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The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives
Open accessAbstract
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.
Overview
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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.
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In the paper
“Interestingly, AD cybrid Aβ levels also increased.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 3. Support for the Hypothesis
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“Mean COX activity was lower in cybrid lines containing AD subject mtDNA than it was in cybrid lines containing control subject mtDNA [90, 91].”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 3. Support for the Hypothesis
What the sources say
- Not checked yetcites [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 yetcites [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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“NAD+/NADH ratios in AD and MCI cybrids were lower than they were in control cybrids”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 3. Support for the Hypothesis
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In the paper
“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].”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 3. Support for the Hypothesis
What the sources say
- Not checked yetcites [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 yetcites [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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This was despite the fact that AD and MCI respiration was relatively uncoupled, or less efficient, than control cybrid respiration.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 3. Support for the Hypothesis
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“The AD and MCI lines showed reduced basal oxygen consumption, which suggests reduced respiratory flux.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 3. Support for the Hypothesis
What the sources say
- Not checked yetcites [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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“AD and MCI cybrid glycolysis fluxes were also relatively lower”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 3. Support for the Hypothesis
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“Mean COX activity was lower in subjects with AD-affected mothers than it was in the other two groups.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 3. Support for the Hypothesis
What the sources say
- Not checked yetcites [142] Mosconi L de Leon M Murray J E L Lu J Javier E McHugh P Swerdlow RH mitochondria Reduced cytochrome oxidase activity in adult children of mothers with Alzheimer's disease J Alzheimers Dis 2011 27 483 490 21841246 PMC3291954 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“Among 27 individuals in which the exons of each COX gene were sequenced, no two individuals exhibited an identical composite genotype.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 3. Support for the Hypothesis
What the sources say
- Not checked yetcites [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
Strength:plain· not yet calibratedn = 27Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“First, the mitochondrial cascade hypothesis maintains gene inheritance defines an individual's baseline mitochondrial function.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 2. The Mitochondrial Cascade Hypothesis: Basis and Overview
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclear
- It may state two separate claims as one. 37
- Probably not a substantial claim. 10
None of the sources cited for this claim have been checked yet.
In the paper
“AD cybrids showed decreased ATP and increased oxidative stress, stress signaling, and apoptosis.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 3. Support for the Hypothesis
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In the paper
“AD cybrid mitochondrial were relatively depolarized, smaller on average, and less able to buffer calcium.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 3. Support for the Hypothesis
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 3. Support for the Hypothesis
What the sources say
- Not checked yetcites [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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In LOAD, age-associated changes in mitochondrial function, which mtDNA may mediate, will prove critical.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 2. The Mitochondrial Cascade Hypothesis: Basis and Overview
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds.
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In the paper
“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].”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 2. The Mitochondrial Cascade Hypothesis: Basis and Overview
What the sources say
- Not checked yetcites [112] Katzman R Alzheimer's disease N Engl J Med 1986 314 964 973 2870433 source
- Not checked yetcites [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
- Not checked yetcites [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
- Not checked yetcites [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 yetcites [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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § 3. Support for the Hypothesis · plain
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our hypothesis unequivocally states in sporadic, late-onset AD, mitochondrial function effects APP expression, APP processing, or Aβ accumulation.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 2. The Mitochondrial Cascade Hypothesis: Basis and Overview
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“then greater mitochondrial durability should associate with slower brain aging and lesser mitochondrial durability should associate with faster brain aging.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 2. The Mitochondrial Cascade Hypothesis: Basis and Overview
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In the paper
“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].”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 2. The Mitochondrial Cascade Hypothesis: Basis and Overview
What the sources say
- Not checked yetcites [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 yetcites [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
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- Not checked yetcites [62] Anandatheerthavarada HK Devi L Amyloid precursor protein and mitochondrial dysfunction in Alzheimer's disease Neuroscientist 2007 13 626 638 17911214 source
- Not checked yetcites [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
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In the paper
“Existing data suggest mitochondrial function declines throughout much of adulthood and that adaptive changes, at least initially, mitigate this decline [47, 80-82].”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 2. The Mitochondrial Cascade Hypothesis: Basis and Overview
What the sources say
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Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Third, AD and MCI cybrid molecular changes persist in culture, thereby suggesting AD and MCI subject mtDNA differs from control subject mtDNA.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 3. Support for the Hypothesis
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 3. Support for the Hypothesis
What the sources say
- Not checked yetcites [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
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Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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].”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 3. Support for the Hypothesis
What the sources say
- Not checked yetcites [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
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In the paper
“Overall, we feel we can confidently state APP and Aβ homeostasis are exquisitely regulated processes, and bioenergetic metabolism regulates these processes.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 3. Support for the Hypothesis
What the sources say
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Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Regional reductions occur during aging, and become more pervasive with MCI and AD [195, 196].”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 4. Biomarker Data: Relationships and Implications
What the sources say
- Not checked yetcites [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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Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Relative to control subjects, MCI and AD subjects typically show low CSF Aβ, high total tau, and high phosphorylated tau levels [201, 202].”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 4. Biomarker Data: Relationships and Implications
What the sources say
- Not checked yetcites [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 yetcites [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
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Regional reductions in brain glucose utilization occur with aging and to a greater extent in MCI and AD [185-193].”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 4. Biomarker Data: Relationships and Implications
What the sources say
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- Not checked yetcites [188] Chetelat G Landeau B Salmon E Yakushev I Bahri MA Mezenge F Perrotin A Bastin C Manrique A Scheurich A Scheckenberger M Desgranges B Eustache F Fellgiebel A Relationships between brain metabolism decrease in normal aging and changes in structural and functional connectivity Neuroimage 2013 76 167 177 23518010 source
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- Not checked yetcites [190] Kantarci K Senjem ML Lowe VJ Wiste HJ Weigand SD Kemp BJ Frank AR Shiung MM Boeve BF Knopman DS Petersen RC Jack CR Jr. Effects of age on the glucose metabolic changes in mild cognitive impairment AJNR Am J Neuroradiol 2010 31 1247 1253 20299441 PMC2890033 source
- Not checked yetcites [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
- Not checked yetcites [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
- Not checked yetcites [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
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Glucose utilization and synaptic density directly correlate, so to some extent FDG PET reflects synaptic integrity [194].”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 4. Biomarker Data: Relationships and Implications
What the sources say
- Not checked yetcites [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
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 4. Biomarker Data: Relationships and Implications
What the sources say
- Not checked yetcites [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
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Finally, we predict falling Aβ CSF levels reflect falling Aβ production more than it reflects decreased solubility or increased incorporation into plaques.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 4. Biomarker Data: Relationships and Implications
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 4. Biomarker Data: Relationships and Implications
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 4. Biomarker Data: Relationships and Implications
What the sources say
- Not checked yetcites [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
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As bioenergetic stress worsens, the brain shifts from a state of bioenergetic hypermetabolism to one of hypometabolism, and Aβ production falls.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 4. Biomarker Data: Relationships and Implications
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 4. Biomarker Data: Relationships and Implications
What the sources say
- Not checked yetcites [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 yetcites [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
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Under conditions of mild bioenergetic stress the brain become relatively hypermetabolic. Bioenergetic hypermetabolism, in turn, increases Aβ production.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 4. Biomarker Data: Relationships and Implications
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 4. Biomarker Data: Relationships and Implications
What the sources say
- Not checked yetcites [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 yetcites [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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 4. Biomarker Data: Relationships and Implications
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“one literature- based analysis concludes 85% of those over 85 meet at least one of the new AD criteria [26].”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 5. New AD Definitions: Relationships and Implications
What the sources say
- Not checked yetcites [26] Swerdlow RH Brain aging, Alzheimer's disease, and mitochondria Biochimica et biophysica acta 2011 1812 1630 1639 21920438 PMC3210037 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Cognitive speed and multitasking abilities, for example, become less robust with advancing age.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 5. New AD Definitions: Relationships and Implications
What the sources say
- Not checked yetcites [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 yetcites [242] Borson S Cognition, aging, and disabilities: conceptual issues Phys Med Rehabil Clin N Am 2010 21 375 382 20494283 PMC2876094 source
- Not checked yetcites [243] Folstein M Folstein S Functional expressions of the aging brain Nutr Rev 2010 68 Suppl 2 S70 73 21091951 source
- Not checked yetcites [244] Eckert MA Slowing down: age-related neurobiological predictors of processing speed Frontiers in neuroscience 2011 5 25 21441995 PMC3061488 source
- Not checked yetcites [245] Salthouse TA Selective review of cognitive aging Journal of the International Neuropsychological Society: JINS 2010 16 754 760 20673381 PMC3637655 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 5. New AD Definitions: Relationships and Implications
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“After all, many with plaques will remain asymptomatic for years or even decades, and perhaps some will never develop symptoms [241].”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 5. New AD Definitions: Relationships and Implications
What the sources say
- Not checked yetcites [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
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“An agent claimed to inhibit Aβ oligomer formation did not meet its primary endpoint and further development was discontinued [257, 258].”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 6. Therapeutic Development: Implications
What the sources say
- Not checked yetcites [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 yetcites [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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“especially since inhibiting β secretase-mediated APP cleavage should change levels of APP and its α secretase-generated sAPPα product.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 6. Therapeutic Development: Implications
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds.
In the paper
“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].”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 6. Therapeutic Development: Implications
What the sources say
- Not checked yetcites [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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 6. Therapeutic Development: Implications
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the presence of a mitochondrial-APP-presenilin nexus suggests drugs that modify this nexus may yet modify AD.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 6. Therapeutic Development: Implications
Tests✓ Asserted: passes✗ Checkable: fails✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may be too vague to check against evidence.
In the paper
“despite the fact these approaches appear to accelerate, not impact, or at best very minimally slow symptomatic subject progression.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 6. Therapeutic Development: Implications
What the sources say
- Not checked yetcites [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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 6. Therapeutic Development: Implications
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Early on, these mitochondrial changes increase Aβ production and cause it to accumulate.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 7. Conclusions
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At the clinical level, it tends to lump rather than split age-associated and AD-associated cognitive changes.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 7. Conclusions
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We believe manipulating mitochondrial function and cell bioenergetic pathways will ultimately achieve this goal.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 7. Conclusions
Tests✓ Asserted: passes✗ Checkable: fails✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. It may be too vague to check against evidence. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The mitochondrial cascade hypothesis sees Aβ as a marker of brain aging, and not AD's singular cause.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 7. Conclusions
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“According to our hypothesis, arresting brain aging will arrest both the development and progression of AD.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 7. Conclusions
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 6. Therapeutic Development: Implications
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearIt may state two separate claims as one.
- 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.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“If correct, we believe, such approaches will benefit both asymptomatic and symptomatic individuals.”
§ The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives > 6. Therapeutic Development: Implications
Tests✓ Asserted: passes✗ Checkable: fails✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may be too vague to check against evidence. It may state two separate claims as one.
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”
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?
In the citing paper
“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
Citations
Cites
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“To better unify and reconcile clinical and amyloid cascade hypothesis-based perspectives, new AD definitions were recently proposed [18-20].”
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“One set of updated criteria, published in 2011, consider Aβ an “upstream” biomarker [20].”
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“Clinically, MCI subjects exhibit objective cognitive deficits or decline, may struggle to complete previously routine activities, but essentially retain independent function [94-96].”
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“Sequence analysis of a candidate gene, the APP gene, in a handful of these familial AD (FAD) kindreds revealed APP mutations [10].”
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BackgroundRole of mitochondrial dysfunction in Alzheimer's disease
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BackgroundInfluentialHigh aggregate burden of somatic mtDNA point mutations in aging and Alzheimer's disease brain
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BackgroundCopper-Dependent Inhibition of Human Cytochrome c Oxidase by a Dimeric Conformer of Amyloid-β1-42
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BackgroundMarked changes in mitochondrial DNA deletion levels in Alzheimer brains
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Brain aging, Alzheimer's disease, and mitochondria
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Analysis of European mitochondrial haplogroups with Alzheimer disease risk
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Germline mitochondrial DNA mutations aggravate ageing and can impair brain development
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Self-citationAβ Species Removal After Aβ 42 Immunization
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Cybrids in Alzheimer's disease: A cellular model of the disease?
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Self-citationNicastrin, Presenilin, APH-1, and PEN-2 Form Active γ-Secretase Complexes in Mitochondria
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Pathogenesis of Alzheimer's disease.
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“We were further impressed by the fact that mitochondrial dysfunction could potentially produce other AD-associated molecular phenomena, such as increased oxidative stress markers [53, 54].”
BackgroundMaternal 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
Brain mitochondrial dysfunction in aging
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“Existing data suggest mitochondrial function declines throughout much of adulthood and that adaptive changes, at least initially, mitigate this decline [47, 80-82].”
BackgroundAltered cerebral energy metabolism in Alzheimer's disease: a PET study.
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Lifespan brain activity, β-amyloid, and Alzheimer's disease
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Plasma Amyloid-β as a Predictor of Dementia and Cognitive Decline
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Low cerebrospinal fluid concentration of mitochondrial DNA in preclinical Alzheimer disease
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The Alzheimer's disease mitochondrial cascade hypothesis: an update
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“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].”
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“The cybrid lines containing AD subject mtDNA, the “AD cybrids”, differed from the control subject-generated “control cybrids” in other ways; results from 18 different AD cybrid studies were recently summarized elsewhere [21].”
BackgroundResultInfluentialSelf-citationPrevalence of Alzheimer’s disease in very elderly people: A prospective neuropathological study
Polvikoski, T., Sulkava, R., Myllykangas, L., Notkola, I.-L., Niinistö, L., Verkkoniemi, A., Kainulainen, K., Kontula, K., Pérez–Tur, J., Hardy, J., et al. (2001) · Neurology · doi:10.1212/wnl.56.12.1690 · Cited by 197
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“To accomplish this we adopted an already existing mitochondria-centric aging theory [68-70], and extended it to possibly explain how aging might account for AD and AD histology.”
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APOE ε2 is associated with intact cognition but increased Alzheimer pathology in the oldest old
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Aβ-independent processes—rethinking preclinical AD
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Brain injury biomarkers are not dependent on β‐amyloid in normal elderly
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Cytoplasmic Inheritance of Chloramphenicol Resistance in Mouse Tissue Culture Cells
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“The cybrid technique, developed in the 1970's [87], assesses mtDNA functional correlates.”
MethodA mitochondrial DNA clone is associated with increased risk for Alzheimer disease.
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Mitochondrial function in brain tissue in primary degenerative dementia
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“Chinnery PF, Taylor GA, Howell N, Andrews RM, Morris CM, Taylor RW, McKeith IG, Perry RH, Edwardson JA, Turnbull DM. Mitochondrial DNA haplogroups and susceptibility to AD and dementia with Lewy bodies.”
BackgroundInfluentialAlzheimer'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
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Slowing down: age-related neurobiological predictors of processing speed
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LIFE EXPECTANCY IN ALZHEIMER'S DISEASE (AD)
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Is aging part of Alzheimer's disease, or is Alzheimer's disease part of aging?
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“The amyloid cascade hypothesis etiologically lumps late-onset AD (LOAD) with FAD, and de-emphasizes potential connections between LOAD and aging [9].”
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Age, sex and laterality effects on cerebral glucose metabolism in healthy adults
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“Existing data suggest mitochondrial function declines throughout much of adulthood and that adaptive changes, at least initially, mitigate this decline [47, 80-82].”
BackgroundDrug development for Alzheimer's disease: where are we now and where are we headed?
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“Additionally, others had already shown mitochondrial dysfunction affects tau phosphorylation [55, 56], and can induce inflammation [57].”
BackgroundInduction of Alzheimer Antigens by an Uncoupler of Oxidative Phosphorylation
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“Additionally, others had already shown mitochondrial dysfunction affects tau phosphorylation [55, 56], and can induce inflammation [57].”
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Neuropathology after active Aβ42 immunotherapy: implications for Alzheimer’s disease pathogenesis
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“We do not yet know exactly how mtDNA in AD and MCI cybrids differs from mtDNA in control cybrids, but differences between AD and control subject mtDNA certainly occur.”
BackgroundInfluentialSelf-citationPeskind, E. R., Li, G., Shofer, J., Quinn, J. F., Kaye, J. A., Clark, C. M., Farlow, M. R., DeCarli, C., Raskind, M. A., Schellenberg, G. D., et al. (2006) · Archives of Neurology · doi:10.1001/archneur.63.7.936 · Cited by 131
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Altered metabolic properties of cultured skin fibroblasts in Alzheimer's disease
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“Chinnery PF, Taylor GA, Howell N, Andrews RM, Morris CM, Taylor RW, McKeith IG, Perry RH, Edwardson JA, Turnbull DM. Mitochondrial DNA haplogroups and susceptibility to AD and dementia with Lewy bodies.”
BackgroundInfluentialMild Cognitive Impairment, Dementia, and Their Subtypes in Oldest Old Women
Yaffe, K. S., Middleton, L. E., Lui, L., Spira, A. P., Stone, K. L., Racine, C. A., Ensrud, K. E., & Kramer, J. H. (2011) · Archives of Neurology · doi:10.1001/archneurol.2011.82 · Cited by 123 · cited 1×
“felt this was necessary because with advancing age AD prevalence and incidence skyrockets [71-75].”
BackgroundA comparison of familial and sporadic Alzheimer's disease
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Worker functions and traits associated with occupations and the development of AD
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An inherited variable poly-T repeat genotype in TOMM40 in Alzheimer disease
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Origin of the distinction between Alzheimer's disease and senile dementia
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“In order to establish AD as a bona fide disease, early criteria excluded patients with senile dementia [2, 7].”
BackgroundJohnson, S. C., La Rue, A., Hermann, B. P., Xu, G., Koscik, R. L., Jonaitis, E. M., Bendlin, B. B., Hogan, K. J., Roses, A. D., Saunders, A. M., et al. (2011) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2010.11.012 · Cited by 112
Reduced gray matter volume in normal adults with a maternal family history of Alzheimer disease
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Self-citationNeuropathological background of twenty-seven centenarian brains
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“AD histology changes are found even more frequently [76-78].”
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“Chinnery PF, Taylor GA, Howell N, Andrews RM, Morris CM, Taylor RW, McKeith IG, Perry RH, Edwardson JA, Turnbull DM. Mitochondrial DNA haplogroups and susceptibility to AD and dementia with Lewy bodies.”
BackgroundInfluentialComprehensive Search for Alzheimer Disease Susceptibility Loci in the APOE Region
Jun, G., Vardarajan, B. N., Buros, J. L., Yu, C., Hawk, M., Dombroski, B. A., Crane, P. K., Larson, E. B., Mayeux, R. P., Haines, J. L., et al. (2012) · Archives of Neurology · doi:10.1001/archneurol.2012.2052 · Cited by 103
Cruchaga, C. (2011) · Archives of Neurology · doi:10.1001/archneurol.2011.155 · Cited by 103
Okonkwo, O. C., Xu, G., Oh, J. M., Dowling, N. M., Carlsson, C. M., Gallagher, C. L., Birdsill, A. C., Palotti, M. L., Wharton, W., Hermann, B. P., et al. (2012) · Cerebral Cortex · doi:10.1093/cercor/bhs381 · Cited by 103
Mitochondrial DNA haplogroups and susceptibility to AD and dementia with Lewy bodies
Chinnery, P. F., Taylor, G. A., Howell, N., Andrews, R. M., Morris, C. M., Taylor, R. W., McKeith, I. G., Perry, R. H., Edwardson, J. A., & Turnbull, D. M. (2000) · Neurology · doi:10.1212/wnl.55.2.302 · Cited by 102
MRI is a sensitive marker of subtle white matter pathology in hypoperfused mice
Holland, P. R., Bastin, M. E., Jansen, M. A., Merrifield, G. D., Coltman, R., Scott, F., Nowers, H., Khallout, K., Marshall, I., Wardlaw, J. M., et al. (2010) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.11.009 · Cited by 102
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 1×
“Mean COX activity was lower in cybrid lines containing AD subject mtDNA than it was in cybrid lines containing control subject mtDNA [90, 91].”
BackgroundProgressive regional atrophy in normal adults with a maternal history of Alzheimer disease
Honea, R. A., Swerdlow, R. H., Vidoni, E. D., & Burns, J. M. (2011) · Neurology · doi:10.1212/wnl.0b013e31820e7b74 · Cited by 99
Self-citationBekris, L. M., Lutz, F., & Yu, C. (2011) · Journal of Human Genetics · doi:10.1038/jhg.2011.123 · Cited by 99
Mosconi, L., de Leon, M., Murray, J., E, L., Lu, J., Javier, E., McHugh, P., & Swerdlow, R. H. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-110866 · Cited by 97
Association between mitochondrial DNA variations and Alzheimer's disease in the ADNI cohort
Lakatos, A., Derbeneva, O. A., Younes, D., Keator, D. B., Bakken, T. E., Lvova, M., Brandon, M. C., Guffanti, G., Reglődi, D., Saykin, A. J., et al. (2010) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.04.031 · Cited by 97
Amyloid precursor protein and mitochondrial dysfunction in Alzheimer's disease
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Mitochondrial haplogroup H and Alzheimer's disease—Is there a connection?
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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
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Cited by
Sorted by citations
Oxidative Stress, Synaptic Dysfunction, and Alzheimer’s Disease
Tönnies, E., & Trushina, E. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-161088 · Cited by 1,750
“The mitochondrial cascade hypothesis states that in sporadic, late-onset AD, loss of mitochondrial function associated with age affects the expression and processing of A PP initiating A accumulation [33].”
BackgroundFang, E. F., Hou, Y., Palikaras, K., Adriaanse, B. A., Kerr, J. S., Yang, B., Lautrup, S., Hasan-Olive, M. M., Caponio, D., Dan, X., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-018-0332-9 · Cited by 1,740
Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
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“The mitochondrial cascade hypothesis proposes that mitochondrial dysfunction is the primary trigger for events leading to sporadic late AD onset [517].”
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Swerdlow, R. H. (2018) · Journal of Alzheimer’s Disease · doi:10.3233/jad-170585 · Cited by 850
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Metadata
- Authors
- Swerdlow, R. H., Burns, J. M., & Khan, S. M.
- Affiliations
- University of Kansas (US)
- Gencia (United States) (US)
- Corresponding author
- Swerdlow, Russell H.
- Venue
- 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)
- 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
- FWCI
- 4.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, 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.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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.
What counts as a claim ›How we measure confidence ›How we check this ›
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