The Alzheimer’s Disease Mitochondrial Cascade Hypothesis

Swerdlow, Russell H.; Burns, Jeffrey M.; Khan, Shaharyar M.

doi:10.3233/jad-2010-100339

Cited by 562Alzheimer's disease research and treatmentsMitochondrial Function and PathologyDementia and Cognitive Impairment Research

The Alzheimer’s Disease Mitochondrial Cascade Hypothesis

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Swerdlow, Russell H., Burns, Jeffrey M., Khan, Shaharyar M.·2010·Journal of Alzheimer s Disease

DOI 10.3233/jad-2010-100339PMC PMC2883665

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Abstract

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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Models based on early-onset, autosomal dominant AD may provide limited insight into late-onset, non-autosomal dominant AD.
“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 mitochondrial cascade hypothesis, toxic cascades in AD are not initiated by Aβ, but by mitochondria.
“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]
If the mitochondrial cascade hypothesis is correct, early-onset, autosomal dominant and late-onset, non-autosomal dominant AD cases do not share a common etiology.
“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]
According to the mitochondrial cascade hypothesis, Aβ is not an upstream biomarker of AD, but is instead a downstream marker of evolving mitochondrial dysfunction.
“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]
Aβ deposition within an aging brain simply indicates critical age-related changes are occurring.
“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]

According to the mitochondrial cascade hypothesis, mitochondrial function constitutes the crucial link between brain aging and AD.
“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]
The mitochondrial cascade hypothesis 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.
“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]
When mitochondrial decline surpasses a threshold, compensatory mechanisms fail and late-onset Alzheimer's disease ensues.
“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]
Mitochondrial function declines with age.
“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]
The mitochondrial cascade hypothesis views Aβ more as a downstream biomarker of brain aging than as the primary upstream Alzheimer's disease biomarker.
“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]
The age-related decline in mitochondrial function promotes some features of brain aging, including Aβ accumulation.
“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]
Mitochondrial function declines with age and leads to increased production of reactive oxygen species.
“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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Rostagno, A. A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms24010107 · Cited by 391 · see citing works
Mitochondrial DNA inherited variants are associated with successful aging and longevity in humans
BENEDICTIS, G. D., Rose, G., Carrieri, G., Luca, M. D., Falcone, E., Passarino, G., Bonafè, M., Monti, D., Baggio, G., Bertolini, S., et al. (1999) · The FASEB Journal · doi:10.1096/fasebj.13.12.1532 · Cited by 390 · cited 1× · see citing works
“Genetic association studies report mtDNA polymorphisms and haplogroups influence longevity; mtDNA haplogroups may also influence AD risk [94,95].”
Background
Oxidative stress increases expression and activity of BACE in NT2 neurons
Tamagno, E., Bardini, P., Obbili, A., Vitali, A., Borghi, R., Zaccheo, D., Pronzato, M. A., Danni, O., Smith, M. A., Perry, G., et al. (2002) · Neurobiology of Disease · doi:10.1006/nbdi.2002.0515 · Cited by 385 · cited 1× · see citing works
“These findings are not surprising; the effects of oxidative stress on kinase and β-secretase activation are well recognized [66,67].”
Background
Hippocampal atrophy as a quantitative trait in a genome-wide association study identifying novel susceptibility genes for Alzheimer's disease
Potkin, S. G., Guffanti, G., Lakatos, A., Turner, J. A., Kruggel, F., Fallon, J. H., Saykin, A. J., Orro, A., Lupoli, S., Salvi, E., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0006501 · Cited by 376 · cited 1× · see citing works
“It now appears polymorphisms in a neighboring gene, TOMM40, associate with AD risk [99, 100,101].”
Background
Inhibition of energy metabolism alters the processing of amyloid precursor protein and induces a potentially amyloidogenic derivative
Gabuzda, D., Busciglio, J., Chen, L. B., Matsudaira, P., & Yankner, B. A. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)36875-8 · Cited by 373 · cited 1× · see citing works
“Treating cells with sodium azide, a cytochrome oxidase inhibitor, shifts AβPP processing to an amyloidogenic derivative [63,64].”
Background
High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer's disease brain
Lin, M. T. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.2.133 · Cited by 366 · cited 1× · see citing works
“Young control, elderly control, and late-onset AD autopsy brains were evaluated for homoplasmic and heteroplasmic COX2 gene mutations [51].”
Background
Cardiorespiratory fitness and brain atrophy in early Alzheimer disease.
Burns, J. M., Cronk, B. B., Anderson, H. S., Donnelly, J. E., Thomas, G. P., Harsha, A., Brooks, W. M., & Swerdlow, R. H. (2008) · Neurology · doi:10.1212/01.wnl.0000317094.86209.cb · Cited by 363 · see citing works
Self-citation
Dynamin-Like Protein 1 Reduction Underlies Mitochondrial Morphology and Distribution Abnormalities in Fibroblasts from Sporadic Alzheimer's Disease Patients
Wang, X., Su, B., Fujioka, H., & Zhu, X. (2008) · The American Journal of Pathology · doi:10.2353/ajpath.2008.071208 · Cited by 341 · see citing works
Accelerated Weight Loss May Precede Diagnosis in Alzheimer Disease
Johnson, D. K., Wilkins, C. H., & Morris, J. C. (2006) · Archives of Neurology · doi:10.1001/archneur.63.9.1312 · Cited by 339 · cited 1× · see citing works
“Systemic manifestations Weight loss manifests early in AD and during the lead-up to it [105,106,107,108,109,110,111, 112,113,114].”
Background
Copper-Dependent Inhibition of Human CytochromecOxidase by a Dimeric Conformer of Amyloid-β1-42
Crouch, P. J., Blake, R., Duce, J. A., Ciccotosto, G. D., Li, Q.-X., Barnham, K. J., Curtain, C. C., Cherny, R. A., Cappai, R., Dyrks, T., et al. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.4276-04.2005 · Cited by 327 · see citing works
Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity
Chang, S., Ma, T. R., Miranda, R. D., Balestra, M. E., Mahley, R. W., & Huang, Y. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508254102 · Cited by 319 · cited 1× · see citing works
“tein E or its degradation products also appear to influence mitochondrial function [102].”
Background
Does insulin dysfunction play a role in Alzheimer's disease?
Gasparini, L. (2002) · Trends in Pharmacological Sciences · doi:10.1016/s0165-6147(02)02037-0 · Cited by 314 · cited 1× · see citing works
“Accumulating evidence suggests insulin signaling is altered in AD [126].”
Background
Stimulation of “Stress-regulated” Mitogen-activated Protein Kinases (Stress-activated Protein Kinases/c-Jun N-terminal Kinases and p38-Mitogen-activated Protein Kinases) in Perfused Rat Hearts by Oxidative and Other Stresses
Clerk, A., Fuller, S. J., Michael, A., & Sugden, P. H. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.13.7228 · Cited by 314 · cited 1× · see citing works
“These findings are not surprising; the effects of oxidative stress on kinase and β-secretase activation are well recognized [66,67].”
Background
Marked changes in mitochondrial DNA deletion levels in Alzheimer brains
Corral-Debrinski, M., Horton, T., Lott, M. T., Shoffner, J. M., McKee, A. C., Beal, M. F., Graham, B. H., & Wallace, D. C. (1994) · Genomics · doi:10.1006/geno.1994.1525 · Cited by 309 · cited 1× · see citing works
“Relative to age-matched control brains, mtDNA deletion levels are elevated in AD subject brains [53,54].”
Background
PET amyloid ligand [ 11 C]PIB uptake is increased in mild cognitive impairment
Kemppainen, N. M., Aalto, S., Wilson, I. A., Någren, K., Helin, S., Brück, A., Oikonen, V., Kailajärvi, M., Scheinin, M., Viitanen, M. H., et al. (2007) · Neurology · doi:10.1212/01.wnl.0000260969.94695.56 · Cited by 306 · cited 1× · see citing works
“ing the MCI phase of AD [91,92], and even before.”
Background
Amyloid-β Dynamics Correlate with Neurological Status in the Injured Human Brain
Brody, D. L., Magnoni, S., Schwetye, K. E., Spinner, M. L., Esparza, T. J., Stocchetti, N., Zipfel, G. J., & Holtzman, D. M. (2008) · Science · doi:10.1126/science.1161591 · Cited by 295 · cited 1× · see citing works
“On the contrary, neurologic recovery from acute brain injury associates with increased Aβ production [89].”
Background
Analysis of European mitochondrial haplogroups with Alzheimer disease risk
van der Walt, J. M., Dementieva, Y. A., Martin, E. R., Scott, W. K., Nicodemus, K. K., Kroner, C. C., Welsh-Bohmer, K. A., Saunders, A. M., Roses, A. D., Small, G. W., et al. (2004) · Neuroscience Letters · doi:10.1016/j.neulet.2004.04.051 · Cited by 280 · cited 1× · see citing works
“Genetic association studies report mtDNA polymorphisms and haplogroups influence longevity; mtDNA haplogroups may also influence AD risk [94,95].”
Background
Cybrids in Alzheimer's disease: a cellular model of the disease?
Swerdlow, R. H., Parks, J. K., Cassarino, D. S., Maguire, D. J., Maguire, R. S., Bennett, J. P., Davis, R. E., & Parker, W. D. (1997) · Neurology · doi:10.1212/wnl.49.4.918 · Cited by 272 · see citing works
Self-citation
Weight Loss Precedes Dementia in Community‐Dwelling Older Adults
Barrett-Connor, E. L., Edelstein, S. L., Corey‐Bloom, J., & Wiederholt, W. C. (1996) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.1996.tb01362.x · Cited by 266 · see citing works
Mitochondria dysfunction of Alzheimer's disease cybrids enhances Aβ toxicity
Cardoso, S. M., Santana, I. J., Swerdlow, R. H., & Oliveira, C. R. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02438.x · Cited by 262 · cited 1× · see citing works
“Azide-mediated cytochrome oxidase inhibition increases free radical production [69], and oxygen radical production is increased in AD cybrid cell lines with reduced cytochrome oxidase Vmax activities [24, 70].”
Background
Cybrids in Alzheimer's disease: A cellular model of the disease?
Swerdlow, R. H., & Parker, D. W. (1998) · Neurology · doi:10.1212/wnl.51.1.326-a · Cited by 260 · see citing works
The Transmembrane Aspartates in Presenilin 1 and 2 Are Obligatory for γ-Secretase Activity and Amyloid β-Protein Generation
Kimberly, W. T., Xia, W., Rahmati, T., Wolfe, M. S., & Selkoe, D. J. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.5.3173 · Cited by 251 · cited 1× · see citing works
“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].”
Background
Calcium homeostasis and reactive oxygen species production in cells transformed by mitochondria from individuals with sporadic Alzheimer's disease
Sheehan, J. P., Swerdlow, R. H., Miller, S. W., Davis, R. E., Parks, J. K., Parker, W. D., & Tuttle, J. B. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-12-04612.1997 · Cited by 249 · cited 1× · see citing works
“We isolated platelets from AD and age-matched control subjects and fused those platelets with both human neuroblastoma SH-SY5Y cells and human NT2 teratocarcinoma cells depleted of their endogenous mtDNA [24,25].”
Method
Maternal family history of Alzheimer's disease predisposes to reduced brain glucose metabolism
Mosconi, L., Brys, M., Switalski, R., Mistur, R., Glodzik, L., Pirraglia, E., Tsui, W., De Santi, S., & de Leon, M. J. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0705036104 · Cited by 237 · cited 1× · see citing works
“Mosconi and colleagues used PET to study AD endophenotypes in middle-aged individuals without an AD diagnosis [43].”
Background
Pathogenesis of Alzheimer's disease.
Swerdlow, R. H. (2007) · PubMed Central · Cited by 236 · see citing works
Coenzyme a-acetylating enzymes in Alzheimer's disease: Possible cholinergic ‘compartment’ of pyruvate dehydrogenase
Perry, E. K., Perry, R. H., Tomlinson, B. E., Blessed, G., & Gibson, P. H. (1980) · Neuroscience Letters · doi:10.1016/0304-3940(80)90220-7 · Cited by 236 · cited 1× · see citing works
“Deficiencies of two Krebs cycle enzymes, pyruvate dehydrogenase complex and ketoglutarate dehydrogenase complex, were reported in the 1980's [17,18,19].”
Background
Mitochondrial DNA damage as a mechanism of cell loss in Alzheimer's disease
de la Monte, S. M., Luong, T., Neely, T. R., Robinson, D., & Wands, J. R. (2000) · Laboratory Investigation · doi:10.1038/labinvest.3780140 · Cited by 227 · cited 1× · see citing works
“els of retrievable, intact mtDNA are reduced in AD brains [58,59].”
Background
Weight Change in Alzheimer's Disease
White, H. K., Pieper, C. F., Schmader, K. E., & Fillenbaum, G. G. (1996) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.1996.tb00912.x · Cited by 227 · cited 1× · see citing works
“Systemic manifestations Weight loss manifests early in AD and during the lead-up to it [105,106,107,108,109,110,111, 112,113,114].”
Background
Incident dementia in women is preceded by weight loss by at least a decade
Knopman, D. S., Edland, S. D., Cha, R. H., Petersen, R. C., & Rocca, W. A. (2007) · Neurology · doi:10.1212/01.wnl.0000267661.65586.33 · Cited by 226 · see citing works
A Specific Enzyme-Linked Immunosorbent Assay for Measuring β-Amyloid Protein Oligomers in Human Plasma and Brain Tissue of Patients With Alzheimer Disease
Xia, W., Yang, T., Shankar, G. M., Smith, I. M., Shen, Y., Walsh, D. M., & Selkoe, D. J. (2009) · Archives of Neurology · doi:10.1001/archneurol.2008.565 · Cited by 215 · cited 2× · see citing works
“While a systemic increase in body Aβ levels could cause this, in AD Aβ levels actually drop in some tissues [27].”
Background
Annonacin, a Natural Mitochondrial Complex I Inhibitor, Causes Tau Pathology in Cultured Neurons
Escobar-Khondiker, M., Höllerhage, M., Muriel, M., Champy, P., Bach, A., Depienne, C., Respondek, G., Yamada, E. S., Lannuzel, A., Yagi, T., et al. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.1644-07.2007 · Cited by 212 · cited 1× · see citing works
“Tau phosphorylation increases in rats and cultured neurons exposed to ETC inhibitors [60,61,62].”
Background
Cardiorespiratory Fitness and Preserved Medial Temporal Lobe Volume in Alzheimer Disease
Honea, R. A., Thomas, G., Harsha, A., Anderson, H. S., Donnelly, J. E., Brooks, W. M., & Burns, J. M. (2009) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0b013e31819cb8a2 · Cited by 211 · cited 1× · see citing works
“This correlates with brain atrophy and is not due to differences in cognitive function or baseline physical activity [124,125].”
Background
The Alzheimer's disease mitochondrial cascade hypothesis: an update
Swerdlow, R. H., & Khan, S. M. (2009) · Experimental Neurology · doi:10.1016/j.expneurol.2009.01.011 · Cited by 206 · cited 6× · see citing works
“In developing our hypothesis, we have therefore considered aging theory and how it may relate to late-onset AD [15,16].”
BackgroundInfluential
The mitochondrial complex I inhibitor rotenone triggers a cerebral tauopathy
Höglinger, G. U., Lannuzel, A., Escobar-Khondiker, M., Michel, P. P., Duyckaerts, C. J., Féger, J., Champy, P., Prigent, A., Medja, F., Lombès, A., et al. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03493.x · Cited by 203 · cited 1× · see citing works
“Tau phosphorylation increases in rats and cultured neurons exposed to ETC inhibitors [60,61,62].”
Background
Functional mitochondria are required for amyloid β‐mediated neurotoxicity
Cardoso, S. M., Santos, S., Swerdlow, R. H., & Oliveira, C. R. (2001) · The FASEB Journal · doi:10.1096/fj.00-0561fje · Cited by 203 · cited 1× · see citing works
“In one study particularly relevant to this discussion, NT2 wild type and NT2 ρ0 cells were exposed to Aβ42 protein oligomers [79].”
Background
β‐Amyloid fragment 25–35 selectively decreases complex IV activity in isolated mitochondria
Canevari, L., Clark, J. B., & Bates, T. E. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)01028-5 · Cited by 196 · see citing works
Declining brain glucose metabolism in normal individuals with a maternal history of Alzheimer disease
Mosconi, L., Mistur, R., Switalski, R., Brys, M., Glodzik, L., Rich, K., Pirraglia, E., Tsui, W., De Santi, S., & de Leon, M. J. (2009) · Neurology · doi:10.1212/01.wnl.0000333247.51383.43 · Cited by 188 · cited 1× · see citing works
“greater longitudinal CMRglu reductions than FH- or FHp subjects [44].”
Background
Regulation of neuron mitochondrial biogenesis and relevance to brain health
Onyango, I. G., Lu, J., Rodova, M., Lezi, E., Crafter, A. B., & Swerdlow, R. H. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2009.07.014 · Cited by 188 · cited 1× · see citing works
“Efforts to date have been hindered by an incomplete understanding of the mechanisms that mediate brain mitochondrial biogenesis, as well as a dearth of compounds that induce brain mitochondrial biogenesis at brain-achievable concentrations [133,135].”
Background
Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease
Fukui, H., Diaz, F., Garcia, S., & Moraes, C. T. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0705738104 · Cited by 185 · cited 1× · see citing works
“nundrum using genetically altered mice [88].”
Rosiglitazone Induces Mitochondrial Biogenesis in Mouse Brain
Strum, J. C., Shehee, R., Virley, D. J., Richardson, J. C., Mattie, M. D., Selley, P., Ghosh, S., Nock, C. M., Saunders, A. M., & Roses, A. D. (2007) · Journal of Alzheimer s Disease · doi:10.3233/jad-2007-11108 · Cited by 183 · see citing works
Alzheimer's disease cybrids replicate beta-amyloid abnormalities through cell death pathways.
Khan, S. M., Cassarino, D. S., Abramova, N. N., Keeney, P. M., Borland, M. K., Pa, T., Krebs, C. T., Bennett, J. C., Parks, J. K., Swerdlow, R. H., et al. (2000) · PubMed · Cited by 176 · see citing works
Impaired platelet mitochondrial activity in Alzheimer's disease and mild cognitive impairment
Valla, J., Schneider, L., Niedzielko, T., Coon, K. D., Caselli, R., Sabbagh, M. N., Ahern, G. L., Baxter, L., Alexander, G., Walker, D. G., et al. (2006) · Mitochondrion · doi:10.1016/j.mito.2006.10.004 · Cited by 159 · cited 1× · see citing works
“ing the MCI phase of AD [91,92], and even before.”
Background
Comprehensive analysis of APOE and selected proximate markers for late-onset Alzheimer's disease: Patterns of linkage disequilibrium and disease/marker association
Yu, C., Seltman, H. J., Peskind, E. R., Galloway, N. M., Zhou, P. X., Rosenthal, E. A., Wijsman, E. M., Tsuang, D. W., Devlin, B., & Schellenberg, G. D. (2007) · Genomics · doi:10.1016/j.ygeno.2007.02.002 · Cited by 155 · cited 1× · see citing works
“It now appears polymorphisms in a neighboring gene, TOMM40, associate with AD risk [99, 100,101].”
Background
Reduced Posterior Cingulate Mitochondrial Activity in Expired Young Adult Carriers of the APOE ε4 Allele, the Major Late-Onset Alzheimer's Susceptibility Gene
Valla, J., Yaari, R., Wolf, A. B., Kusne, Y., Beach, T. G., Roher, A. E., Corneveaux, J. J., Huentelman, M. J., Caselli, R. J., & Reiman, E. M. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-100129 · Cited by 150 · see citing works
Increased risk of dementia in mothers of Alzheimer's disease cases: Evidence for maternal inheritance
Edland, S. D., Silverman, J. M., Peskind, E. R., Tsuang, D., Wijsman, E., & Morris, J. C. (1996) · Neurology · doi:10.1212/wnl.47.1.254 · Cited by 145 · cited 2× · see citing works
“This phenomenon persists after correcting for increased female longevity and higher rates of AD among women [40].”
BackgroundResult
Is aging part of Alzheimer's disease, or is Alzheimer's disease part of aging?
Swerdlow, R. H. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.06.021 · Cited by 144 · cited 3× · see citing works
“Late onset AD typically demonstrates neither clearcut Mendelian nor maternal inheritance [28].”
Background
Genetic association study on in and around the APOE in late-onset Alzheimer disease in Japanese
Takei, N., Miyashita, A., Tsukie, T., Arai, H., Asada, T., Imagawa, M., Shoji, M., Higuchi, S., Urakami, K., Kimura, H., et al. (2009) · Genomics · doi:10.1016/j.ygeno.2009.01.003 · Cited by 142 · see citing works
Increased fibrillar amyloid-β burden in normal individuals with a family history of late-onset Alzheimer’s
Mosconi, L., Rinne, J. O., Tsui, W. H., Berti, V., Li, Y., Wang, H., Murray, J., Scheinin, N., Någren, K., Williams, S., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0914141107 · Cited by 135 · cited 2× · see citing works
“PIB PET imaging reveals amyloid accumulates in the middle aged children of asymptomatic at least some AD subjects [47].”
Background
Mitochondria in cybrids containing mtDNA from persons with mitochondriopathies
Swerdlow, R. H. (2007) · Journal of Neuroscience Research · doi:10.1002/jnr.21167 · Cited by 128 · cited 2× · see citing works
“Cybrid studies suggest at least part of the AD cytochrome oxidase defect is a consequence of mtDNA encoding [24,26].”
Background
Mitochondria in Alzheimer's disease
Swerdlow, R. H., & Kish, S. J. (2002) · International review of neurobiology · doi:10.1016/s0074-7742(02)53013-0 · Cited by 126 · cited 2× · see citing works
“The AD cytochrome oxidase defect was first demonstrated in AD subject platelet mitochondria, and later shown to occur in the AD brain [21,22].”
Background
Factors associated with survival to 75 years of age in middle-aged men and women. The Framingham Study
Goldberg, R. J. (1996) · Archives of Internal Medicine · doi:10.1001/archinte.156.5.505 · Cited by 125 · see citing works
A comparison of familial and sporadic Alzheimer's disease
Duara, R., Lopez-Alberola, R. F., Barker, W. W., Loewenstein, D. A., Zatinsky, M., Eisdorfer, C. E., & Weinberg, G. B. (1993) · Neurology · doi:10.1212/wnl.43.7.1377 · Cited by 122 · cited 1× · see citing works
“This was not entirely consistent with available epidemiologic data indicating both parents contribute to their children’s lifetime AD risk [39], but by the mid 1990s several studies reported among late onset AD subjects who report an AD-affected or demented parent, the affected parent is more often a mother [40, 41].”
Result
Peripheral insulin and brain structure in early Alzheimer disease
Burns, J. M., Donnelly, J. E., Anderson, H. S., Mayo, M. S., Spencer-Gardner, L. S., Thomas, G., Cronk, B. B., Haddad, Z., Klima, D., Hansen, D., et al. (2007) · Neurology · doi:10.1212/01.wnl.0000276952.91704.af · Cited by 120 · cited 1× · see citing works
“We examined relationships between peripheral insulin, cognitive function, and brain volume in non-diabetic AD subjects [128].”
Background
Bone Density and Brain Atrophy in Early Alzheimer's Disease
Loskutova, N., Honea, R. A., Vidoni, E. D., Brooks, W. M., & Burns, J. M. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-1185 · Cited by 118 · cited 1× · see citing works
“We also found AD subjects have reduced lean (muscle) mass and bone density [116,117,118].”
Background
The Thiazolidinedione Pioglitazone Alters Mitochondrial Function in Human Neuron-Like Cells
Ghosh, S., Patel, N., Rahn, D. A., McAllister, J., Sadeghi, S., Horwitz, G., Berry, D., Wang, K. X., & Swerdlow, R. H. (2007) · Molecular Pharmacology · doi:10.1124/mol.106.033845 · Cited by 116 · cited 2× · see citing works
“We and others previously proposed using brain mitochondrial biogenesis induction to treat AD [133,134].”
Background
Mitochondrial function impairment induced by amyloid β-peptide on PC12 cells
Pereira, C., Santos, M. S., & Oliveira, C. (1998) · NeuroReport · doi:10.1097/00001756-199806010-00015 · Cited by 115 · see citing works
Body Mass Index and Cognitive Decline in Mild Cognitive Impairment
Cronk, B. B., Johnson, D. K., & Burns, J. M. (2010) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0b013e3181a6bf3f · Cited by 109 · cited 1× · see citing works
“We extended this finding by showing body composition and cognitive decline rates correlate; MCI subjects with low body mass index (BMI) values progress more rapidly than those with high BMI values [119].”
Background
Reduced gray matter volume in normal adults with a maternal family history of Alzheimer disease
Honea, R. A., Swerdlow, R. H., Vidoni, E. D., Goodwin, J., & Burns, J. M. (2010) · Neurology · doi:10.1212/wnl.0b013e3181c918cb · Cited by 106 · cited 1× · see citing works
“We recently used VBM to analyze MRI scans from non-demented elderly individuals reporting FHm, FHp, and FH- AD family histories [45].”
Method
Cybrids in Alzheimer's disease: A cellular model of the disease?
Schon, E. A., Shoubridge, E. A., & Moraes, C. T. (1998) · Neurology · doi:10.1212/wnl.51.1.326 · Cited by 101 · cited 3× · see citing works
“Azide-mediated cytochrome oxidase inhibition increases free radical production [69], and oxygen radical production is increased in AD cybrid cell lines with reduced cytochrome oxidase Vmax activities [24, 70].”
Background
Amyloid precursor protein and mitochondrial dysfunction in Alzheimer's disease
Anandatheerthavarada, H. K., & Devi, L. (2007) · The Neuroscientist · doi:10.1177/1073858407303536 · Cited by 95 · see citing works
Reduced Limbic and Hypothalamic Volumes Correlate with Bone Density in Early Alzheimer's Disease
Loskutova, N., Honea, R. A., Brooks, W. M., & Burns, J. M. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-1364 · Cited by 91 · see citing works
Effect of energy shortage and oxidative stress on amyloid precursor protein metabolism in COS cells
Gasparini, L., Racchi, M., Benussi, L., Curti, D., Binetti, G., Bianchetti, A., Trabucchi, M., & Govoni, S. (1997) · Neuroscience Letters · doi:10.1016/s0304-3940(97)00536-3 · Cited by 89 · cited 1× · see citing works
“Treating cells with sodium azide, a cytochrome oxidase inhibitor, shifts AβPP processing to an amyloidogenic derivative [63,64].”
Background
Mitochondrial Gene Therapy Augments Mitochondrial Physiology in a Parkinson's Disease Cell Model
Keeney, P. M., Quigley, C. K., Dunham, L. D., Papageorge, C. M., Iyer, S., Thomas, R. R., Schwarz, K. M., Trimmer, P. A., Khan, S. M., Portell, F. R., et al. (2009) · Human Gene Therapy · doi:10.1089/hum.2009.023 · Cited by 88 · cited 1× · see citing works
“To this end we are developing a chimeric recombinant human transcription factor A (rhTFAM) protein that can transduce cell plasma and mitochondrial membranes, bind mtDNA, and activate both mtDNA expression and replication [137].”
Background
Multiple SNPs within and surrounding the apolipoprotein E gene influence cerebrospinal fluid apolipoprotein E protein levels
Bekris, L. M., Millard, S. P., Galloway, N. M., Vuletic, S., Albers, J. J., Li, G., Galasko, D. R., DeCarli, C., Farlow, M. R., Clark, C. M., et al. (2008) · Journal of Alzheimer's Disease · doi:10.3233/jad-2008-13303 · Cited by 85 · cited 1× · see citing works
“This association may arise via effects on APOE expression, or may exist independent of APOE [102,103,104].”
Background
A chronic Alzheimer’s model evoked by mitochondrial poison sodium azide for pharmacological investigations
Szabados, T., Dul, C., Majtényi, K., Hargitai, J., Pénzes, Z., & Urbanics, R. (2004) · Behavioural Brain Research · doi:10.1016/j.bbr.2004.01.016 · Cited by 84 · cited 1× · see citing works
“Tau phosphorylation increases in rats and cultured neurons exposed to ETC inhibitors [60,61,62].”
Background
Treating neurodegeneration by modifying mitochondria: potential solutions to a “complex” problem
Swerdlow, R. H. (2007) · Antioxidants & Redox Signaling · doi:10.1089/ars.2007.1676 · Cited by 81 · cited 1× · see citing works
“Our hypothesis predicts therapies that enhance neuron aerobic metabolism may benefit late-onset AD patients [129,130].”
Background
Family patterns of coronary heart disease mortality: The Framingham Longevity Study
Brand, F. N., Kiely, D. K., Kannel, W. B., & Myers, R. H. (1992) · Journal of Clinical Epidemiology · doi:10.1016/0895-4356(92)90009-c · Cited by 81 · cited 1× · see citing works
“One large epidemiology study found that while maternal and paternal longevity both influence an individual’s life expectancy, maternal longevity has a greater impact [96, 97].”
Background
Association of parental dementia with cognitive and brain MRI measures in middle-aged adults
Debette, S., Wolf, P. A., Beiser, A., Au, R., Himali, J. J., Pikula, A., Auerbach, S. H., DeCarli, C. S., & Seshadri, S. S. (2009) · Neurology · doi:10.1212/wnl.0b013e3181c67833 · Cited by 77 · see citing works
Cardiorespiratory Fitness in Early-stage Alzheimer Disease
Burns, J. M., Mayo, M. S., Anderson, H. S., Smith, H. J., & Donnelly, J. E. (2008) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0b013e31815a9ddc · Cited by 65 · cited 1× · see citing works
“We determined peak oxygen consumption (VO 2 ) in an AD subject cohort [123].”
Background
APOE mRNA and protein expression in postmortem brain are modulated by an extended haplotype structure
Bekris, L. M., Galloway, N. M., Montine, T. J., Schellenberg, G. D., & Yu, C. (2009) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30993 · Cited by 63 · cited 1× · see citing works
“This association may arise via effects on APOE expression, or may exist independent of APOE [102,103,104].”
Background
Ultrastructural localization of Alzheimer amyloid ?/A4 protein precursor in the cytoplasm of neurons and senile plaque-associated astrocytes
Yamaguchi, H., Yamazaki, T., Ishiguro, K., Shoji, M., Nakazato, Y., & Hirai, S. (1992) · Acta Neuropathologica · doi:10.1007/bf00304629 · Cited by 55 · see citing works
Tauists, Baptists, Syners, Apostates, and new data
Trojanowski, J. Q. (2002) · Annals of Neurology · doi:10.1002/ana.10281 · Cited by 53 · cited 1× · see citing works
“Tau, prion, and environmental causes have all been proposed to initiate AD and mediate progression [11,12,13].”
Background
Mitochondria‐derived oxidative stress induces a heat shock protein response
Barrett, M. J., Alones, V., Wang, K. X., Phan, L., & Swerdlow, R. H. (2004) · Journal of Neuroscience Research · doi:10.1002/jnr.20249 · Cited by 51 · cited 1× · see citing works
“Azide-mediated cytochrome oxidase inhibition increases free radical production [69], and oxygen radical production is increased in AD cybrid cell lines with reduced cytochrome oxidase Vmax activities [24, 70].”
Background
Elevated levels of the Kearns–Sayre syndrome mitochondrial DNA deletion in temporal cortex of Alzheimer's patients
Hamblet, N. S., & Castora, F. J. (1997) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/s0027-5107(97)00158-9 · Cited by 44 · cited 1× · see citing works
“Relative to age-matched control brains, mtDNA deletion levels are elevated in AD subject brains [53,54].”
Background
Cell and animal models of mtDNA biology: progress and prospects
Khan, S. M., Smigrodzki, R. M., & Swerdlow, R. H. (2006) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00224.2006 · Cited by 43 · cited 1× · see citing works
“We have also proposed the enhancement of mitochondrial gene expression to treat AD [136].”
Background
Mitochondrial medicine and the neurodegenerative mitochondriopathies
Swerdlow, R. H. (2009) · Pharmaceuticals · doi:10.3390/ph2030150 · Cited by 43 · cited 1× · see citing works
“Our hypothesis predicts therapies that enhance neuron aerobic metabolism may benefit late-onset AD patients [129,130].”
Background
Alzheimer's Disease and Transmissible Virus Dementia (Creutzfeldt‐Jakob Disease)
BROWN, P., SALAZAR, A. M., GIBBS, C. J., & GAJDUSEK, D. C. (1982) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1982.tb26849.x · Cited by 43 · cited 1× · see citing works
“Tau, prion, and environmental causes have all been proposed to initiate AD and mediate progression [11,12,13].”
Background
The Outcome of Elderly Patients with Cognitive Complaints but Normal Neuropsychological Tests
Nunes, T., Fragata, I., Ribeiro, F., Palma, T., Marôco, J. P., Cannas, J., Secca, M. F., Menezes, C. M., Carmo, I., Cunha, G., et al. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-1210 · Cited by 40 · cited 1× · see citing works
“Similarly, cognitive complaints that are unaccompanied by signs (subjective cognitive impairment; SCI) may portend an increased AD risk [29].”
Background
Correlation of the clinical severity of Alzheimer's disease with an aberration in mitochondrial DNA (mtDNA)
Brown, A. M., Sheu, R. K.-F., Mohs, R., Haroutunian, V., & Blass, J. P. (2001) · Journal of Molecular Neuroscience · doi:10.1385/jmn:16:1:41 · Cited by 40 · cited 1× · see citing works
“els of retrievable, intact mtDNA are reduced in AD brains [58,59].”
Background
Polymorphic variation in cytochrome oxidase subunit genes
Lu, J., Wang, K., Rodova, M., Esteves, R., Berry, D., E, L., Crafter, A., Barrett, M., Cardoso, S. M., Onyango, I., et al. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-100123 · Cited by 33 · cited 2× · see citing works
“synonymous mtDNA COX gene substitution [49].”
Background
Apolipoprotein E and Alzheimer's disease: signal transduction mechanisms
Strittmatter, W. J. (2001) · Biochemical Society Symposia · doi:10.1042/bss0670101 · Cited by 30 · cited 1× · see citing works
“Apolipoprotein E protein has been shown to influence Aβ trafficking and cell signal transduction, either of which could affect Aβ toxicity [100,101].”
Background
Amyloid imaging of alzheimer’s disease using pittsburgh compound B
Johnson, K. A. (2006) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-006-0052-5 · Cited by 23 · cited 1× · see citing works
“Pittsburgh Compound B (PIB) is a PET ligand that binds brain amyloid deposits [46].”
Background
Regulation of Alzheimer ß-Amyloid Precursor Trafficking and Metabolism
Gandy, S., & Petanceska, S. S. (2001) · Advances in experimental medicine and biology · doi:10.1007/978-1-4615-1249-3_7 · Cited by 16 · cited 1× · see citing works
“Apolipoprotein E protein has been shown to influence Aβ trafficking and cell signal transduction, either of which could affect Aβ toxicity [96,97].”
Background
Hypotheses Concerning the Aetiology of Alzheimer's Disease
Tolédano, A. (1988) · Pharmacopsychiatry · doi:10.1055/s-2007-1017060 · Cited by 14 · see citing works
Homotaurine: A failed drug for Alzheimer’s disease and now a nutraceutical for memory protection
Swanoski, M. T. (2009) · American Journal of Health-System Pharmacy · doi:10.2146/ajhp080576 · Cited by 12 · see citing works
Prevalence of dementia after age 90: Results from The 90+ Study
Corrada, M. M., Brookmeyer, R., Berlau, D., Paganini-Hill, A., & Kawas, C. H. (2008) · Neurology · doi:10.1212/01.wnl.0000310773.65918.cd · Cited by 11 · see citing works
If we live long enough, will we all be demented?
Hogan, D. B. (2008) · Neurology · doi:10.1212/01.wnl.0000319660.82871.17 · Cited by 7 · see citing works
Untitled work
Price (1999) · doi:10.1002/1531-8249(199903)45:3

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[111]Johnson DK Wilkins CH Morris JC Accelerated Weight Loss May Precede Diagnosis in Alzheimer Disease Arch Neurol 2006 63 1312 1317 16966511
[112]Stewart R Masaki K Xue QL Peila R Petrovitch H White LR Launer LJ A 32-Year Prospective Study of Change in Body Weight and Incident Dementia: The Honolulu-Asia Aging Study Archives of Neurology 2005 62 55 60 15642850
[113]BarrettConnor E Edelstein SL CoreyBloom J Wiederholt WC Weight loss precedes dementia in community-dwelling older adults Journal of the American Geriatrics Society 1996 44 1147 1152 8855991
[114]White H Pieper C Schmader K Fillenbaum G Weight change in Alzheimer's disease J Am Geriatr Soc 1996 44 265 272 8600194

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 2,305 · see citing works
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 · see citing works
Self-citation
Mitochondrial 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 · see citing works
“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).”
Background
The 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 · see citing works
“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].”
Background
Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease
Calkins, M. J., Manczak, M., Mao, P., Shirendeb, U., & Reddy, P. H. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr381 · Cited by 646 · see citing works
“AD is also associated with inflammatory responses, synaptic damage and mitochondrial structural and functional abnormalities (3-10).”
Background
Microglial cell dysregulation in brain aging and neurodegeneration
von Bernhardi, R., Eugenín-von Bernhardi, L., & Eugenín, J. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00124 · Cited by 556 · see citing works
“…reactive species, and other mediators, contributes to the increased expression of Aβ as well to functional and degenerative changes of neurons, perpetuating abnormal activation of glia, synaptic dysfunction and cell damage. elevated oxidative stress (Swerdlow, 2007; Swerdlow et al., 2010).”
Background
Impaired Mitochondrial Biogenesis Contributes to Mitochondrial Dysfunction in Alzheimer's Disease
Sheng, B., Wang, X.-L., Su, B., Lee, H.-G., Casadesus, G., Perry, G., & Zhu, X.-W. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07581.x · Cited by 538 · see citing works
“Mitochondria dysfunction plays an important role in AD, but the mechanism is still unclear (Zhu et al. 2004; Reddy and Beal 2005, 2008; Swerdlow 2009; Swerdlow et al. 2010).”
Energy metabolism and inflammation in brain aging and Alzheimer’s disease
Yin, F., Sancheti, H., Patil, I., & Cadenas, E. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.04.200 · Cited by 538 · see citing works
“The ‘mitochondrial cascade hypothesis’ proposes that in late-onset sporadic AD, the genetic makeup of a person’s electron transport train sets the basis for oxidant production and the tone for oxidative damage, which drives the progression of other pathologies characteristic of AD [4].”
Phosphorylated Tau in Alzheimer’s Disease and Other Tauopathies
Rawat, P., Sehar, U., Bisht, J., Selman, A., Culberson, J., & Reddy, P. H. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232112841 · Cited by 509 · see citing works
Estrogen: A master regulator of bioenergetic systems in the brain and body
Rettberg, J. R., Yao, J., & Brinton, R. D. (2014) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2013.08.001 · Cited by 534 · see citing works
“The end result is a vicious cycle in which excessive Ab accumulation and sustained mitochondrial dysfunction synergistically exacerbate each other, leading to activation of a multitude of neurodegenerative pathways (Cardoso et al., 2004; Silva et al., 2011; Swerdlow et al., 2010; Yao et al., 2011).”
Impaired mitochondrial function in psychiatric disorders
Manji, H. K., Kato, T., Prospero, N. A. D., Ness, S. L., Beal, M. F., Krams, M., & Chen, G. (2012) · Nature reviews. Neuroscience · doi:10.1038/nrn3229 · Cited by 478 · see citing works
Mitochondrial Diseases of the Brain
Chaturvedi, R. K., & Beal, M. F. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.03.018 · Cited by 416 · see citing works
“hypothesis” mitochondrial dysfunction is the primary event in pathogenesis of AD[241].”
Background
The Role of Mitochondria in Neurodegenerative Diseases: the Lesson from Alzheimer’s Disease and Parkinson’s Disease
Monzio Compagnoni, G., Di Fonzo, A., Corti, S., Comi, G. P., Bresolin, N., & Masliah, E. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-01926-1 · Cited by 378 · see citing works
“On the other hand, according to the mitochondrial cascade hypothesis, mitochondrial dysfunction would represent the initial trigger of most AD cases and the other pathological features should be considered as a secondary effect [10, 11].”
Background
Mitochondrial Dysfunction, Oxidative Stress, Neuroinflammation, and Metabolic Alterations in the Progression of Alzheimer's Disease: A Meta-Analysis of In Vivo Magnetic Resonance Spectroscopy Studies
Song, T., Song, X., Zhu, C., Patrick, R., Skurla, M., Santangelo, I., Green, M., Harper, D., Ren, B., Forester, B. P., et al. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101503 · Cited by 346 · see citing works
Glucose metabolism in normal aging and Alzheimer's disease: methodological and physiological considerations for PET studies
Mosconi, L. (2013) · Clinical and Translational Imaging · doi:10.1007/s40336-013-0026-y · Cited by 328 · see citing works
“Maternally transmitted mtDNA abnormalities, if confirmed, would act as an upstream event in NL individuals with AD-affected mothers, whereas mitochondrial damage secondary to AD pathology would be more likely in LOAD cases caused by factors other than mtDNA changes.”
BackgroundInfluential
Sex differences in Alzheimer risk: Brain imaging of endocrine vs chronologic aging
Mosconi, L., Berti, V., Quinn, C., McHugh, P., Petrongolo, G., Varsavsky, I., Osorio, R. S., Pupi, A., Vallabhajosula, S., Isaacson, R. S., et al. (2017) · Neurology · doi:10.1212/wnl.0000000000004425 · Cited by 319 · see citing works
The Therapeutic Potential of Metformin in Neurodegenerative Diseases
Rotermund, C., Machetanz, G., & Fitzgerald, J. C. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00400 · Cited by 310 · see citing works
“Energy metabolism and mitochondrial dysfunction have been proposed as a primary event in mechanisms underlying AD such as synaptic degeneration, Aβ deposition and formation of neurofibrillary tangles (325).”
Background
Brain aging, Alzheimer's disease, and mitochondria
Swerdlow, R. H. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2011.08.012 · Cited by 306 · see citing works
“An alternative to the amyloid cascade hypothesis [141 – 143], the mitochondrial cascade hypothesis [123,146 – 148], sees brain aging and AD as part of a continuum.”
Background
Hippocampal mutant APP and amyloid beta-induced cognitive decline, dendritic spine loss, defective autophagy, mitophagy and mitochondrial abnormalities in a mouse model of Alzheimer’s disease
Mańczak, M., Kandimalla, R. J. L., Yin, X., & Reddy, P. H. (2018) · Human Molecular Genetics · doi:10.1093/hmg/ddy042 · Cited by 290 · see citing works
“In summary, our study observations suggest that hippocampal accumulation of mutant APP and Ab responsible for (1) cognitive impairments, (2) abnormal mitochondrial dynamics (increased fission and decreased fusion), (3) defective biogenesis, (4) reduced autophagy/mitophagy, (4) loss of dendritic protein MAP2, (5) dendr…”
BackgroundInfluential
Retracted
Mechanistic insights and perspectives involved in neuroprotective action of quercetin
Grewal, A. K., Singh, T. G., Sharma, D., Sharma, V., Singh, M., Rahman, M. H., Najda, A., Walasek-Janusz, M., Kamel, M. S., Albadrani, G. M., et al. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111729 · Cited by 287 · see citing works
Presenilin 2 modulates endoplasmic reticulum (ER)–mitochondria interactions and Ca 2+ cross-talk
Zampese, E., Fasolato, C., Kipanyula, M. J., Bortolozzi, M., Pozzan, T., & Pizzo, P. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1100735108 · Cited by 285 · see citing works
“This finding, together with the generally accepted concept that mitochondrial deficits are key events in most neurodegenerative diseases (16, 17), and more specifically in AD (18, 19), led us to investigate the effect of presenilins on ER–mitochondria cross-talk.”
Background
Mitochondrial dysfunction and oxidative stress in Alzheimer’s disease, and Parkinson’s disease, Huntington’s disease and Amyotrophic Lateral Sclerosis -An updated review
Alqahtani, T., Deore, S. L., Kide, A. A., Shende, B. A., Sharma, R., Chakole, R. D., Nemade, L. S., Kale, N. K., Borah, S., Deokar, S. S., et al. (2023) · Mitochondrion · doi:10.1016/j.mito.2023.05.007 · Cited by 289 · see citing works
Parkin-mediated mitophagy in mutant hAPP neurons and Alzheimer's disease patient brains
Ye, X., Sun, X., Starovoytov, V., & Cai, Q. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv056 · Cited by 274 · see citing works
“Mitochondrial dysfunction is a prominent feature of both familial and sporadic Alzheimer’s disease (AD) and plays an important role in AD pathophysiology (1,2).”
Background
Tau Accumulation Causes Mitochondrial Distribution Deficits in Neurons in a Mouse Model of Tauopathy and in Human Alzheimer's Disease Brain
Kopeikina, K. J., Carlson, G. A., Pitstick, R., Ludvigson, A. E., Peters, A., Luebke, J. I., Koffie, R. M., Frosch, M. P., Hyman, B. T., & Spires‐Jones, T. L. (2011) · American Journal Of Pathology · doi:10.1016/j.ajpath.2011.07.004 · Cited by 272 · see citing works
“In the current study, we tested the hypothesis that mitochondrial trafficking defects would occur in vivo as a consequence of tau over-expression and/or its mislocalization and aggregation, and also asked whether defects in mitochondrial trafficking could be detected in human AD.”
BackgroundInfluential
Female Sex and Alzheimer's Risk: The Menopause Connection
Scheyer, O., Rahman, A., Hristov, H., Berkowitz, C., Isaacson, R. S., Diaz Brinton, R., & Mosconi, L. (2018) · The Journal of Prevention of Alzheimer's Disease · doi:10.14283/jpad.2018.34 · Cited by 268 · see citing works
“As mitochondria are the generators of ATP required for cognitive and other brain functions, and mitochondrial deficits have long been implicated in AD (26), a follow-up PET study investigated whether AD biomarker changes in postmenopausal women were related to altered mitochondrial activity (8).”
Mitochondrial Aspects of Synaptic Dysfunction in Alzheimer’s Disease
Cai, Q., & Tammineni, P. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160726 · Cited by 274 · see citing works
“Undeniably, aberrant accumulation of damaged mitochondria has been shown as a prominent feature in both familial and sporadic AD [22, 23].”
Insulin Resistance and Alzheimer’s Disease: Bioenergetic Linkages
Neth, B. J., & Craft, S. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00345 · Cited by 275 · see citing works
“An increased production of ROS, such as hydrogen peroxide, seen in mitochondrial dysfunction also leads to an activation of PLA2 provoking further myelin breakdown (Adibhatla and Hatcher, 2008; Sun et al., 2010; Yao et al., 2011).”
BackgroundInfluential
Mitochondrial Calcium: Effects of Its Imbalance in Disease
Matuz‐Mares, D., González‐Andrade, M., Araiza-Villanueva, M. G., Vilchis‐Landeros, M. M., & Vázquez‐Meza, H. (2022) · Antioxidants · doi:10.3390/antiox11050801 · Cited by 273 · see citing works
Hippocampal phosphorylated tau induced cognitive decline, dendritic spine loss and mitochondrial abnormalities in a mouse model of Alzheimer’s disease
Kandimalla, R. J. L., Mańczak, M., Yin, X., Wang, R., & Reddy, P. H. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx381 · Cited by 260 · see citing works
“In addition, AD is also associated with synaptic damage and loss of synapses, abnormal mitochondrial structural and functional alterations and the proliferation of reactive astrocytes and microglia and neuronal loss (1, 3-5, 9-12).”
Retracted
Abnormal Mitochondrial Dynamics in the Pathogenesis of Alzheimer's Disease
Zhu, X., Perry, G., Smith, M. A., & Wang, X. (2012) · Journal of Alzheimer's Disease · doi:10.3233/jad-2012-129005 · Cited by 242 · see citing works
“Mitochondrial dynamics are regulated by a delicate fusion mitochondrial ﬁssion [17].”
Zebrafish: an emerging real-time model system to study Alzheimer’s disease and neurospecific drug discovery
Saleem, S., & Kannan, R. R. (2018) · Cell Death Discovery · doi:10.1038/s41420-018-0109-7 · Cited by 241 · see citing works
Amyloid-β and Mitochondria in Aging and Alzheimer's Disease: Implications for Synaptic Damage and Cognitive Decline
Reddy, P. H., Mańczak, M., Mao, P., Calkins, M. J., Reddy, A. P., & Shirendeb, U. P. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-100504 · Cited by 240 · see citing works
“Recently, oxidative stress and mitochondrial abnormalities have been implicated in the development of late-onset AD [22–26], and aging has been identified as the ‘number 1’ risk factor in AD progression and pathology.”
PARP-1 involvement in neurodegeneration: A focus on Alzheimer’s and Parkinson’s diseases
Martire, S., Mosca, L., & D’Erme, M. (2015) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2015.04.001 · Cited by 228 · see citing works
Molecular and Cellular Basis of Neurodegeneration in Alzheimer’s Disease
Jeong, S. (2017) · Molecules and Cells · doi:10.14348/molcells.2017.0096 · Cited by 230 · see citing works
“Mitochondrial dysfunction in the brains of AD patients correlates with a wide range of mitochondrial abnormalities including mitochondrial DNA defects, decreased levels of mitochondrial enzyme activities, impaired mitochondrial trafficking, and increased oxidative stress (Reddy and Reddy, 2011; Swerdlow et al., 2010).”
BackgroundInfluential
Soluble forms of tau are toxic in Alzheimer's disease
Kopeikina, K., Hyman, B., & Spires-Jones, T. (2012) · Translational Neuroscience · doi:10.2478/s13380-012-0032-y · Cited by 232 · see citing works
Is Alzheimer’s disease a systemic disease?
Morris, J. K., Honea, R. A., Vidoni, E. D., Swerdlow, R. H., & Burns, J. M. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2014.04.012 · Cited by 219 · see citing works
“[166,167].”
Mitochondria as a Therapeutic Target for Aging and Neurodegenerative Diseases
Reddy, P. H., & Reddy, T. P. (2011) · Current Alzheimer Research · doi:10.2174/156720511795745401 · Cited by 227 · see citing works
AMP‐activated protein kinase: a potential player in Alzheimer’s disease
Salminen, A., Kaarniranta, K., Haapasalo, A., Soininen, H. S., & Hiltunen, M. O. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07331.x · Cited by 221 · see citing works
Oxidant/Antioxidant Imbalance in Alzheimer’s Disease: Therapeutic and Diagnostic Prospects
Wojsiat, J., Zoltowska, K. M., Laskowska-Kaszub, K., & Wojda, U. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/6435861 · Cited by 221 · see citing works
Deubiquitinating enzymes regulate PARK2-mediated mitophagy
Wang, Y., Serricchio, M., Jauregui, M., Shanbhag, R., Stoltz, T., Paolo, C. T. D., Kim, P. K., & McQuibban, G. A. (2015) · Autophagy · doi:10.1080/15548627.2015.1034408 · Cited by 220 · see citing works
Alterations in Mitochondrial Quality Control in Alzheimer’s Disease
Cai, Q., & Tammineni, P. (2016) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2016.00024 · Cited by 215 · see citing works
“…prominent mitochondria-related anomalies in AD include the accumulation of damaged mitochondria in both familial and sporadic forms of the disease (Swerdlow et al., 2010), as well as changes in mitochondrial structure, dynamics, and motility in vulnerable neurons of affected brain regions…”
Background
Low cerebrospinal fluid concentration of mitochondrial DNA in preclinical Alzheimer disease
Podlesniy, P., Figueiro‐Silva, J., Llado, A., Antonell, A., Sanchez‐Valle, R., Alcolea, D., Lleo, A., Molinuevo, J. L., Serra, N., & Trullas, R. (2013) · Annals of Neurology · doi:10.1002/ana.23955 · Cited by 219 · see citing works
“Converging evidence indicates that AD is associated with alterations in bioenergetics and mitochondrial function.(13,14) Neurons are highly dependent on aerobic energy provided by mitochondria, which contain several copies of their own DNA (mtDNA).”
Background
Cerium oxide nanoparticles protect against Aβ-induced mitochondrial fragmentation and neuronal cell death
Dowding, J. M., Song, W., Bossy, K., Karakoti, A., Kumar, A., Kim, A., Bossy, B., Seal, S., Ellisman, M. H., Perkins, G., et al. (2014) · Cell Death & Differentiation · doi:10.1038/cdd.2014.72 · Cited by 221 · see citing works
“Ab signaling is linked with peroxynitrite production.(1,15) Ab or peroxynitrite trigger mitochondrial fragmentation, which in turn can lead to bioenergetic failure, impaired Ca2þ homeostasis, synaptic injury, axonal transport defects and neuronal cell death.”
Background
Mitochondrial Dysfunction: a Potential Therapeutic Target to Treat Alzheimer’s Disease
Nand, S., Singh, C., Singh, A., Singh, M. P., & Singh, S. P. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-01945-y · Cited by 213 · see citing works
Mitochondrial Dysfunction: Different Routes to Alzheimer’s Disease Therapy
Picone, P., Nuzzo, D., Caruana, L., Scafidi, V., & Carlo, M. D. (2014) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2014/780179 · Cited by 208 · see citing works
“Many lines of evidence suggest that the mitochondrion plays a central role in neurodegenerative diseases, including AD [2], and the so called mitochondrial cascade hypothesis proposes that mitochondrial dysfunction is the primary event in AD pathology [3].”
Mitochondria-Targeted Drugs
Zinovkin, R. A., & Zamyatnin, A. A. (2019) · Current Molecular Pharmacology · doi:10.2174/1874467212666181127151059 · Cited by 209 · see citing works
Cellular Proteostasis in Neurodegeneration
Kurtishi, A., Rosen, B., Patil, K. S., Alves, G. W., & Møller, S. G. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1334-z · Cited by 203 · see citing works
The role of mitochondrial dysfunction in age-related diseases
Lane, R. K., Hilsabeck, T., & Rea, S. L. (2015) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2015.05.021 · Cited by 205 · see citing works
“It has been hypothesized that part of the maternal bias may be due to the unequal inheritance of COX genes; while most subunits are encoded by nuclear DNA, three are inherited from the mother's mtDNA [43].”
BackgroundInfluential
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Authors: Swerdlow, R. H., Burns, J. M., & Khan, S. M.
Affiliations: University of Kansas (US)
Gencia (United States) (US)
Corresponding author: Swerdlow, Russell H.
ORCID: Swerdlow, Russell H.
Burns, Jeffrey M.
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
DOI: 10.3233/jad-2010-100339
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: cc-by-nc
creativecommons.org/licenses/by-nc/4.0/ (unspecified)
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: Health Sciences › Medicine › Physiology › 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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