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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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Cited by
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Items 101–200 of 562
Mitochondria in Alzheimer's disease and their potential role in Alzheimer's proteostasis
Weidling, I. W., & Swerdlow, R. H. (2020) · Experimental Neurology · doi:10.1016/j.expneurol.2020.113321 · Cited by 104
“mitochondrial function, either during the initial compensation phase or the subsequent uncompensated phase (Swerdlow et al., 2010).”
BackgroundVeeresh, P., Kaur, H., Sarmah, D., Mounica, L., Verma, G., Kotian, V., Kesharwani, R., Kalia, K., Borah, A., Wang, X., et al. (2019) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.14212 · Cited by 98
Mitochondria as pharmacological targets in Down syndrome
Valenti, D., Braidy, N., Rasmo, D. D., Signorile, A., Rossi, L., Atanasov, A. G., Volpicella, M., Henrion‐Caude, A., Nabavi, S. M., & Vacca, R. A. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.08.014 · Cited by 99
“The “mitochondrial cascade hypothesis” suggests that mitochondrial dysfunction is a primary major event in the pathogenesis of AD [166].”
BackgroundAngelova, M. I., Bitbol, A., Seigneuret, M., Staneva, G., Kodama, A., Sakuma, Y., Kawakatsu, T., Imai, M., & Puff, N. (2018) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2018.02.026 · Cited by 103
Stefanova, N. A., Kozhevnikova, O. S., Vitovtov, A. O., Maksimova, K. Y., Logvinov, S. V., Rudnitskaya, E. A., Korbolina, E. E., Muraleva, N. A., & Kolosova, N. G. (2014) · Cell Cycle · doi:10.4161/cc.28255 · Cited by 97
“In contrast, there is growing evidence that mitochondrial damage and oxidative stress lead to activation of the Aβ cascade.(3,6,7) In regard to inflammatory cells, microglia can form a protective network for the brain to control neurotrophic factors, limit oxidative stress, and foster neuronal regeneration.”
BackgroundBen-Sadoun, G., Sacco, G., Manera, V., Bourgeois, J., König, A., Foulon, P., Fosty, B., Brémond, F., d’Arripe-Longueville, F., & Robert, P. H. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160268 · Cited by 105
“Indeed, evidence collected so far suggests that bioenergetics functions, mainly aerobic metabolism functioning and aerobic fitness, are associated with cognitive functioning [59, 60], and could play a major in the early development of neuropathology [8, 61, 62].”
Mitophagy regulates integrity of mitochondria at synapses and is critical for synaptic maintenance
Han, S., Jeong, Y. Y., Sheshadri, P., Su, X. Y., & Cai, Q. (2020) · EMBO Reports · doi:10.15252/embr.201949801 · Cited by 96
“Importantly, the earliest features of the onset of the highly prevalent Alzheimer’s disease (AD) have been linked to mitochondrial pathology — abnormal accumulation of damaged mitochondria (Gibson & Shi, 2010; Swerdlow et al , 2010; Cai & Tammineni, 2016; Reddy & Oliver, 2019).”
Mitochondrial DNA and inflammatory diseases
Escames, G., López, L. C., García, J. A., García‐Corzo, L., Ortiz, F., & Acuña-Castroviejo, D. (2011) · Human Genetics · doi:10.1007/s00439-011-1057-y · Cited by 97
“Inversely, mitochondrial inheritance was related to the risk of AD (Chen et al. 2000; Swerdlow et al. 2010).”
BackgroundEstrogen Regulation of Mitochondrial Bioenergetics
Yao, J., & Brinton, R. D. (2012) · Advances in pharmacology · doi:10.1016/b978-0-12-394816-8.00010-6 · Cited by 103
“This creates a vicious cycle in which excessive Aβ accumulation and sustained mitochondrial dysfunction synergize to activate a cascade of neurodegenerative pathways (Cardoso, Santana et al., 2004; Silva et al., 2011; Swerdlow et al., 2010; Swerdlow & Khan, 2009).”
BackgroundGenetics of Alzheimer’s Disease
Ridge, P. G., Ebbert, M., & Kauwe, J. S. K. (2013) · BioMed Research International · doi:10.1155/2013/254954 · Cited by 104
Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity
Solesio, M. E., Peixoto, P. M., Debure, L., Madamba, S. M., de Leon, M. J., Wisniewski, T., Pavlov, E. V., & Fossati, S. (2018) · Aging Cell · doi:10.1111/acel.12787 · Cited by 92
“A causal relationship has been found between mitochondrial dysfunction and amyloid b (Ab)induced neuronal and vascular degeneration (Abramov, Scorziello & Duchen, 2007; Fossati et al., 2010; Swerdlow et al., 2010).”
BackgroundGarbuz, D. G., Zatsepina, O. G., & Evgen’ev, M. B. (2021) · Molecular Biology · doi:10.1134/s002689332104004x · Cited by 95
Lipid metabolism and neuroinflammation in Alzheimer’s disease: a role for liver X receptors
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Functional Genomics of Brain Aging and Alzheimers Disease: Focus on Selective Neuronal Vulnerability
Wang, X., Michaelis, M. L., & Michaelis, E. K. (2010) · Current Genomics · doi:10.2174/138920210793360943 · Cited by 94
“, the mitochondrial cascade hypothesis [125], the Ca 2+ hypothesis of aging and AD [126, 127], the synaptic disruption hypothesis of AD and aging [128, 129], and the neuroinflammation hypothesis of aging and AD [130].”
BackgroundCa 2+ dysregulation in neurons from transgenic mice expressing mutant presenilin 2
Kipanyula, M. J., Contreras, L., Zampese, E., Lazzari, C., Wong, A., Pizzo, P., Fasolato, C., & Pozzan, T. (2012) · Aging Cell · doi:10.1111/j.1474-9726.2012.00858.x · Cited by 93
Austad, S. N., Ballinger, S. W., Buford, T. W., Carter, C. S., Smith, D. L., Darley-Usmar, V. M., & Zhang, J. (2021) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.06.014 · Cited by 94
Tian, N., Cao, Z., & Zhang, Y. (2014) · Neuroscience Bulletin · doi:10.1007/s12264-013-1419-7 · Cited by 93
Hayden, M. R. (2019) · Brain Sciences · doi:10.3390/brainsci9100262 · Cited by 95
Linnertz, C. L., Anderson, L., Gottschalk, W. K., Crenshaw, D. G., Lutz, M. W., Allen, J., Saith, S., Mihovilovic, M., Burke, J. R., Welsh-Bohmer, K. A., et al. (2014) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2013.08.280 · Cited by 90
“Mitochondrial dysfunction is widely considered to be a key component of the pathophysiology of AD [28,29].”
Kushairi, N., Phan, C., Sabaratnam, V., David, P. R., & Naidu, M. K. (2019) · Antioxidants · doi:10.3390/antiox8080261 · Cited by 90
“Oxidative stress is closely related to the pathogenesis of neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases [1,2].”
BackgroundAlzheimer’s disease and its treatment–yesterday, today, and tomorrow
Kim, A. Y., Jerdi, S. A., MacDonald, R., & Triggle, C. R. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1399121 · Cited by 99
“Other hypotheses such as those linked to diabetes (de la Monte and Wands, 2008) and mitochondrial dysfunction (Cardoso et al., 2004; Swerdlow et al., 2010) are considered tangentially as linked to the putative bene fi ts of drugs, such as the anti-diabetes drug metformin.”
BackgroundKukreja, L., Kujoth, G. C., Prolla, T. A., LEUVEN, F. V., & Vassar, R. J. (2014) · Molecular Neurodegeneration · doi:10.1186/1750-1326-9-16 · Cited by 85
“Reduced mitochondrial function is hypothesized to occur during aging and in AD (reviewed in [5]) and may result from age-associated accumulation of point mutations and deletions in mtDNA (reviewed in [49]).”
BackgroundLeuner, K., Stockburger, C., Denzer, I., Eckert, G. P., & Müller, W. E. (2014) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-394625-6.00007-6 · Cited by 89
Swerdlow, R. H. (2020) · International review of neurobiology · doi:10.1016/bs.irn.2020.01.008 · Cited by 88
Alzheimer’s disease: as it was in the beginning
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Could Alzheimer’s Disease Originate in the Periphery and If So How So?
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How the Wnt signaling pathway protects from neurodegeneration: the mitochondrial scenario
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“AD is one of the most common causes of dementia worldwide and mitochondrial dysfunction has been widely associated with degeneration observed during the early stages of the disease (Du et al., 2010; Swerdlow et al., 2010; Balietti et al., 2013).”
BackgroundNarne, P., Pandey, V., Simhadri, P. K., & Phanithi, P. B. (2016) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2016.11.007 · Cited by 80
Stefanova, N. A., Muraleva, N. A., Skulachev, V. P., & Kolosova, N. G. (2013) · Journal of Alzheimer's Disease · doi:10.3233/jad-131034 · Cited by 80
“An alternative hypothesis of AD development, called the mitochondrial cascade hypothesis, states that damage to mitochondrial DNA results in mitochondrial dysfunction contributing to the accumulation of A [8, 50, 51].”
Zatsepina, O. G., Evgen’ev, M. B., & Garbuz, D. G. (2021) · Cells · doi:10.3390/cells10071638 · Cited by 80
The Alzheimer’s Disease Mitochondrial Cascade Hypothesis: A Current Overview
Swerdlow, R. H. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-221286 · Cited by 88
“The “mitochondrial cascade hypothesis,” or at least a version initially summarized in 2004, attempts to tie myriad AD phenomena together within an aging-compatible context [10–15].”
Cao, J., Zhong, M. B., Toro, C. A., Zhang, L., & Cai, D. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.03.016 · Cited by 82
APOE and neuroenergetics: an emerging paradigm in Alzheimer's disease
Wolf, A. B., Caselli, R. J., Reiman, E. M., & Valla, J. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.10.011 · Cited by 84
“Long-standing efforts have focused on the relevance of neuroenergetics in AD both as a mediator of b-amyloid-induced changes and as an independent driver (Reddy and Beal, 2008; Smith et al., 2002; Swerdlow et al., 2010; Yao et al., 2011).”
BackgroundCarelli, S., Rey, F., Ottolenghi, S., Zuccotti, G., & Samaja, M. (2021) · Neural Regeneration Research · doi:10.4103/1673-5374.322430 · Cited by 80
“…impaired activity of pyruvate dehydrogenase, ketoglutarate dehydrogenase and cytochrome oxidase, impaired oxygen consumption and altered morphology, implies that mitochondrial dysfunction is the initial trigger for AD (Swerdlow et al., 2010; Swerdlow, 2018; Monzio Compagnoni et al., 2020).”
Nanozyme-based strategies for efficient theranostics of brain diseases
Xu, R., Zhang, S., Wang, P., Zhang, R., Lin, P., Wang, Y., Gao, L., Wei, H., Zhang, X., Ling, D., et al. (2023) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2023.215519 · Cited by 77
A disease with a sweet tooth: exploring the Warburg effect in Alzheimer’s disease
Atlante, A., Lidia de, B. A. R. I., Bobba, A., & Amadoro, G. (2017) · Biogerontology · doi:10.1007/s10522-017-9692-x · Cited by 77
“that bioenergetics failure in vulnerable neurons may be the primary driver of sporadic AD (Swerdlow et al. 2010; Kapogiannis and Mattson 2011; Demetrius and Driver 2015; Caldwell et al. 2015; Cai and Tammineni 2016; Hu et al. 2016; Pedros et al. 2016), with perturbations in cerebral glucose and insulin signalling (Che…”
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Larsen, P. A., Hunnicutt, K. E., Larsen, R. J., Yoder, A. D., & Saunders, A. M. (2018) · Chromosome Research · doi:10.1007/s10577-018-9573-4 · Cited by 79
“Importantly, these processes would precede macroscopic pathologies such as protein aggregation and neuronal atrophy observed in neurodegenerative diseases (Swerdlow et al. 2010; Larsen et al. 2017; Swerdlow 2017).”
BackgroundOpening up the DNA methylome of dementia
Delgado‐Morales, R., & Esteller, M. (2017) · Molecular Psychiatry · doi:10.1038/mp.2016.242 · Cited by 74
Garabadu, D., & Verma, J. (2019) · Neurochemistry International · doi:10.1016/j.neuint.2019.04.006 · Cited by 75
Synaptic Mitochondria: An Early Target of Amyloid-β and Tau in Alzheimer’s Disease
Torres, A. K., Jara, C., Park-Kang, H. S., Polanco, C. M., Tapia, D., Alarcón, F., de la Peña, A., Llanquinao, J., Vargas-Mardones, G., Álvarez‐Indo, J., et al. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-215139 · Cited by 80
“1), determines the changes that mitochondria will acquire during aging, and impairs function [29, 51].”
Perkins, M., Wolf, A. B., Chavira, B., Shonebarger, D., Meckel, J. P., Leung, L., Ballina, L. E., Ly, S., Saini, A., Jones, T. B., et al. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-151205 · Cited by 79
“Here, mitochondrial oxidative metabolism is altered in young adult APOE4 carriers in a manner that is opposite to what is seen in the disease state.”
ResultBaluchnejadmojarad, T., Mohamadi-Zarch, S.-M., & Roghani, M. (2019) · Metabolic Brain Disease · doi:10.1007/s11011-019-00481-6 · Cited by 75
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Neural regeneration therapies for Alzheimer's and Parkinson's disease-related disorders
Reddy, A. P., Ravichandran, J., & Carkaci‐Salli, N. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2019.06.020 · Cited by 71
Gadhave, K., Kumar, D., Uversky, V. N., & Giri, R. (2020) · Medicinal Research Reviews · doi:10.1002/med.21719 · Cited by 71
“tochondria play various functions in the body, disturbing mitochondria have crucial connections with the AD pathogenesis.(33) Endoplasmic reticulum stress and oxidative stress are strongly associated with neuronal injury in AD.”
BackgroundInfluentialNeurodegenerative disease and obesity: what is the role of weight loss and bariatric interventions?
Ashrafian, H., Harling, L., Darzi, A. W., & Athanasiou, T. (2013) · Metabolic Brain Disease · doi:10.1007/s11011-013-9412-4 · Cited by 73
“Furthermore, mitochondrial involvement is also increasingly recognised in AD, specifically in the sporadic form.(Swerdlow et al. 2010) AD is also classified clinically (Cohn-Hokke et al.”
BackgroundHroudová, J., Singh, N., Fišar, Z., & Ghosh, K. K. (2016) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2016.03.084 · Cited by 71
Mak, E., Gabel, S., Mirette, H., Su, L., Williams, G. B., Waldman, A., Wells, K., Ritchie, K., Ritchie, C., & O’Brien, J. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2016.10.001 · Cited by 71
“In light of these findings, others have implicated the mitochondrial DNA in the genetic transmission of AD (Mosconi et al., 2011; Swerdlow et al., 2010).”
Kuruva, C. S., Mańczak, M., Yin, X., Ogunmokun, G., Reddy, A. P., & Reddy, P. H. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx226 · Cited by 71
RetractedVisual system manifestations of Alzheimer's disease
Kusne, Y. N., Wolf, A. B., Townley, K., Conway, M. D., & Peyman, G. A. (2016) · Acta Ophthalmologica · doi:10.1111/aos.13319 · Cited by 74
“Numerous processes including neuroinflammation, metabolism, oxidative stress, vascular dysfunction, and genetic factors are also thought to be important (Johnson et al. 2010; Swerdlow et al. 2010; Mayeux & Stern 2012; Sagare et al. 2012; Tanzi 2012; Iadecola 2013; Heneka et al. 2015).”
BackgroundFahanik‐Babaei, J., Baluchnejadmojarad, T., Nikbakht, F., & Roghani, M. (2018) · Metabolic Brain Disease · doi:10.1007/s11011-018-0338-8 · Cited by 76
Demarest, T. G., Varma, V. R., Estrada, D. J., Babbar, M., Basu, S., Mahajan, U. V., Moaddel, R., Croteau, D. L., Thambisetty, M., Mattson, M. P., et al. (2020) · Acta Neuropathologica · doi:10.1007/s00401-020-02152-8 · Cited by 74
Panes-Fernández, J., Godoy, P. A., Silva-Grecchi, T., Celis, M. T., Ramírez-Molina, O., Gavilán, J., Muñoz-Montesino, C., Castro, P. A., Moraga‐Cid, G., Yévenes, G. E., et al. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00709 · Cited by 71
“Mitochondrial cascade hypothesis in AD proposes that a mitochondrial perturbation precede the synaptic damage, the neuronal cell death, and the deficits in learning/memory ability in AD (Swerdlow et al., 2010; Swerdlow, 2018).”
BackgroundTaveira, M., Sousa, C., Valentão, P., Ferreres, F., Teixeira, J. P., & Andrade, P. B. (2013) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2013.12.013 · Cited by 70
Chen, Y., Zheng, H., Huang, X., Han, S., Zhang, D., Ni, J., & He, X. (2015) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.12473 · Cited by 69
Jackson, H. M., Soto, I., Graham, L. C., Carter, G. W., & Howell, G. R. (2013) · BMC Genomics · doi:10.1186/1471-2164-14-831 · Cited by 66
“These pathways have previously been linked to aging including down-regulation of protein synthesis/mRNA processing and mitochondrial dysfunction [47-54].”
BackgroundMitochondrial Abnormalities in Alzheimer’s Disease
Silva, D. F., Selfridge, J. E., Lu, J., E, L., Cardoso, S. M., & Swerdlow, R. H. (2012) · Advances in Pharmacology · doi:10.1016/b978-0-12-394816-8.00003-9 · Cited by 86
“It may also be the case that mitochondrial or bioenergetic dysfunction may actually constitute the primary, etiologic cause of AD (Swerdlow et al., 2010).”
BackgroundHameed, S., Fuh, J., Senanarong, V., Ebenezer, E. G. M., Looi, I., Dominguez, J. C., Park, K. W., Karanam, A. K., & Simon, O. (2020) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-190143 · Cited by 69
Caspases in Alzheimer’s Disease: Mechanism of Activation, Role, and Potential Treatment
Wójcik, P., Jastrzębski, M. K., Zięba, A., Matosiuk, D., & Kaczor, A. A. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03847-1 · Cited by 78
“According to this theory, various mechanisms, including oxidative stress and proteasome dysfunction, contribute to mitochondrial dysfunction in neuro-degenerative diseases such as AD [93].”
BackgroundSarasija, S., & Norman, K. R. (2015) · Genetics · doi:10.1534/genetics.115.182808 · Cited by 69
“Furthermore, mitochondria dysfunction is highly reported in AD models and patients and may occur prior to the formation of amyloid plaques (Swerdlow et al. 2010; Cali et al. 2012; Leuner et al. 2012; Schon and Area-Gomez 2013; Sepulveda-Falla et al. 2014).”
BackgroundAlzheimer’s Disease Risk Genes and Lipid Regulators
Gaamouch, F. E., Jing, P., Xia, J., & Cai, D. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160169 · Cited by 67
“with AD pathology [144, 145].”
Alzheimer's Disease: From Mitochondrial Perturbations to Mitochondrial Medicine
Cardoso, S., Carvalho, C., Correia, S. C., Seiça, R. M. F., & Moreira, P. I. (2016) · Brain Pathology · doi:10.1111/bpa.12402 · Cited by 69
“Knowing that APP processing is a highly regulated event directly affected by bioenergetics metabolism and, having in mind the previous assumption that with advancing age mitochondrial function changes, investigators hypothesized that the accumulation of Ab could be a consequence of mitochondria damage during aging rat…”
BackgroundBlivet, G., Meunier, J., Roman, F. J., & Touchon, J. (2018) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1016/j.trci.2017.12.003 · Cited by 67
“The implication of various altered processes in AD, such as mitochondrial dysfunction [14] or inflammatory processes [15], support transcranial stimulation.”
BackgroundLiang, J., Wang, C., Zhang, H., Huang, J., Xie, J., & Chen, N. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.755665 · Cited by 70
Metabolic Stress and Disorders Related to Alterations in Mitochondrial Fission or Fusion.
Babbar, M., & Sheikh, M. S. (2013) · PubMed · Cited by 70
Alzheimer’s Disease Pathologic Cascades: Who Comes First, What Drives What
Swerdlow, R. H. (2011) · Neurotoxicity Research · doi:10.1007/s12640-011-9272-9 · Cited by 69
“The ‘‘mitochondrial cascade hypothesis’’ places mitochondrial dysfunction at the apex of the lateonset, non-autosomal dominant AD pathology cascade (Swerdlow 2007c, 2011; Swerdlow et al. 2010; Swerdlow and Khan 2004, 2009) (Fig.”
Impact of Tau on Neurovascular Pathology in Alzheimer's Disease
Canepa, E., & Fossati, S. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2020.573324 · Cited by 67
Lin, M., Fang, S., Hsu, J. C., Huang, C., Lee, P., Huang, C.-C., Chen, H.-F., Lam, C., & Lee, J. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.800883 · Cited by 68
Volmar, C., Salah-Uddin, H., Janczura, K. J., Halley, P., Lambert, G., Wodrich, A. P. K., Manoah, S., Patel, N. H., Sartor, G. C., Mehta, N., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1707544114 · Cited by 67
Reassessment of Pioglitazone for Alzheimer’s Disease
Saunders, A. M., Burns, D. K., & Gottschalk, W. K. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.666958 · Cited by 71
Wang, S., Song, J., Tan, M., Albers, K. M., & Jia, J. (2012) · European Journal of Neurology · doi:10.1111/j.1468-1331.2012.03670.x · Cited by 64
“Mitochondrial dysfunction has been proposed to be the primary event that contributes to the fundamental features of AD neuropathology, including Ab deposition, synaptic degeneration, and neurofibrillary tangle formation [21].”
BackgroundPositive Feedback Loops in Alzheimer’s Disease: The Alzheimer’s Feedback Hypothesis
Doig, A. J. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-180583 · Cited by 67
Review on anti-alzheimer drug development: approaches, challenges and perspectives
Abdallah, A. E. (2024) · RSC Advances · doi:10.1039/d3ra08333k · Cited by 63
Ettcheto, M., Petrov, D., Pedrós, I., Alva, N., Carbonell, T., Beas‐Zárate, C., Pallàs, M., Auladell, C., Folch, J., & Camins, A. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160150 · Cited by 64
“Likewise, Swerdlow and Khan, proposed the so-called “mitochondrial cascade” hypothesis, suggesting that mitochondria damage occurs prior to brain A accumulation [14–17].”
BackgroundKorábečný, J., Nepovimová, E., Cikánková, T., Špilovská, K., Vašková, L., Mezeiová, E., Kuča, K., & Hroudová, J. (2018) · Neuroscience · doi:10.1016/j.neuroscience.2017.06.034 · Cited by 64
Mitochondrial Permeability Transition: A Pore Intertwines Brain Aging and Alzheimer’s Disease
Jia, K., & Du, H. (2021) · Cells · doi:10.3390/cells10030649 · Cited by 63
New cyclophilin D inhibitor rescues mitochondrial and cognitive function in Alzheimer’s disease
Samanta, S., Akhter, F., Roy, A., Chen, D., Turner, B., Wang, Y., Clemente, N., Wang, C., Swerdlow, R. H., Battaile, K. P., et al. (2023) · Brain · doi:10.1093/brain/awad432 · Cited by 62
Strategies, Development, and Pitfalls of Therapeutic Options for Alzheimer's Disease
Haas, C. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-110986 · Cited by 61
“As such insults accumulate, despite the efforts of intrinsic antioxidant mechanisms, the neuron is no longer able to compensate physiologically, not only preventing its participation in neuronal networks required for cognitive, behavioral, or motor function [342–344], but predisposing it to additional insults [345].”
BackgroundOrtíz, G. G., Pacheco-Moisés, F. P., Mireles-Ramírez, M. A., Flores-Alvarado, L. J., González-Usigli, H., Sánchez-González, V., Sánchez-López, A. L., Sánchez-Romero, L., Díaz-Barba, E. I., Gutiérrez, J. F. S., et al. (2017) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2017.01.003 · Cited by 62
Silva, D. F., Esteves, A. R., Arduíno, D. M., Oliveira, C. R., & Cardoso, S. M. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-110423 · Cited by 61
Mitochondrial DNA deletions in Alzheimer's brains: A review
Phillips, N., Simpkins, J. W., & Roby, R. K. (2013) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2013.04.508 · Cited by 62
The Role of Mitochondrial Dysfunction in the Progression of Alzheimer’s Disease
Desler, C., Lillenes, M. S., Tønjum, T., & Rasmussen, L. J. (2017) · Current Medicinal Chemistry · doi:10.2174/0929867324666170616110111 · Cited by 61
“been demonstrated to accumulate in brain tissue in both familial and sporadic forms of AD [12-15].”
BackgroundVenturelli, M., Pedrinolla, A., Galazzo, I. B., Fonte, C., Smania, N., Tamburin, S., Muti, E., Crispoltoni, L., Stabile, A. M., Pistilli, A., et al. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.00169 · Cited by 62
Müller, W. E., Eckert, A., Eckert, G. P., Fink, H., Friedland, K., Gauthier, S. G., Hoerr, R., Ihl, R., Kasper, S. F., & Möller, H. (2017) · The World Journal of Biological Psychiatry · doi:10.1080/15622975.2017.1308552 · Cited by 61
“…an alternative concept is the ‘mitochondrial cascade hypothesis’ put forward more than 10 years ago by Swerdlow and co-workers (Swerdlow & Khan 2004; Swerdlow et al. 2010, 2014) assuming mitochondrial dysfunction as the major pathomechanism of AD, which slowly develops through aging (Figure 2).”
BackgroundMutations that affect mitochondrial functions and their association with neurodegenerative diseases
Dhillon, V. S., & Fenech, M. F. (2013) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2013.09.001 · Cited by 61
“The kinetics of these events ultimately determine the age at which clinical manifestation of disease starts [95].”
BackgroundRegulator of Cell Cycle (RGCC) Expression during the Progression of Alzheimer's Disease
Counts, S., & Mufson, E. J. (2017) · Cell Transplantation · doi:10.3727/096368916x694184 · Cited by 58
Wang, X.-F., Xu, L., Li, D., Zhou, R. L., Greenbaum, J., Chen, Y., Zeng, C., Peng, L., Wu, K., Ao, Z., et al. (2017) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2017.07.044 · Cited by 60
“More importantly, mitochondrial dysfunction led to AD pathologies, including accumulation of Aβ and abnormal of tau phosphorylation [89].”
BackgroundMitochondrial Dysfunction and Stress Responses in Alzheimer’s Disease
Weidling, I. W., & Swerdlow, R. H. (2019) · Biology · doi:10.3390/biology8020039 · Cited by 59
“passes a threshold, thus favoring disease progression [47].”
BackgroundATP synthase and Alzheimer’s disease: putting a spin on the mitochondrial hypothesis
Ebanks, B., Ingram, T. L., & Chakrabarti, L. (2020) · Aging · doi:10.18632/aging.103867 · Cited by 59
Mitochondria and Alzheimer’s Disease: the Role of Mitochondrial Genetic Variation
Ridge, P. G., & Kauwe, J. S. K. (2018) · Current Genetic Medicine Reports · doi:10.1007/s40142-018-0132-2 · Cited by 59
“In addition, morphological changes in the mitochondria, such as abnormal sizes and shapes (including both enlarged, very small, and elongated mitochondria [16–18], and reduced numbers of cristae [16]), are observed [11, 19], and enzymes of the electron transport chain encoded in the mitochondrial genome are altered an…”
BackgroundNuclear and mitochondrial DNA oxidation in Alzheimer's disease
Santos, R. X., Correia, S. C., Zhu, X., Lee, H.-G., Petersen, R. B., Nunomura, A., Smith, M. A., Perry, G., & Moreira, P. I. (2012) · Free Radical Research · doi:10.3109/10715762.2011.648188 · Cited by 57
Taylor, M. K., Swerdlow, R. H., & Sullivan, D. K. (2019) · Nutrients · doi:10.3390/nu11081910 · Cited by 61
Al-Sheddi, E. S., Farshori, N. N., Al-Oqail, M. M., Musarrat, J., Al-Khedhairy, A. A., & Siddiqui, M. A. (2015) · Pharmaceutical Biology · doi:10.3109/13880209.2015.1035795 · Cited by 56
“It has also been suggested by some authors that the mitochondria plays an important role in cell protection and could be used as an essential therapeutic target (Swerdlow et al., 2010).”
BackgroundPerspectives on Oxidative Stress in Alzheimer’s Disease and Predictions of Future Research Emphases
Butterfield, D. A. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-179912 · Cited by 57
“…neuronalmitochondrialanterogradeandretrograde transporttoandfromenergy-starvedpre-synapticter-minals[73–77];4)decreasedneuriticlength(which woulddecreaseefficiencyofneuronalcommuni-cation,clearlyimportantinadiseaseassociated with decreased cognition…”
Eckroat, T. J., Manross, D. L., & Cowan, S. C. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21175965 · Cited by 56
Role of melatonin supplementation in neurodegenerative disorders
Polimeni, G. (2014) · Frontiers in bioscience · doi:10.2741/4217 · Cited by 57
The role of mitochondrial dysfunction in Alzheimer's disease: A potential pathway to treatment
Reiss, A. B., Ahmed, S., Dayaramani, C., Glass, A. D., Gomolin, I. H., Pinkhasov, A., Stecker, M. M., Wısnıewskı, T., & Leon, J. D. (2022) · Experimental Gerontology · doi:10.1016/j.exger.2022.111828 · Cited by 55
Tau acts as a mediator forAlzheimer's disease‐related synaptic deficits
Liao, D., Miller, E. C., & Teravskis, P. J. (2014) · European Journal of Neuroscience · doi:10.1111/ejn.12504 · Cited by 53
Mitochondrial links between brain aging and Alzheimer’s disease
Wilkins, H., & Swerdlow, R. H. (2021) · Translational Neurodegeneration · doi:10.1186/s40035-021-00261-2 · Cited by 53
Ridge, P. G., Maxwell, T. J., Corcoran, C. D., Norton, M. C., Tschanz, J. T., O’Brien, E., Kerber, R. A., Cawthon, R., Munger, R. G., & Kauwe, J. S. K. (2012) · PLoS ONE · doi:10.1371/journal.pone.0045134 · Cited by 52
“Numerous mitochondrial modifications in patients with AD have been reported; these include morphological changes [20,21], alterations in the enzymes of the electron transport chain, including cytochrome c oxidase [22,23], changes in the mitochondrial proteome [24], and reduced numbers of mitochondria [22].”
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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