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Cited by 786Alzheimer's disease research and treatmentsMitochondrial Function and PathologyDementia and Cognitive Impairment Research

The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives

Open access
Swerdlow, Russell H., Burns, Jeffrey M., Khan, Shaharyar M.·2014·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
DOI 10.1016/j.bbadis.2013.09.010PMC PMC3962811
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Abstract

Ten years ago we first proposed the Alzheimer's disease (AD) mitochondrial cascade hypothesis. This hypothesis maintains gene inheritance defines an individual's baseline mitochondrial function; inherited and environmental factors determine rates at which mitochondrial function changes over time; and baseline mitochondrial function and mitochondrial change rates influence AD chronology. Our hypothesis unequivocally states in sporadic, late-onset AD, mitochondrial function affects amyloid precursor protein (APP) expression, APP processing, or beta amyloid (Aβ) accumulation and argues if an amyloid cascade truly exists, mitochondrial function triggers it. We now review the state of the mitochondrial cascade hypothesis, and discuss it in the context of recent AD biomarker studies, diagnostic criteria, and clinical trials. Our hypothesis predicts biomarker changes reflect brain aging, new AD definitions clinically stage brain aging, and removing brain Aβ at any point will marginally impact cognitive trajectories. Our hypothesis, therefore, offers unique perspective into what sporadic, late-onset AD is and how to best treat it.

AI snapshot

Written from the paper’s full text.

TL;DR

This review updates the Alzheimer’s disease (AD) mitochondrial cascade hypothesis, arguing that inherited baseline mitochondrial function and age-related mitochondrial decline influence AD chronology and Aβ homeostasis, especially in sporadic late-onset AD. It predicts that Aβ is primarily a marker of brain aging rather than the singular cause of AD, so removing brain Aβ will only marginally affect cognitive trajectories.

Key findings

  • The hypothesis has three parts: gene inheritance defines baseline mitochondrial function; inherited and environmental factors determine the rate of mitochondrial change; and baseline function plus change rate influence AD chronology. In sporadic late-onset AD, mitochondrial function is proposed to affect APP expression, APP processing, or Aβ accumulation; if an amyloid cascade exists, mitochondrial function triggers it.
  • AD and MCI cybrid lines, generated by transferring subject platelet mitochondria into mtDNA-depleted neuroblastoma and teratocarcinoma cells, showed lower mean COX activity and other changes; results from 18 different AD cybrid studies were summarized. AD and MCI cybrids also showed reduced basal oxygen consumption, lower NAD+/NADH ratios, and lower glycolysis fluxes, while AD cybrid Aβ levels increased.
  • The paper cites the Jack et al. biomarker timeline: Aβ plaque deposition and reduced CSF Aβ occur first, followed by CSF tau rise, hippocampal atrophy, memory decline, and dementia, with full progression taking approximately 10 to 20 years. From the mitochondrial cascade perspective, Aβ biomarkers primarily indicate brain aging; plaque deposition occurs during compensated brain aging and plateaus before symptoms, and one literature-based analysis concludes 85% of those over 85 meet at least one of the new AD criteria.
  • Aβ-based trials are described as generally disappointing: an Aβ vaccine reduced plaque burden but clinical analyses were at best unimpressive; antibody infusions failed primary endpoints; a γ-secretase inhibitor reached phase III but was stopped early due to safety issues and accelerated decline in the treatment group. The hypothesis predicts Aβ removal will help only to the extent Aβ toxicity contributes to LOAD, and instead advocates mitochondrial or bioenergetic medicine approaches.

Methods

  • Narrative review and perspective, not a systematic review or meta-analysis; it synthesizes prior cybrid, genetic, biomarker, diagnostic criteria, and clinical trial literature to update the mitochondrial cascade hypothesis.
  • Cybrid method described: platelet mitochondria from AD, MCI, and control subjects were transferred into mtDNA-depleted SH-SY5Y neuroblastoma and NT2 teratocarcinoma lines; outcomes included COX activity, respiratory and glycolytic fluxes, redox state, oxidative stress, apoptosis, and Aβ levels.
  • Main analysis is conceptual integration and prediction; the paper also reviews genetic association studies involving mtDNA haplogroups, TOMM40/APOE, and TFAM, and discusses biomarker timelines and AD diagnostic criteria.

Limitations

  • Stated in the paper: exact mtDNA differences between AD/MCI cybrids and control cybrids are not known; mtDNA haplogroup or haplotype associations with AD remain uncertain because of inconsistencies; TOMM40’s role is debated and linkage disequilibrium with APOE confounds interpretation; TFAM associations are preliminary; and the mechanism underlying CSF tau rise remains uncertain.
  • Stated in the paper: the hypothesis assumes LOAD and autosomal dominant FAD may share downstream mechanisms but differ upstream, so benefits in FAD may not extrapolate well to LOAD.
  • Evident from the text: this is a narrative review authored by a proponent of the mitochondrial cascade hypothesis, with no systematic search strategy or quantitative synthesis; conclusions rely on selected evidence and predictions rather than new primary clinical trial data.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.bbadis.2013.09.010

Cites

275 of 275 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 176 cited sources checked · 0 supported · 0 flagged

  • Findingnone given

    AD cybrid Aβ levels increased.

    “Interestingly, AD cybrid Aβ levels also increased.”
    Quote in the paperNot a substantial claim
  • Findingcitation

    Mean COX activity was lower in cybrid lines containing AD subject mtDNA than in cybrid lines containing control subject mtDNA.

    “Mean COX activity was lower in cybrid lines containing AD subject mtDNA than it was in cybrid lines containing control subject mtDNA [90, 91].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [90] Sheehan JP Swerdlow RH Miller SW Davis RE Parks JK Parker WD Tuttle JB Calcium homeostasis and reactive oxygen species production in cells transformed by mitochondria from individuals with sporadic Alzheimer's disease J Neurosci 1997 17 4612 4622 9169522 PMC6573324 source

      Not checked in the free run.

    • cites [91] Swerdlow RH Parks JK Cassarino DS Maguire DJ Maguire RS Bennett JP Jr. Davis RE Parker WD Jr. Cybrids in Alzheimer's disease: a cellular model of the disease? Neurology 1997 49 918 925 9339668 source

      Not checked in the free run.

  • Findingown data

    NAD+/NADH ratios in AD and MCI cybrids were lower than in control cybrids.

    “NAD+/NADH ratios in AD and MCI cybrids were lower than they were in control cybrids”
    Quote in the paperSubstantial claim
  • Findingcitation

    MCI cybrid lines generated through transfer of MCI platelet mitochondria to mtDNA-depleted cells showed low mean COX activity and other downstream molecular changes.

    “Two studies in which “MCI cybrid” lines were generated through transfer of MCI platelet mitochondria to mtDNA-depleted cells observed low mean COX activity and other downstream molecular changes [92, 93].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [92] Silva DF Santana I Esteves AR Baldeiras I Arduino DM Oliveira CR Cardoso SM Prodromal Metabolic Phenotype in MCI Cybrids: Implications for Alzheimers Disease Curr Alzheimer Res 2012 22746213 source

      Not checked in the free run.

    • cites [93] Silva DF Selfridge JE Lu J E L Roy N Hutfles L Burns JM Michaelis EK Yan S Cardoso SM Swerdlow RH Bioenergetic flux, mitochondrial mass and mitochondrial morphology dynamics in AD and MCI cybrid cell lines Hum Mol Genet 2013 Epub ahead of print PMC3888119 23740939 source

      Not checked in the free run.

  • Findingown data

    AD and MCI respiration was relatively uncoupled, or less efficient, than control cybrid respiration.

    “This was despite the fact that AD and MCI respiration was relatively uncoupled, or less efficient, than control cybrid respiration.”
    Quote in the paperSubstantial claim
  • May combine two claims. 37
  • Classified as probably not a substantial claim. 10

  • May combine two claims.

    Findingcitation

    AD cybrids showed decreased ATP and increased oxidative stress, stress signaling, and apoptosis.

    “AD cybrids showed decreased ATP and increased oxidative stress, stress signaling, and apoptosis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    AD cybrid mitochondria were relatively depolarized, smaller on average, and less able to buffer calcium.

    “AD cybrid mitochondrial were relatively depolarized, smaller on average, and less able to buffer calcium.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Among fifty subjects, 20% had at least one non-synonymous polymorphism in the three mtDNA COX genes, and synonymous polymorphisms were even more common.

    “We also sequenced the three mtDNA COX genes in fifty subjects. 20% had at least one non-synonymous polymorphism, and synonymous polymorphisms were even more common.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [171] Lu J Wang K Rodova M Esteves R Berry D E L Crafter A Barrett M Cardoso SM Onyango I Parker WD Fontes J Burns JM Swerdlow RH Polymorphic variation in cytochrome oxidase subunit genes Journal of Alzheimer's disease: JAD 2010 21 141 154 PMC2910218 20413852 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    In LOAD, age-associated changes in mitochondrial function, which mtDNA may mediate, are critical.

    “In LOAD, age-associated changes in mitochondrial function, which mtDNA may mediate, will prove critical.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    Both mothers and fathers contribute to their offspring's AD risk, but mothers contribute more because mtDNA is maternally inherited.

    “In this respect, both mothers and fathers contribute to their offspring's AD risk, but because mitochondrial DNA (mtDNA) is maternally inherited mothers contribute more.”
    • Also stated in: § 3. Support for the Hypothesis · plain
      “epidemiologic studies find that although both parents contribute to an individual's AD risk [112], mothers contribute more than fathers [113-116].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [112] Katzman R Alzheimer's disease N Engl J Med 1986 314 964 973 2870433 source

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    • cites [113] Edland SD Silverman JM Peskind ER Tsuang D Wijsman E Morris JC Increased risk of dementia in mothers of Alzheimer's disease cases: evidence for maternal inheritance Neurology 1996 47 254 256 8710088 source

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    • cites [114] Duara R Lopez-Alberola RF Barker WW Loewenstein DA Zatinsky M Eisdorfer CE Weinberg GB A comparison of familial and sporadic Alzheimer's disease Neurology 1993 43 1377 1384 8327141 source

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    • cites [115] Bassett SS Avramopoulos D Fallin D Evidence for parent of origin effect in late-onset Alzheimer disease Am J Med Genet 2002 114 679 686 12210287 source

      Not checked in the free run.

    • cites [116] Gomez-Tortosa E Barquero MS Baron M Sainz MJ Manzano S Payno M Ros R Almaraz C Gomez-Garre P Jimenez-Escrig A Variability of age at onset in siblings with familial Alzheimer disease Archives of neurology 2007 64 1743 1748 18071037 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    In sporadic, late-onset AD, mitochondrial function affects APP expression, APP processing, or Aβ accumulation.

    “Our hypothesis unequivocally states in sporadic, late-onset AD, mitochondrial function effects APP expression, APP processing, or Aβ accumulation.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    The mitochondrial cascade hypothesis predicts that new AD definitions clinically stage brain aging.

    “Our hypothesis predicts biomarker changes reflect brain aging, new AD definitions clinically stage brain aging, and removing brain Aβ at any point will marginally impact cognitive trajectories.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Greater mitochondrial durability should associate with slower brain aging and lesser mitochondrial durability should associate with faster brain aging.

    “then greater mitochondrial durability should associate with slower brain aging and lesser mitochondrial durability should associate with faster brain aging.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    APP and Aβ, as well as the entire γ-secretase complex, physically associate with mitochondria and can effect changes in mitochondrial function.

    “accumulating data certainly do suggest APP and Aβ, as well as the entire γ-secretase complex, physically associate with mitochondria and can effect changes in mitochondrial function [58-67].”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [58] Caspersen C Wang N Yao J Sosunov A Chen X Lustbader JW Xu HW Stern D McKhann G Yan SD Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease FASEB J 2005 19 2040 2041 16210396 source

      Not checked in the free run.

    • cites [59] Lustbader JW Cirilli M Lin C Xu HW Takuma K Wang N Caspersen C Chen X Pollak S Chaney M Trinchese F Liu S Gunn-Moore F Lue LF Walker DG Kuppusamy P Zewier ZL Arancio O Stern D Yan SS Wu H ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease Science (New York, N.Y.) 2004 304 448 452 15087549 source

      Not checked in the free run.

    • cites [60] Manczak M Anekonda TS Henson E Park BS Quinn J Reddy PH Mitochondria are a direct site of A beta accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression Human molecular genetics 2006 15 1437 1449 16551656 source

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    • cites [61] Anandatheerthavarada HK Biswas G Robin MA Avadhani NG Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuronal cells J Cell Biol 2003 161 41 54 12695498 PMC2172865 source

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    • cites [62] Anandatheerthavarada HK Devi L Amyloid precursor protein and mitochondrial dysfunction in Alzheimer's disease Neuroscientist 2007 13 626 638 17911214 source

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    • cites [63] Devi L Prabhu BM Galati DF Avadhani NG Anandatheerthavarada HK Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer's disease brain is associated with mitochondrial dysfunction J Neurosci 2006 26 9057 9068 16943564 PMC6675337 source

      Not checked in the free run.

    • cites [64] Crouch PJ Blake R Duce JA Ciccotosto GD Li QX Barnham KJ Curtain CC Cherny RA Cappai R Dyrks T Masters CL Trounce IA Copper-dependent inhibition of human cytochrome c oxidase by a dimeric conformer of amyloid-beta1-42 J Neurosci 2005 25 672 679 15659604 PMC6725334 source

      Not checked in the free run.

    • cites [65] Hansson CA Frykman S Farmery MR Tjernberg LO Nilsberth C Pursglove SE Ito A Winblad B Cowburn RF Thyberg J Ankarcrona M Nicastrin, presenilin, APH-1, and PEN-2 form active gamma-secretase complexes in mitochondria J Biol Chem 2004 279 51654 51660 15456764 source

      Not checked in the free run.

    • cites [66] Hansson Petersen CA Alikhani N Behbahani H Wiehager B Pavlov PF Alafuzoff I Leinonen V Ito A Winblad B Glaser E Ankarcrona M The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae Proc Natl Acad Sci U S A 2008 105 13145 13150 18757748 PMC2527349 source

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    • cites [67] Teng FY Tang BL Widespread gamma-secretase activity in the cell, but do we need it at the mitochondria? Biochem Biophys Res Commun 2005 328 1 5 15670741 source

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  • May combine two claims.

    Premisecitation

    Mitochondrial function declines throughout much of adulthood, and adaptive changes at least initially mitigate this decline.

    “Existing data suggest mitochondrial function declines throughout much of adulthood and that adaptive changes, at least initially, mitigate this decline [47, 80-82].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [47] Hirai K Aliev G Nunomura A Fujioka H Russell RL Atwood CS Johnson AB Kress Y Vinters HV Tabaton M Shimohama S Cash AD Siedlak SL Harris PL Jones PK Petersen RB Perry G Smith MA Mitochondrial abnormalities in Alzheimer's disease J Neurosci 2001 21 3017 3023 11312286 PMC6762571 source

      Not checked in the free run.

    • cites [80] Boveris A Navarro A Brain mitochondrial dysfunction in aging IUBMB Life 2008 60 308 314 18421773 source

      Not checked in the free run.

    • cites [81] Navarro A Boveris A The mitochondrial energy transduction system and the aging process Am J Physiol Cell Physiol 2007 292 C670 686 17020935 source

      Not checked in the free run.

    • cites [82] Barrientos A Casademont J Cardellach F Estivill X Urbano-Marquez A Nunes V Reduced steady-state levels of mitochondrial RNA and increased mitochondrial DNA amount in human brain with aging Brain Res Mol Brain Res 1997 52 284 289 9495550 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    AD and MCI cybrid molecular changes persist in culture, suggesting AD and MCI subject mtDNA differs from control subject mtDNA.

    “Third, AD and MCI cybrid molecular changes persist in culture, thereby suggesting AD and MCI subject mtDNA differs from control subject mtDNA.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Cognitively intact children of AD mothers, relative to children of AD fathers, show greater age-associated brain atrophy, faster longitudinal brain atrophy, increased Aβ plaque deposition, elevated CSF oxidative stress markers, and AD-like CSF Aβ changes.

    “Subsequent studies found that the cognitively intact children of AD mothers, relative to the cognitively intact children of AD fathers, show greater degrees of age-associated brain atrophy, faster rates of longitudinal brain atrophy, increased Aβ plaque deposition, elevated cerebrospinal fluid (CSF) oxidative stress markers, and AD-like CSF Aβ changes [130-137].”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [130] Berti V Mosconi L Glodzik L Li Y Murray J De Santi S Pupi A Tsui W De Leon MJ Structural brain changes in normal individuals with a maternal history of Alzheimer's Neurobiol Aging 2011 32 2325.e2317 2326 21316814 PMC3115436 source

      Not checked in the free run.

    • cites [131] Mosconi L Berti V Swerdlow RH Pupi A Duara R de Leon M Maternal transmission of Alzheimer's disease: prodromal metabolic phenotype and the search for genes Hum Genomics 2010 4 170 193 20368139 PMC3033750 source

      Not checked in the free run.

    • cites [132] Mosconi L Glodzik L Mistur R McHugh P Rich KE Javier E Williams S Pirraglia E De Santi S Mehta PD Zinkowski R Blennow K Pratico D de Leon MJ Oxidative stress and amyloid-beta pathology in normal individuals with a maternal history of Alzheimer's Biol Psychiatry 2010 68 913 921 20817151 PMC2967599 source

      Not checked in the free run.

    • cites [133] Mosconi L Mistur R Switalski R Brys M Glodzik L Rich K Pirraglia E Tsui W De Santi S de Leon MJ Declining brain glucose metabolism in normal individuals with a maternal history of Alzheimer disease Neurology 2009 72 513 520 19005175 PMC2677512 source

      Not checked in the free run.

    • cites [134] Mosconi L Rinne JO Tsui WH Berti V Li Y Wang H Murray J Scheinin N Nagren K Williams S Glodzik L De Santi S Vallabhajosula S de Leon MJ Increased fibrillar amyloid-{beta} burden in normal individuals with a family history of late-onset Alzheimer's Proc Natl Acad Sci U S A 2010 107 5949 5954 20231448 PMC2851906 source

      Not checked in the free run.

    • cites [135] Honea RA Swerdlow RH Vidoni E Burns JM Progressive regional atrophy in normaladults with a maternal history of Alzheimer disease Neurology 2011 76 822 829 21357834 PMC3053329 source

      Not checked in the free run.

    • cites [136] Honea RA Swerdlow RH Vidoni ED Goodwin J Burns JM Reduced gray matter volume in normal adults with a maternal family history of Alzheimer disease Neurology 2010 74 113 120 20065246 PMC2809030 source

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    • cites [137] Honea RA Vidoni ED Swerdlow RH Burns JM Maternal family history is associated with Alzheimer's disease biomarkers J Alzheimers Dis 2012 31 659 668 22669011 PMC3608420 source

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  • May combine two claims.

    Interpretationcitation

    Inheritance determines an individual's baseline mitochondrial function and durability, and maternal inheritance plays a greater role than paternal inheritance.

    “These and other data in this section argue inheritance determines an individual's baseline mitochondrial function and durability, and maternal inheritance plays a greater role than paternal inheritance [30].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Ross JM Stewart JB Hagstrom E Brene S Mourier A Coppotelli G Freyer C Lagouge M Hoffer BJ Olson L Larsson NG Germline mitochondrial DNA mutations aggravate ageing and can impair brain development Nature 2013 PMC3820420 23965628 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    APP and Aβ homeostasis are exquisitely regulated processes, and bioenergetic metabolism regulates these processes.

    “Overall, we feel we can confidently state APP and Aβ homeostasis are exquisitely regulated processes, and bioenergetic metabolism regulates these processes.”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [177] Brody DL Magnoni S Schwetye KE Spinner ML Esparza TJ Stocchetti N Zipfel GJ Holtzman DM Amyloid-beta dynamics correlate with neurological status in the injured human brain Science 2008 321 1221 1224 18755980 PMC2577829 source

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    • cites [178] Kang JE Lim MM Bateman RJ Lee JJ Smyth LP Cirrito JR Fujiki N Nishino S Holtzman DM Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle Science 2009 326 1005 1007 19779148 PMC2789838 source

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    • cites [179] Nitsch RM Farber SA Growdon JH Wurtman RJ Release of amyloid beta-protein precursor derivatives by electrical depolarization of rat hippocampal slices Proc Natl Acad Sci U S A 1993 90 5191 5193 8506366 PMC46681 source

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    • cites [180] Kamenetz F Tomita T Hsieh H Seabrook G Borchelt D Iwatsubo T Sisodia S Malinow R APP processing and synaptic function Neuron 2003 37 925 937 12670422 source

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    • cites [182] Bero AW Yan P Roh JH Cirrito JR Stewart FR Raichle ME Lee JM Holtzman DM Neuronal activity regulates the regional vulnerability to amyloid-beta deposition Nat Neurosci 2011 14 750 756 21532579 PMC3102784 source

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    • cites [183] Bateman RJ Wen G Morris JC Holtzman DM Fluctuations of CSF amyloid-beta levels: implications for a diagnostic and therapeutic biomarker Neurology 2007 68 666 669 17325273 source

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    • cites [184] Jagust WJ Mormino EC Lifespan brain activity, beta-amyloid, and Alzheimer's disease Trends Cogn Sci 2011 15 520 526 21983147 PMC3206968 source

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  • May combine two claims.

    Premisecitation

    Regional reductions in brain volumes occur during aging, and become more pervasive with MCI and AD.

    “Regional reductions occur during aging, and become more pervasive with MCI and AD [195, 196].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [195] Hedden T Gabrieli JD Insights into the ageing mind: a view from cognitive neuroscience Nat Rev Neurosci 2004 5 87 96 14735112 source

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    • cites [196] McEvoy LK Brewer JB Quantitative structural MRI for early detection of Alzheimer's disease Expert review of neurotherapeutics 2010 10 1675 1688 20977326 PMC3182103 source

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  • May combine two claims.

    Premisecitation

    Relative to control subjects, MCI and AD subjects typically show low CSF Aβ, high total tau, and high phosphorylated tau levels.

    “Relative to control subjects, MCI and AD subjects typically show low CSF Aβ, high total tau, and high phosphorylated tau levels [201, 202].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [201] Blennow K Hampel H Weiner M Zetterberg H Cerebrospinal fluid and plasma biomarkers in Alzheimer disease Nat Rev Neurol 2010 6 131 144 20157306 source

      Not checked in the free run.

    • cites [202] Blennow K Zetterberg H The application of cerebrospinal fluid biomarkers in early diagnosis of Alzheimer disease The Medical clinics of North America 2013 97 369 376 23642576 source

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  • May combine two claims.

    Premisecitation

    Regional reductions in brain glucose utilization occur with aging and to a greater extent in MCI and AD.

    “Regional reductions in brain glucose utilization occur with aging and to a greater extent in MCI and AD [185-193].”
    Quote in the paperNot a substantial claim0 of 9 sources checked
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    • cites [191] Li Y Rinne JO Mosconi L Pirraglia E Rusinek H DeSanti S Kemppainen N Nagren K Kim BC Tsui W de Leon MJ Regional analysis of FDG and PIB-PET images in normal aging, mild cognitive impairment, and Alzheimer's disease European journal of nuclear medicine and molecular imaging 2008 35 2169 2181 18566819 PMC2693402 source

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    • cites [192] Mosconi L Mistur R Switalski R Tsui WH Glodzik L Li Y Pirraglia E De Santi S Reisberg B Wisniewski T de Leon MJ FDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer's disease European journal of nuclear medicine and molecular imaging 2009 36 811 822 19142633 PMC2774795 source

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    • cites [193] Scheef L Spottke A Daerr M Joe A Striepens N Kolsch H Popp J Daamen M Gorris D Heneka MT Boecker H Biersack HJ Maier W Schild HH Wagner M Jessen F Glucose metabolism, gray matter structure, and memory decline in subjective memory impairment Neurology 2012 79 1332 1339 22914828 source

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  • May combine two claims.

    Premisecitation

    Glucose utilization and synaptic density directly correlate, so FDG PET reflects synaptic integrity.

    “Glucose utilization and synaptic density directly correlate, so to some extent FDG PET reflects synaptic integrity [194].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [194] Jacobs B Chugani HT Allada V Chen S Phelps ME Pollack DB Raleigh MJ Developmental changes in brain metabolism in sedated rhesus macaques and vervet monkeys revealed by positron emission tomography Cerebral cortex (New York, N.Y.: 1991) 1995 5 222 233 7613078 source

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  • May combine two claims.

    Premisecitation

    In individuals who develop AD, Aβ plaque deposition and reduced CSF Aβ occur first, followed by CSF tau rise, years before clinical signs; later hippocampal atrophy, memory decline, and dementia occur; full progression takes approximately 10 to 20 years.

    “Their timeline states that in individuals who develop AD, Aβ plaque deposition and reduced CSF Aβ occur first. Next, CSF tau levels rise. These changes manifest years before clinical signs or symptoms develop. Later on hippocampal atrophy appears, followed shortly thereafter by memory decline and eventually dementia. Full progression from Aβ changes to clinical decline takes approximately 10 to 20”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [205] Jack CR Jr. Knopman DS Jagust WJ Shaw LM Aisen PS Weiner MW Petersen RC Trojanowski JQ Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade Lancet Neurol 2010 9 119 128 20083042 PMC2819840 source

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  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Falling Aβ CSF levels reflect falling Aβ production more than decreased solubility or increased incorporation into plaques.

    “Finally, we predict falling Aβ CSF levels reflect falling Aβ production more than it reflects decreased solubility or increased incorporation into plaques.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Subjects with positive Aβ biomarkers will more likely develop cognitive decline than subjects with negative Aβ biomarkers because positive Aβ biomarkers indicate more advanced brain aging.

    “Over a given time period subjects with positive Aβ biomarkers will more likely develop cognitive decline than subjects with negative Aβ biomarkers not because positive Aβ biomarkers necessarily indicate AD, but because positive Aβ biomarkers indicate more advanced (beyond what is inferred when no Aβ biomarkers are present) brain aging.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Aβ accumulates for over a decade before symptoms arise, which infers brains tolerate Aβ reasonably well.

    “Also, the fact that Aβ accumulates for over a decade before symptoms arise [214], a finding that infers brains tolerate Aβ reasonably well, does not challenge our hypothesis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [214] Villemagne VL Burnham S Bourgeat P Brown B Ellis KA Salvado O Szoeke C Macaulay SL Martins R Maruff P Ames D Rowe CC Masters CL Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study Lancet Neurol 2013 12 357 367 23477989 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    As bioenergetic stress worsens, the brain shifts from bioenergetic hypermetabolism to hypometabolism, and Aβ production falls.

    “As bioenergetic stress worsens, the brain shifts from a state of bioenergetic hypermetabolism to one of hypometabolism, and Aβ production falls.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Normal age-related CSF Aβ levels vary with age; CSF Aβ levels seem to decline during young adulthood, and during late mid-life may slightly increase.

    “Studies of non-demented individuals report that while CSF Aβ levels seem to decline during young adulthood, during late mid-life CSF Aβ levels may actually slightly increase [219, 220].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [219] Shoji M Kanai M Matsubara E Tomidokoro Y Shizuka M Ikeda Y Ikeda M Harigaya Y Okamoto K Hirai S The levels of cerebrospinal fluid Abeta40 and Abeta42(43) are regulated age-dependently Neurobiol Aging 2001 22 209 215 11182470 source

      Not checked in the free run.

    • cites [220] Peskind ER Li G Shofer J Quinn JF Kaye JA Clark CM Farlow MR DeCarli C Raskind MA Schellenberg GD Lee VM Galasko DR Age and apolipoprotein E*4 allele effects on cerebrospinal fluid beta-amyloid 42 in adults with normal cognition Arch Neurol 2006 63 936 939 16831961 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Under conditions of mild bioenergetic stress the brain becomes relatively hypermetabolic; bioenergetic hypermetabolism increases Aβ production.

    “Under conditions of mild bioenergetic stress the brain become relatively hypermetabolic. Bioenergetic hypermetabolism, in turn, increases Aβ production.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Brains of mice engineered to overproduce mutant APP and PS1 in the setting of less COX holoenzyme show reduced plaque deposition, less fibrillar Aβ, and less oxidative stress than APP-PS1 mice that can freely produce COX.

    “The brains of these mice show reduced plaque deposition, less fibrillar Aβ, and less oxidative stress than APP-PS1 mice that can freely produce COX [175, 176].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [175] Fukui H Diaz F Garcia S Moraes CT Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease Proc Natl Acad Sci U S A 2007 104 14163 14168 17715058 PMC1955773 source

      Not checked in the free run.

    • cites [176] Pinto M Pickrell AM Fukui H Moraes CT Mitochondrial DNA damage in a mouse model of Alzheimer's disease decreases amyloid beta plaque formation Neurobiol Aging 2013 34 2399 2407 23702344 PMC4020357 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Plaque formation rates vary over time; after rapid accumulation, plaque deposition gradually slows and by symptom manifestation is essentially done.

    “Plaque formation rates also vary over time [217]. After a period of rapid accumulation, plaque deposition gradually slows and by the time symptoms manifest plaque deposition is essentially done [20, 205, 218].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [217] Jack CR Jr. Wiste HJ Lesnick TG Weigand SD Knopman DS Vemuri P Pankratz VS Senjem ML Gunter JL Mielke MM Lowe VJ Boeve BF Petersen RC Brain beta-amyloid load approaches a plateau Neurology 2013 80 890 896 23446680 PMC3653215 source

      Not checked in the free run.

    • cites [20] Sperling RA Aisen PS Beckett LA Bennett DA Craft S Fagan AM Iwatsubo T Jack CR Jr. Kaye J Montine TJ Park DC Reiman EM Rowe CC Siemers E Stern Y Yaffe K Carrillo MC Thies B Morrison-Bogorad M Wagster MV Phelps CH Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease Alzheimers Dement 2011 7 280 292 21514248 PMC3220946 source

      Not checked in the free run.

    • cites [205] Jack CR Jr. Knopman DS Jagust WJ Shaw LM Aisen PS Weiner MW Petersen RC Trojanowski JQ Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade Lancet Neurol 2010 9 119 128 20083042 PMC2819840 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    One literature-based analysis concludes 85% of those over 85 meet at least one of the new AD criteria.

    “one literature- based analysis concludes 85% of those over 85 meet at least one of the new AD criteria [26].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Swerdlow RH Brain aging, Alzheimer's disease, and mitochondria Biochimica et biophysica acta 2011 1812 1630 1639 21920438 PMC3210037 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Cognitive speed and multitasking abilities become less robust with advancing age.

    “Cognitive speed and multitasking abilities, for example, become less robust with advancing age.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [195] Hedden T Gabrieli JD Insights into the ageing mind: a view from cognitive neuroscience Nat Rev Neurosci 2004 5 87 96 14735112 source

      Not checked in the free run.

    • cites [242] Borson S Cognition, aging, and disabilities: conceptual issues Phys Med Rehabil Clin N Am 2010 21 375 382 20494283 PMC2876094 source

      Not checked in the free run.

    • cites [243] Folstein M Folstein S Functional expressions of the aging brain Nutr Rev 2010 68 Suppl 2 S70 73 21091951 source

      Not checked in the free run.

    • cites [244] Eckert MA Slowing down: age-related neurobiological predictors of processing speed Frontiers in neuroscience 2011 5 25 21441995 PMC3061488 source

      Not checked in the free run.

    • cites [245] Salthouse TA Selective review of cognitive aging Journal of the International Neuropsychological Society: JINS 2010 16 754 760 20673381 PMC3637655 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    According to the mitochondrial cascade hypothesis, in asymptomatic individuals plaques indicate a higher risk of AD (or at least a higher risk of developing symptomatic AD) because their presence indicates a more advanced state of brain aging.

    “According to our hypothesis, in asymptomatic individuals plaques indicate a higher AD risk (or at least a higher risk of developing symptomatic AD) as their presence indicates a more advanced state of brain aging.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Many with plaques will remain asymptomatic for years or even decades, and perhaps some will never develop symptoms.

    “After all, many with plaques will remain asymptomatic for years or even decades, and perhaps some will never develop symptoms [241].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [241] Berlau DJ Corrada MM Head E Kawas CH APOE epsilon2 is associated with intact cognition but increased Alzheimer pathology in the oldest old Neurology 2009 72 829 834 19255410 PMC2667799 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An agent claimed to inhibit Aβ oligomer formation did not meet its primary endpoint and further development was discontinued.

    “An agent claimed to inhibit Aβ oligomer formation did not meet its primary endpoint and further development was discontinued [257, 258].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [257] Aisen PS Gauthier S Ferris SH Saumier D Haine D Garceau D Duong A Suhy J Oh J Lau WC Sampalis J Tramiprosate in mild-to-moderate Alzheimer's disease - a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study) Archives of medical science: AMS 2011 7 102 111 22291741 PMC3258678 source

      Not checked in the free run.

    • cites [258] Sabbagh MN Drug development for Alzheimer's disease: where are we now and where are we headed? The American journal of geriatric pharmacotherapy 2009 7 167 185 19616185 PMC2948028 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Inhibiting β secretase-mediated APP cleavage should change levels of APP and its α secretase-generated sAPPα product.

    “especially since inhibiting β secretase-mediated APP cleavage should change levels of APP and its α secretase-generated sAPPα product.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A γ secretase inhibitor reached phase III testing, but safety issues and accelerated decline in the treatment group brought this trial to an early end.

    “A γ secretase inhibitor did make it to phase III testing, but safety issues and accelerated decline in the treatment group brought this trial to an early end [255].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [255] Doody RS Raman R Farlow M Iwatsubo T Vellas B Joffe S Kieburtz K He F Sun X Thomas RG Aisen PS Siemers E Sethuraman G Mohs R A phase 3 trial of semagacestat for treatment of Alzheimer's disease N Engl J Med 2013 369 341 350 23883379 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The mitochondrial cascade hypothesis predicts that Aβ-based interventions failed not because these trials enrolled the wrong patients, but because Aβ does not cause LOAD.

    “The mitochondrial cascade hypothesis, though, predicts Aβ-based interventions failed not because these trials enrolled the wrong patients, but because Aβ does not cause LOAD.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The presence of a mitochondrial-APP-presenilin nexus suggests drugs that modify this nexus may yet modify AD.

    “the presence of a mitochondrial-APP-presenilin nexus suggests drugs that modify this nexus may yet modify AD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Aβ-based approaches appear to accelerate, not impact, or at best very minimally slow symptomatic subject progression.

    “despite the fact these approaches appear to accelerate, not impact, or at best very minimally slow symptomatic subject progression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [252] Vellas B Carrillo MC Sampaio C Brashear HR Siemers E Hampel H Schneider LS Weiner M Doody R Khachaturian Z Cedarbaum J Grundman M Broich K Giacobini E Dubois B Sperling R Wilcock GK Fox N Scheltens P Touchon J Hendrix S Andrieu S Aisen P Designing drug trials for Alzheimer's disease: What we have learned from the release of the phase III antibody trials: A report from the EU/US/CTAD Task Force Alzheimers Dement 2013 9 438 444 23809364 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Aβ-based interventions designed to remove or prevent Aβ from accumulating before this process naturally stops will prove superfluous and ineffective.

    “To us, this suggests Aβ-based interventions designed to remove or prevent Aβ from accumulating before this process naturally stops on its own will prove superfluous and, therefore, ineffective.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Early on, mitochondrial changes increase Aβ production and cause it to accumulate.

    “Early on, these mitochondrial changes increase Aβ production and cause it to accumulate.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The mitochondrial cascade hypothesis tends to lump rather than split age-associated and AD-associated cognitive changes at the clinical level.

    “At the clinical level, it tends to lump rather than split age-associated and AD-associated cognitive changes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    Manipulating mitochondrial function and cell bioenergetic pathways will ultimately achieve the goal of arresting brain aging and AD.

    “We believe manipulating mitochondrial function and cell bioenergetic pathways will ultimately achieve this goal.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    The mitochondrial cascade hypothesis sees Aβ as a marker of brain aging, and not AD's singular cause.

    “The mitochondrial cascade hypothesis sees Aβ as a marker of brain aging, and not AD's singular cause.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Arresting brain aging will arrest both the development and progression of AD.

    “According to our hypothesis, arresting brain aging will arrest both the development and progression of AD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Removing Aβ will not actually remove the cause of AD but instead an epiphenomenon of aging.

    “We suspect the latter possibility will prove to be the case, and that removing Aβ will not actually remove the cause of AD but instead an epiphenomenon of aging.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: The mitochondrial cascade hypothesis perspective assumes that removing Aβ will transform the course of neither brain aging nor AD.

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    Mitochondrial or bioenergetic medicine approaches will benefit both asymptomatic and symptomatic individuals if the mitochondrial cascade hypothesis is correct.

    “If correct, we believe, such approaches will benefit both asymptomatic and symptomatic individuals.”
    Quote in the paperNot a substantial claim
45 of 45

  • The authors state this as an assumption.

    Although LOAD and autosomal dominant FAD might share some important mechanisms, key differences will nevertheless exist.

    “The mitochondrial cascade hypothesis assumes that although LOAD and autosomal dominant FAD might share some important mechanisms, key differences will nevertheless exist.”

  • The authors state this as an assumption.

    mtDNA differences between AD/MCI and control subjects contribute to AD.

    “While the mitochondrial cascade hypothesis assumes these differences contribute to AD, our hypothesis also predicts mtDNA inheritance as well as the inheritance of genes that maintain mtDNA and mitochondrial function also play an important role.”

  • The authors state this as an assumption.

    Declining mitochondrial function occurs with advancing age.

    “Another assumption, that declining mitochondrial function occurs with advancing age, is generally accepted [35, 80, 81].”

  • The authors state this as an assumption.

    The mitochondrial cascade hypothesis perspective assumes that removing Aβ will transform the course of neither brain aging nor AD.

    “While the mitochondrial cascade hypothesis perspective assumes removing Aβ will transform the course of neither brain aging nor AD”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The mitochondrial dysfunction hypothesis for Alzheimer's disease pathogenesis posits that amyloidosis, cell cycle re-entry, and tau phosphorylation are all caused by mitochondrial failure in the Alzheimer's disease brain.

    “the mitochondrial dysfunction hypothesis for AD pathogenesis posits that amyloidosis, cell cycle re-entry, and tau phosphorylation are all caused by mitochondrial failure in the AD brain (Swerdlow et al., 2014).”

    From An update on the novel and approved drugs for Alzheimer disease (2022) · cites this paper as Swerdlow et al., 2014

Cites

1 retracted

Flagged first, then by citations

11 of the 286 references couldn’t be matched to a known paper.

Research works printed but not linked: 3

  1. Divry, 1927, Etude histochimique des plaques seniles, J. Belg. Neurol. Psychiatry, 9, 643
  2. Rentz, 2006, Amyloid imaging with Pittsburgh Compound-B (PIB) in AD, MCI, and highly intelligent older adults, Neurology, 66, A66
  3. Schultz, 2013, Increased cerebral blood flow in cognitively normal older adults with amyloid, Alzheimers Dement., 3

Cited by

Sorted by citations

Related

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
Venue
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
Publisher
Elsevier BV
Published
2014-08
Volume
1842
Issue
8
Pages
1219-1231
ISSN
0925-4439 (ISSN-L)
DOI
10.1016/j.bbadis.2013.09.010
PMC
PMC3962811
OpenAlex
W1993160420
Semantic Scholar
d0760173f94759d3a732c354d3c64a8ed8c3b296
Cited by
786
References
286
Citations by year
2026: 58 · 2025: 53 · 2024: 75 · 2023: 72 · 2022: 72 · 2021: 91 · 2020: 77 · 2019: 74 · 2018: 56 · 2017: 47 · 2016: 45 · 2015: 38 · 2014: 24 · 2013: 3
FWCI
4.04
Type
journal article
Language
en
Open access
Licence
Locations
  • Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • P30AG035982
  • Frank and Evangeline Thompson Alzheimer's Treatment Program Fund
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, mitochondrial function, amyloid hypothesis, amyloid precursor protein, amyloid-beta deposition, brain aging, Alzheimer's disease biomarkers, cognitive trajectories
MeSH terms
Alzheimer Disease, Animals, Humans, Mitochondria, Models, Biological, Signal Transduction, Biomarkers

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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