viana, G. M., Buri, M. V., Paredes‐Gamero, E. J., Martins, A. M., & D’Almeida, V. (2015) · Journal of Cellular Physiology · doi:10.1002/jcp.25120 · Cited by 11
“…has been described in several LSDs such as Batten disease (Kang et al., 2013) and Niemann-Pick disease (Yu et al., 2005), as well as in some neurodegenerative diseases such as Parkinson’s, Alzheimer’s and amyotrophic lateral sclerosis (Shi et al., 2010; Swerdlow et al., 2010; Exner et al., 2012).”
BackgroundZhao, F., Qiao, P., Yan, N., Gao, D., Liu, M., & Yan, Y. P. (2015) · Neurochemical Research · doi:10.1007/s11064-015-1807-7 · Cited by 11
“Ab can increase ROS production, resulting in mitochondrial dysfunction and neuronal death and the mechanism involves decreasing ATP content and increasing ROS production [72].”
BackgroundFaryadras, K., Golchoobian, R., Iranzadeh, S., & Roghani, M. (2025) · Frontiers in Neuroscience · doi:10.3389/fnins.2025.1567236 · Cited by 11
Mitochondrial DNA affects tau phosphorylation in aging and Alzheimer's disease
Kemna, R. E., Kueck, P. J., Honea, R. A., Clark, Z., Rekowski, M. J., Weidling, I. W., Mayfield, H. D., John, C. S., Burns, J. M., Wilkins, H., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70390 · Cited by 11
Qin, Z., Wu, W., Yang, X., Wang, X., Ding, A., Huang, Y., Tang, J., Jiang, S., Zhang, P., Qian, C., et al. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1592524 · Cited by 13
“…leading to neuroin fl ammation (Heneka et al., 2010; Brunt et al., 2021) Finally, TMAO induces mitochondrial dysfunction, neuronal aging, and mitochondrial damage in the hippocampus, contributing to AD pathology (Swerdlow et al., 2010; 2014; Swerdlow et al., 2017; Li et al., 2018) (Figure 7).”
Reddy, P. H., Kshirsagar, S., Bose, C., Pradeepkiran, J. A., Hindle, A., Singh, S. P., & Reddy, A. P. (2023) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2023.166759 · Cited by 10
Yao, J., He, Z., You, G., Liu, Q., & Li, N. (2023) · Current Issues in Molecular Biology · doi:10.3390/cimb45080402 · Cited by 9
FLZ inhibited γ-secretase selectively and decreased Aβ mitochondrial production in APP-SH-SY5Y cells
Ye, X., Tai, W., Bao, X., Chen, X., & Zhang, D. (2013) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-013-0918-4 · Cited by 10
“…of AD pathology are not very clear while current researches indicate that abnormal metabolism of amyloid precursor protein (APP) and Aβ in mitochondria induces mitochondrial dysfunction and may initiate the AD pathology subsequently (Reddy et al. 2004; Devi et al. 2006; Swerdlow et al. 2010).”
BackgroundGandbhir, O., & Sundaram, P. (2020) · Metabolic Brain Disease · doi:10.1007/s11011-019-00520-2 · Cited by 10
“Aβ accumulation within the mitochondria has been shown to induce dysfunction of many key mitochondrial enzymes (Chen and Yan 2007;Wirths et al. 2004; Pagani and Eckert 2011; Mossmann et al. 2014; Swerdlow et al. 2010).”
BackgroundEffect of Cholinergic Signaling on Neuronal Cell Bioenergetics
Lu, J., Lezi, E., Roy, N., Hutfles, L. J., Selfridge, J. E., Funk, E., Burns, J. M., & Swerdlow, R. H. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-121822 · Cited by 10
“chondrial mass occur in AD [21, 68] and cholinergic”
Elsadany, M., Elghaish, R. A., Khalil, A. S., Ahmed, A. S., Mansour, R. H., Badr, E., & Elserafy, M. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.749792 · Cited by 9
Blivet, G., Roman, F. J., Delrieu, J., & Touchon, J. (2024) · Journal of Integrative Neuroscience · doi:10.31083/j.jin2303057 · Cited by 10
“The assumption of various mechanisms in AD, such as mitochondrial dysfunction [13] or inflammatory processes [14], supports the use of transcranial PBM therapy that has been used in various clinical trials demonstrating improvement in cognitive performance in persons with mild cognitive impairment…”
MethodRock inhibitors in Alzheimer’s disease
Zheng, C., Xia, W., & Zhang, J. (2025) · Frontiers in Aging · doi:10.3389/fragi.2025.1547883 · Cited by 11
“…of studies have used the concept of targeting bioenergetic and mitochondrial mechanisms as a therapeutic strategy for age-related neurodegenerative diseases (Weidling and Swerdlow, 2020; Fang et al., 2019; Cunnane et al., 2020; Swerdlow et al., 2010; Hill et al., 2019; Rigotto and Basso, 2019).”
Miro1: A potential target for treating neurological disorders
Zeng, L., Yang, J., Zhang, C.-H., Zhu, J., Zhong, S., Liu, X., Xie, H., Wang, L., Chen, L., Zhong, M., et al. (2025) · Neuroscience · doi:10.1016/j.neuroscience.2025.05.019 · Cited by 9
“…characterized by multiple pathological factors, including β -amyloid plaques, tau neurofibrillary tangles, and mutations in amyloid precursor protein (APP), presenilin 1(PS1), and presenilin 2 (PS2) (Fukui and Moraes, 2008; Querfurth and LaFerla, 2010; Reddy and Beal, 2008; Swerdlow et al., 2010).”
Targeting mitochondrial dysfunction in Alzheimer's disease: New findings and perspectives
Hroudová, J., & Fišar, Z. (2025) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2025.111491 · Cited by 9
Bender, T., & Dencher, N. A. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/7567959 · Cited by 9
“Although a growing amount of evidence has pointed out the inconsistency of the amyloid cascade hypothesis [6] as reviewed by Herrup [7], amyloid beta (Aβ) peptide is still discussed as an important (but not the sole) player in Alzheimer’s disease [8, 9].”
BackgroundHighlighting the Protective or Degenerative Role of AMPK Activators in Dementia Experimental Models
Nikbakhtzadeh, M., Shaerzadeh, F., & Ashabi, G. (2021) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527320666210526160214 · Cited by 9
Jeong, Y. H., Oh, Y.-C., Kim, T. I., & Yeul, J. (2022) · Nutrients · doi:10.3390/nu14245265 · Cited by 9
Reddy, P. H., Kshirsagar, S., Bose, C., Pradeepkiran, J. A., Hindle, A., Singh, S. P., Reddy, A. P., & Baig, J. (2023) · Cells · doi:10.3390/cells12121646 · Cited by 9
Argentati, C., Tortorella, I., Bazzucchi, M., Emiliani, C., Morena, F., & Martino, S. (2020) · Journal of Personalized Medicine · doi:10.3390/jpm10030115 · Cited by 10
Semwal, B. C., & Garabadu, D. (2020) · NeuroMolecular Medicine · doi:10.1007/s12017-020-08615-1 · Cited by 9
RetractedCortical Metabolic Deficits in a Rat Model of Cholinergic Basal Forebrain Degeneration
Gelfo, F., Petrosini, L., Graziano, A., Bartolo, P. D., Burello, L., Vitale, E., Polverino, A., Iuliano, A., Sorrentino, G., & Mandolesi, L. (2013) · Neurochemical Research · doi:10.1007/s11064-013-1120-2 · Cited by 9
Kulminski, A. M., Jain‐Washburn, E., Nazarian, A., Wilkins, H., Veatch, O. J., Swerdlow, R. H., & Honea, R. A. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.14445 · Cited by 10
Multi-Target-Directed Ligand Approach in Anti-Alzheimer’s Drug Discovery
Patil, V. M., Masand, N., Gautam, V., Kaushik, S., & Wu, D. H. (2023) · Springer eBooks · doi:10.1007/978-981-99-2657-2_13 · Cited by 9
Beresford‐Webb, J., McAllister, C. J., Sleigh, A., Walpert, M., Holland, A. J., & Zaman, S. H. (2025) · Brain Sciences · doi:10.3390/brainsci15020130 · Cited by 10
“…cascade hypothesis” has been proposed to explain AD positing that mitochondrial dysfunction initiates pathological processes, including amyloid precursor protein (APP) dysregulation, amyloid-beta (A β ) accumulation, and oxidative damage, which drive the onset and progression of AD [5,7].”
Yang, X., Dou, Y., & Zhu, S. (2013) · The Analyst · doi:10.1039/c3an00471f · Cited by 8
Kerr, N. R., Kelty, T. J., Mao, X., Childs, T. E., Kline, D. D., Rector, R. S., & Booth, F. W. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1147420 · Cited by 8
“What is interesting, however, is that these findings provide support for the mitochondrial cascade hypothesis by demonstrating that in our LVR model, which display signs of neurodegeneration and cognitive impairment, brain mitochondrial dysfunction is present absent of, or before, any changes in APP processing or Tau…”
ResultBell, M. B., Ouyang, X., Shelton, A., Huynh, N. V., Mueller, T., Chacko, B. K., Jegga, A. G., Chatham, J. C., Miller, C. R., Darley-Usmar, V. M., et al. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15835 · Cited by 7
“In addition, the mitochondrial cascade hypothesis suggests how the organelle can contribute to the development of the disease (Cunnane et al., 2020; Swerdlow, 2020a, 2020b; Swerdlow et al., 2014; Weidling & Swerdlow, 2020).”
Backgroundβ‐Apptists and Tauists, it is time for a sermon from the book of biogenesis
Swerdlow, R. H. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07561.x · Cited by 8
“Autosomal dominant AD cases as a result of APP mutation are extremely rare, though, and considerable data suggest in sporadic AD changes in mitochondrial function may actually exist upstream of APP/Ab perturbations (Swerdlow et al. 2010).”
BackgroundMarmolejo-Garza, A., Châtre, L., Croteau, D. L., Herrón-Bedoya, A., Luu, M. D. A., Bernay, B., Pontin, J., Bohr, V. A., Boddeke, E., & Dolga, A. M. (2024) · Neurobiology of Disease · doi:10.1016/j.nbd.2024.106645 · Cited by 9
“In addition to amyloid-beta and tau pathology, dysfunctions in mitochondrial bio-energetics and redox homeostasis have emerged as critical contributors to neurodegeneration (Swerdlow et al., 2014; Swerdlow and Khan, 2004; Swerdlow et al., 2010; Wilkins and Swerdlow, 2016).”
Inverse correlation between Alzheimer’s disease and cancer from the perspective of hypoxia
Su, Z., Zhang, G., Li, X., & Zhang, H. (2023) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2023.07.002 · Cited by 7
Oh, Y.-C., Jeong, Y. H., Yang, H. J., Li, W., & Yeul, J. (2023) · Current Issues in Molecular Biology · doi:10.3390/cimb45120620 · Cited by 7
“Uncontrolled neuroinflammation and oxidative stress contribute to the pathogenesis of neurodegenerative diseases [1].”
BackgroundPawlosky, R. J., Demarest, T. G., King, M. T., Estrada, D. J., Veech, R. L., & Bohr, V. A. (2025) · Journal of Neurochemistry · doi:10.1111/jnc.16295 · Cited by 8
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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