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Cited by 306Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchMitochondrial Function and Pathology

Brain aging, Alzheimer's disease, and mitochondria

Open access
Swerdlow, Russell H.·2011·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
DOI 10.1016/j.bbadis.2011.08.012PMC PMC3210037
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Abstract

The relationship between brain aging and Alzheimer’s disease (AD) is contentious. One view holds AD results when brain aging surpasses a threshold. The other view postulates AD is not a consequence of brain aging. This review discusses this conundrum from the perspective of different investigative lines that have tried to address it, as well as from the perspective of the mitochondrion, an organelle that appears to play a role in both AD and brain aging. Specific issues addressed include the question of whether AD and brain aging should be conceptually lumped or split, the extent to which AD and brain aging potentially share common molecular mechanisms, whether beta amyloid should be primarily considered a marker of AD or simply brain aging, and the definition of AD itself.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that Alzheimer’s disease (AD) and brain aging may be mechanistically linked, with mitochondrial dysfunction as a possible upstream driver of late-onset AD and beta amyloid (Aβ) as a downstream marker. It contrasts this mitochondrial cascade hypothesis with the amyloid cascade hypothesis and notes that new AD criteria classify many elderly individuals with Aβ changes as having preclinical or prodromal AD.

Key findings

  • AD is strongly age-associated: it affects 5.4 million Americans and is estimated to cost $385 billion per year; about 1 in 8 people over 65 is estimated to have AD, 40–50% past age 85 may have it, and some very elderly subgroups surpass 50%.
  • Aβ pathology is common in non-demented elderly: Pittsburgh Compound B PET studies report roughly 20–40% of non-demented elderly are PIB-positive, rising with age, and 65% of those past 80 show PIB retention; plaques and tangles also occur in non-demented individuals.
  • Mitochondrial changes occur in both brain aging and AD: aging shows reduced complex I and complex IV activity with preserved complex II, a 5-kilobase mtDNA deletion increases with age, and mtDNA mutates at approximately 10 times the rate of nuclear DNA; AD shows reduced COX activity in brain, platelets, and fibroblasts, including MCI platelets and young adult APOE4 carriers.
  • The mitochondrial cascade hypothesis proposes that age-related mitochondrial decline promotes brain aging features including Aβ accumulation; when mitochondrial decline surpasses a threshold, compensatory mechanisms fail and late-onset AD ensues, making Aβ a downstream marker rather than an upstream cause.

Methods

  • Narrative review; no primary data, systematic search, or meta-analysis is described.
  • Synthesizes clinical, neuropathological, neuroimaging, biomarker, and mitochondrial/biochemical literature to compare AD and brain aging.
  • Discusses evidence from prior cohorts and models, including PIB PET studies, cybrid cell lines, COX activity measurements, and APP-processing experiments.

Limitations

  • Stated: descriptive and observational studies cannot assign causality, and mechanistic inferences from descriptive observation are described as frequently inaccurate or misleading; biomarker correlation or chronology does not show that one biomarker change drives another.
  • Stated: the mitochondrial cascade hypothesis is a hypothesis and does not address whether Aβ functions as a toxic intermediate in late-onset, non-autosomal dominant AD; it also implies early-onset autosomal dominant and late-onset AD may not share a common etiology.
  • Evident from the text: as a narrative review, it provides no new experimental data and relies on selected cited literature and speculative synthesis rather than a systematic assessment.

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

Integrity signals

Registry

Crossref · 10.1016/j.bbadis.2011.08.012

Cites

152 of 152 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 220 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Alternative pathologies are frequently seen in demented patients with plaques and tangles.

    “Frequently, however, alternative pathologies are also seen in demented patients with plaques and tangles [50–52].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
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  • Findingcitation

    Brains from AD subjects have fewer CA1 neurons than control subjects.

    “Brains from AD subjects have fewer CA1 neurons than control subjects [47].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] West MJ Coleman PD Flood DG Troncoso JC Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease Lancet 1994 344 769 772 7916070 source

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  • Findingcitation

    In brains from cognitively intact subjects, hippocampal CA1 neuron counts do not correlate with age.

    “In brains from cognitively intact subjects, hippocampal CA1 neuron counts do not correlate with age [47–49].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [47] West MJ Coleman PD Flood DG Troncoso JC Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease Lancet 1994 344 769 772 7916070 source

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  • Findingcitation

    The simple presence of plaques and tangles do not distinguish demented from non-demented individuals because brains of non-demented individuals frequently contain plaques and tangles.

    “In addition, the simple presence of plaques and tangles do not distinguish demented from non-demented individuals because brains of non-demented individuals frequently contain plaques and tangles.”
    Quote in the paperSubstantial claim0 of 4 sources checked
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  • Findingcitation

    Hippocampal atrophy is more noticeable in demented subjects with AD than in non-demented subjects.

    “Hippocampal atrophy is more noticeable in demented subjects with AD than it is in non-demented subjects [41].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Frisoni GB Fox NC Jack CR Jr Scheltens P Thompson PM The clinical use of structural MRI in Alzheimer disease Nat Rev Neurol 2010 6 67 77 20139996 PMC2938772 source

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  • Classified as probably not a substantial claim. 14

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    Findingcitation

    Over time, cognitive decline in those with AAMI and AACD tends to progress, the line from no dementia to dementia is frequently crossed, and AD is often diagnosed.

    “Over time, cognitive decline in those with AAMI and AACD tends to progress, the line from no dementia to dementia is frequently crossed, and AD is often diagnosed [3, 22–31].”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [3] Swerdlow RH Is aging part of Alzheimer's disease, or is Alzheimer's disease part of aging? Neurobiol Aging 2007 28 1465 1480 16876913

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    • cites [24] Elias MF Beiser A Wolf PA Au R White RF D'Agostino RB The preclinical phase of alzheimer disease: A 22-year prospective study of the Framingham Cohort Arch Neurol 2000 57 808 813 10867777 source

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    Findingcitation

    Memory encoding, working memory, and processing speed decline with age; semantic knowledge and autobiographical memory tend to remain intact.

    “Memory encoding, working memory (a component of executive function), and processing speed all decline with age. Although this decline probably proceeds throughout adulthood it truly becomes evident after the age of 60. Semantic knowledge and autobiographical memory, on the other hand, tend to remain intact.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [15] 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 [16] Borson S Cognition, aging, and disabilities: conceptual issues Phys Med Rehabil Clin N Am 2010 21 375 382 20494283 PMC2876094 source

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    • cites [17] Folstein M Folstein S Functional expressions of the aging brain Nutr Rev 2010 68 Suppl 2 S70 S73 21091951 source

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    • cites [18] Salthouse TA Memory aging from 18 to 80 Alzheimer Dis Assoc Disord 2003 17 162 167 14512830

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    Findingcitation

    Advancing age positively correlates with prefrontal cortical atrophy, while hippocampal volumes change to a lesser extent.

    “These neuroimaging studies show advancing age and prefrontal cortical atrophy positively correlate, while hippocampal volumes change to a lesser extent.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] 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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    Findingcitation

    Tau phosphorylation is found in the temporal lobe transentorhinal region of young adults and with advancing age spreads to additional regions.

    “Tau phosphorylation, an event believed to precede tangle formation, is actually found in the temporal lobe transentorhinal region of young adults and with advancing age tau phosphorylation anatomically spreads to include additional regions [57].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Braak H Braak E Staging of Alzheimer's disease-related neurofibrillary changes Neurobiol Aging 1995 16 271 278 discussion 278-284 7566337

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    Findingcitation

    Electron transport chain function declines, while free radical production increases with age.

    “Electron transport chain function declines, while free radical production increases.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [106] Lenaz G D'Aurelio M Merlo Pich M Genova ML Ventura B Bovina C Formiggini G Parenti Castelli G Mitochondrial bioenergetics in aging Biochim Biophys Acta 2000 1459 397 404 11004456 source

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    • cites [107] Navarro A Boveris A The mitochondrial energy transduction system and the aging process Am J Physiol Cell Physiol 2007 292 C670 C686 17020935 source

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    Findingcitation

    The percentage of non-demented subjects who are PIB-positive increases with advancing age; the majority of those past 80 years of age (65%) show PIB retention.

    “When analyzed according to age, though, the percentage of non-demented subjects who are PIB-positive increases with advancing age and the majority of those past 80 years of age (65%) show PIB retention [67].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Rowe CC Ellis KA Rimajova M Bourgeat P Pike KE Jones G Fripp J Tochon-Danguy H Morandeau L O'Keefe G Price R Raniga P Robins P Acosta O Lenzo N Szoeke C Salvado O Head R Martins R Masters CL Ames D Villemagne VL Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging Neurobiol Aging 2010 31 1275 1283 20472326 source

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    Findingcitation

    A 115-year-old supercentenarian did not clinically dement during life and her brain on autopsy showed very limited tau pathology and almost no fibrillar Aβ deposition.

    “Exemplifying this is a report of a 115 year-old supercentenarian (a term applied to individuals beyond 110 years of age) who did not clinically dement during life and whose brain, on autopsy, showed very limited tau pathology and almost no fibrillar Aβ deposition [82].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] den Dunnen WF Brouwer WH Bijlard E Kamphuis J van Linschoten K Eggens-Meijer E Holstege G No disease in the brain of a 115-year-old woman Neurobiol Aging 2008 29 1127 1132 18534718 source

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    Findingcitation

    Mitochondrial DNA mutation can initiate aging, or at least accelerate the progression of age-associated phenotypes.

    “Several studies report mitochondrial DNA (mtDNA) mutation can initiate aging, or at least accelerate the progression of age-associated phenotypes [108, 109].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    Findingcitation

    Soluble interstitial Aβ levels fall in the setting of trauma-induced coma, and rising levels signal clinical recovery.

    “Soluble interstitial Aβ levels fall in the setting of trauma-induced coma, and rising levels signal clinical recovery [137].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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  • May combine two claims.

    Findingcitation

    Mitochondrial mass, or parameters related to it, appear to change during brain aging; overall studies suggest that with advancing age mitochondrial mass increases or attempts to increase.

    “Mitochondrial mass, or at least parameters related to it, also appear to change during brain aging. Studies are limited, but overall suggest that with advancing age mitochondrial mass increases or attempts to increase.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [116] 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

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    • cites [111] 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

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    Findingcitation

    Oxidative stress markers increase in the aging brain, manifesting as protein carbonylation, lipid oxidation, and mtDNA oxidation.

    “Oxidative stress markers also increase in the aging brain. This manifests in the form of protein carbonylation, lipid oxidation, and mtDNA oxidation [117].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [117] Boveris A Navarro A Brain mitochondrial dysfunction in aging IUBMB Life 2008 60 308 314 18421773 source

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    Findingcitation

    Young adult APOE4 carriers have an increased AD risk and lower posterior cingulate COX activities than young adult non-APOE4 carriers.

    “Young adult APOE4 carriers, who also have an increased AD risk, have lower posterior cingulate COX activities than young adult non-APOE4 carriers [133].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [133] Valla J Yaari R Wolf AB Kusne Y Beach TG Roher AE Corneveaux JJ Huentelman MJ Caselli RJ Reiman EM Reduced posterior cingulate mitochondrial activity in expired young adult carriers of the APOE epsilon4 allele, the major late-onset Alzheimer's susceptibility gene J Alzheimers Dis 2010 22 307 313 20847408 PMC3124564 source

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  • May combine two claims.

    Findingcitation

    A study catalogued low abundance heteroplasmic mutations in COX1; mutation frequency increased with age; the quantity of COX1 mutations within a given brain correlated inversely with its COX activity.

    “Another study catalogued low abundance heteroplasmic mutations in COX1, a COX subunit gene located on the mtDNA [110]. Multiple mutations were detected and the mutation frequency increased with age. For the most part each individual mutation was present in very low amounts, but the number of mutations seemed to have a cumulative impact as the quantity of COX1 mutations within a given brain correl”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [110] Lin MT Simon DK Ahn CH Kim LM Beal MF High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer's disease brain Hum Mol Genet 2002 11 133 145 11809722

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  • May combine two claims.

    Findingcitation

    Many AD cybrid alterations recapitulate phenomena observed in AD brains and include increased oxidative stress, apoptosis markers, and processing of APP to Aβ.

    “Many of these AD cybrid alterations recapitulate phenomena observed in AD brains and include increased oxidative stress, apoptosis markers, and processing of APP to Aβ [123].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [123] Swerdlow RH Mitochondria and cell bioenergetics: Increasingly recognized components and a possible etiologic cause of Alzheimer’s disease Antioxid Redox Signal 2011 in press PMC3329949 21902597

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    Findingcitation

    Oxidative stress may partly account for mtDNA's relatively high mutation rate; mtDNA acquires mutations at approximately 10 times the rate of nuclear DNA.

    “Oxidative stress may partly account for mtDNA’s relatively high mutation rate; mtDNA acquires mutations at approximately 10 times the rate of nuclear DNA [121].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [121] Mecocci P MacGarvey U Kaufman AE Koontz D Shoffner JM Wallace DC Beal MF Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain Ann Neurol 1993 34 609 616 8215249

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  • May combine two claims.

    Findingcitation

    Age-related mitochondrial changes include a decline in complex I and complex IV activity, with preserved complex II activity.

    “Within the brain, age-related mitochondrial changes include a decline in complex I (NADH:ubiquinone oxidoreductase) and complex IV (cytochrome oxidase; COX) activity, with preserved complex II (succinate dehydrogenase) activity [107].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [107] Navarro A Boveris A The mitochondrial energy transduction system and the aging process Am J Physiol Cell Physiol 2007 292 C670 C686 17020935 source

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    Findingcitation

    Spectrophotometric analysis of the holoenzyme reveals the absence of its high affinity cytochrome c binding site and an altered Km.

    “Spectrophotometric analysis of the holoenzyme reveals the absence of its high affinity cytochrome c binding site and an altered Km [129].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [129] Parker WD Jr Parks JK Cytochrome c oxidase in Alzheimer’s disease brain: purification and characterization Neurology 1995 45 482 486 7898701

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  • May combine two claims.

    Findingcitation

    COX inhibition and ATP depletion both reduced non-amyloidogenic, α secretase-mediated APP processing in cell culture experiments.

    “This was directly demonstrated in cell culture experiments in which COX inhibition and ATP depletion both reduced non-amyloidogenic, α secretase-mediated APP processing [95, 96, 98].”
    Quote in the paperSubstantial claim0 of 3 sources checked
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    • cites [98] Webster MT Pearce BR Bowen DM Francis PT The effects of perturbed energy metabolism on the processing of amyloid precursor protein in PC12 cells J Neural Transm 1998 105 839 853 9869322 source

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  • May combine two claims.

    Findingcitation

    Mutations that potentially increase Aβ, or at least Aβ42, are found in very rare autosomal dominant AD kindreds that mostly develop AD before age 60.

    “Mutations that potentially increase Aβ, or at least its 42 amino acid species (Aβ42), are found in very rare autosomal dominant AD kindreds that mostly develop AD before the age of 60 [145].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [145] Swerdlow RH Pathogenesis of Alzheimer's disease Clin Interv Aging 2007 2 347 359 18044185 PMC2685260

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    Findingcitation

    COX protein was increased in tangle-free neurons, and reduced in tangle-containing neurons.

    “In one study, COX protein was increased in tangle-free neurons, and reduced in tangle-containing neurons [140].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [140] Nagy Z Esiri MM LeGris M Matthews PM Mitochondrial enzyme expression in the hippocampus in relation to Alzheimer-type pathology Acta Neuropathol 1999 97 346 354 10208273

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

    Premisecitation

    Large numbers of elderly individuals develop a dementia syndrome and have enough plaques and tangles to qualify for an AD diagnosis.

    “Large numbers of elderly individuals develop a dementia syndrome and have enough plaques and tangles to qualify for an AD diagnosis [3].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Swerdlow RH Is aging part of Alzheimer's disease, or is Alzheimer's disease part of aging? Neurobiol Aging 2007 28 1465 1480 16876913

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  • May combine two claims.

    Interpretationreasoning

    Reduced CA1 neuron counts associate with dementia, and as long as an aging individual is not demented CA1 neuron counts should remain relatively constant.

    “A more conservative conclusion is that reduced CA1 neuron counts associate with dementia, and as long as an aging individual is not demented CA1 neuron counts should remain relatively constant.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    One in every eight persons over 65 is estimated to have AD; 40-50% past age 85 may have it; in some very elderly subgroups the figure surpasses 50%.

    “One in every eight persons over 65 is estimated to have AD, 40–50% past the age of 85 may have it, and in some very elderly subgroups the figure appears to surpass 50% [2, 6–8].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [2] Alzheimer's Association 2011 Alzheimer’s disease facts and figures Alzheimer's and Dementia 2011 7 208 244 21414557

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    • cites [6] Evans DA Funkenstein HH Albert MS Scherr PA Cook NR Chown MJ Hebert LE Hennekens CH Taylor JO Prevalence of Alzheimer's disease in a community population of older persons Higher than previously reported, JAMA 1989 262 2551 2556 2810583

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    • cites [8] Corrada MM Brookmeyer R Berlau D Paganini-Hill A Kawas CH Prevalence of dementia after age 90: results from the 90+ study Neurology 2008 71 337 343 18596243

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    Premisecitation

    According to some studies, AD incidence and prevalence continuously increases with advancing age, reaching a point where a majority beyond a certain age likely have it.

    “According to some studies its incidence and prevalence continuously increases with advancing age, and appears to reach a point at which a majority of those beyond a certain age likely have it [3, 8, 12].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Swerdlow RH Is aging part of Alzheimer's disease, or is Alzheimer's disease part of aging? Neurobiol Aging 2007 28 1465 1480 16876913

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    • cites [8] Corrada MM Brookmeyer R Berlau D Paganini-Hill A Kawas CH Prevalence of dementia after age 90: results from the 90+ study Neurology 2008 71 337 343 18596243

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    • cites [12] Corrada MM Brookmeyer R Paganini-Hill A Berlau D Kawas CH Dementia incidence continues to increase with age in the oldest old: the 90+ study Ann Neurol 2010 67 114 121 20186856 PMC3385995 source

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

    Premisereasoning

    MCI and AACD criteria overlap; the biggest difference is that AACD implies changes are due to brain aging and of minimal concern, while MCI implies changes are not due to brain aging and are of substantial concern.

    “The biggest difference between these two syndromes is that AACD implies changes are due to brain aging and of minimal concern, while MCI implies changes are not due to brain aging and are of substantial concern (Figure 1).”
    Quote in the paperNot a substantial claim

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    Premisecitation

    According to new AD diagnostic criteria, cognitive decline and absence of alternative dementia-associated pathology are no longer required features; altered brain or CSF Aβ is the sole requirement for a research diagnosis of AD.

    “According to the new AD diagnostic criteria cognitive decline and an absence of alternative dementia-associated pathology are no longer required features. At least for research purposes, to qualify for a diagnosis of AD altered brain or CSF Aβ is now the sole requirement [77].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] 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

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

    Premisenone given

    Basing mechanistic inferences on descriptive observation is notoriously unreliable; such inferences are frequently inaccurate and occasionally misleading.

    “Basing mechanistic inferences on descriptive observation is notoriously unreliable; such inferences are frequently inaccurate and occasionally misleading.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Since most young individuals will develop Aβ deposits if they live long enough, almost the entire population that doesn't already have AD is on their way to developing AD.

    “Also, since most young individuals will develop Aβ deposits if they live long enough [9, 54, 79], almost the entire population that doesn’t already have AD is on their way to developing AD [3].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [9] Polvikoski T Sulkava R Rastas S Sutela A Niinisto L Notkola IL Verkkoniemi A Viramo P Juva K Haltia M Incidence of dementia in very elderly individuals: a clinical, neuropathological and molecular genetic study Neuroepidemiology 2006 26 76 82 16352910 source

      Not checked in the free run.

    • cites [54] Arriagada PV Marzloff K Hyman BT Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer's disease Neurology 1992 42 1681 1688 1307688 source

      Not checked in the free run.

    • cites [79] Delaere P He Y Fayet G Duyckaerts C Hauw JJ Beta A4 deposits are constant in the brain of the oldest old: an immunocytochemical study of 20 French centenarians Neurobiol Aging 1993 14 191 194 8487921 source

      Not checked in the free run.

    • cites [3] Swerdlow RH Is aging part of Alzheimer's disease, or is Alzheimer's disease part of aging? Neurobiol Aging 2007 28 1465 1480 16876913

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    According to the new criteria, the primary dividing line between AD and brain aging is the presence or absence of brain or CSF Aβ changes.

    “According to the new criteria, the primary dividing line between AD and brain aging is the presence or absence of brain or CSF Aβ changes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] 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.

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

    Premisecitation

    The new criteria make one critical mechanistic assumption: Aβ is an upstream AD biomarker; other biomarkers including increased CSF tau, CSF phospho-tau, and decreased glucose utilization are downstream.

    “In addition to using Aβ phenomena to distinguish AD from “normal” brain aging, the new criteria make one critical mechanistic assumption. Aβ is identified as an “upstream” AD biomarker [77]. Other biomarkers, including increased CSF tau, CSF phospho-tau, and decreased glucose utilization (as demonstrated by fluorodeoxyglucose PET; FDG PET), are identified as “downstream” biomarkers.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] 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.

  • May combine two claims.

    Interpretationreasoning

    Findings suggest reduced AD COX activity develops either very early in the course of AD, or that low COX activity represents an inherited AD risk factor.

    “Findings such as these suggest reduced AD COX activity develops either very early in the course of AD, or that low COX activity represents an inherited AD risk factor.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    This form of AD is mutation-dependent, not age-related.

    “This form of AD is mutation-dependent, not age-related.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Eventually, a point is reached where adaptive changes are no longer adequate or attempted; at this point neurodegeneration and clinical dementia result, and brain aging segues into AD.

    “Eventually, a point is reached where adaptive changes are no longer adequate or attempted. At this point neurodegeneration and clinical dementia result, and brain aging segues into AD.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [123] Swerdlow RH Mitochondria and cell bioenergetics: Increasingly recognized components and a possible etiologic cause of Alzheimer’s disease Antioxid Redox Signal 2011 in press PMC3329949 21902597

      Not checked in the free run.

    • cites [146] Swerdlow RH Burns JM Khan SM The Alzheimer's disease mitochondrial cascade hypothesis J Alzheimers Dis 2010 20 Suppl 2 S265 S279 20442494 PMC2883665

      Not checked in the free run.

    • cites [147] Swerdlow RH Khan SM A "mitochondrial cascade hypothesis" for sporadic Alzheimer's disease Med Hypotheses 2004 63 8 20 15193340

      Not checked in the free run.

    • cites [148] Swerdlow RH Khan SM The Alzheimer's disease mitochondrial cascade hypothesis: an update Exp Neurol 2009 218 308 315 19416677 PMC2710413

      Not checked in the free run.

    • The authors state this as an assumption: Brain aging and Alzheimer’s disease are mechanistically related.

  • May combine two claims.

    Interpretationreasoning

    Even if anti-Aβ treatments benefit early-onset, autosomal dominant AD patients, this approach may not benefit or only minimally benefit late-onset, non-autosomal dominant AD patients.

    “Also, even if anti-Aβ treatments are ultimately found to meaningfully benefit early-onset, autosomal dominant AD patients, this approach may turn out not to benefit or only minimally benefit late-onset, non-autosomal dominant AD patients.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [123] Swerdlow RH Mitochondria and cell bioenergetics: Increasingly recognized components and a possible etiologic cause of Alzheimer’s disease Antioxid Redox Signal 2011 in press PMC3329949 21902597

      Not checked in the free run.

    • cites [146] Swerdlow RH Burns JM Khan SM The Alzheimer's disease mitochondrial cascade hypothesis J Alzheimers Dis 2010 20 Suppl 2 S265 S279 20442494 PMC2883665

      Not checked in the free run.

    • cites [147] Swerdlow RH Khan SM A "mitochondrial cascade hypothesis" for sporadic Alzheimer's disease Med Hypotheses 2004 63 8 20 15193340

      Not checked in the free run.

    • cites [148] Swerdlow RH Khan SM The Alzheimer's disease mitochondrial cascade hypothesis: an update Exp Neurol 2009 218 308 315 19416677 PMC2710413

      Not checked in the free run.

    • The authors state this as an assumption: Brain aging and Alzheimer’s disease are mechanistically related.

  • May combine two claims.

    Interpretationreasoning

    These changes alter bioenergetic metabolism and would predictably increase Aβ production.

    “These changes alter bioenergetic metabolism and would predictably increase Aβ production.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    A case can be made that similar to non-demented aged subjects, the brains of AD subjects show perturbed mitochondrial function and a subsequent compensatory response; main differences are defects more profound, compensation often inadequate, compensatory responses more likely to break down.

    “A case can be made that similar to what is observed in non-demented aged subjects, the brains of AD subjects show perturbed mitochondrial function and a subsequent compensatory response. Perhaps the main differences are that in AD brains defects are more profound, compensation is often inadequate, and compensatory responses are more likely to simply break down.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    If as stipulated Aβ levels are the primary cause of late-onset AD then other, more upstream events cannot determine Aβ levels.

    “If as stipulated Aβ levels are the primary cause of late-onset AD then other, more upstream events cannot determine Aβ levels.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    APP processing is a highly regulated event.

    “APP processing, though, is a highly regulated event.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    These data imply APP processing is a highly regulated process, and suggest cell bioenergetics at least partly regulate APP processing.

    “These data imply APP processing is a highly regulated process, and suggests cell bioenergetics at least partly regulate APP processing.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    New definitions of Alzheimer's disease infer that most very elderly individuals have some form of it.

    “- New definitions of Alzheimer’s disease infer most very elderly individuals have some form of it.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    Whether Alzheimer's disease and brain aging are mechanistically linked is contentious.

    “- Whether Alzheimer’s disease and brain aging are mechanistically linked is contentious.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted).

    Interpretationcitation

    Aβ accumulation marks this upstream physiologic process.

    “The other paradigm alternatively postulates in late-onset, non-autosomal dominant AD Aβ accumulates because of a more upstream physiologic process, Aβ accumulation marks this upstream process, and reducing Aβ will only benefit patients if Aβ itself also induces neurodysfunction.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [123] Swerdlow RH Mitochondria and cell bioenergetics: Increasingly recognized components and a possible etiologic cause of Alzheimer’s disease Antioxid Redox Signal 2011 in press PMC3329949 21902597

      Not checked in the free run.

    • cites [146] Swerdlow RH Burns JM Khan SM The Alzheimer's disease mitochondrial cascade hypothesis J Alzheimers Dis 2010 20 Suppl 2 S265 S279 20442494 PMC2883665

      Not checked in the free run.

    • cites [147] Swerdlow RH Khan SM A "mitochondrial cascade hypothesis" for sporadic Alzheimer's disease Med Hypotheses 2004 63 8 20 15193340

      Not checked in the free run.

    • cites [148] Swerdlow RH Khan SM The Alzheimer's disease mitochondrial cascade hypothesis: an update Exp Neurol 2009 218 308 315 19416677 PMC2710413

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    The mitochondrial cascade hypothesis holds that brain aging and Alzheimer's disease are part of a continuum.

    “An alternative to the amyloid cascade hypothesis [141–143], the mitochondrial cascade hypothesis [123, 146–148], sees brain aging and AD as part of a continuum.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [123] Swerdlow RH Mitochondria and cell bioenergetics: Increasingly recognized components and a possible etiologic cause of Alzheimer’s disease Antioxid Redox Signal 2011 in press PMC3329949 21902597

      Not checked in the free run.

    • cites [146] Swerdlow RH Burns JM Khan SM The Alzheimer's disease mitochondrial cascade hypothesis J Alzheimers Dis 2010 20 Suppl 2 S265 S279 20442494 PMC2883665

      Not checked in the free run.

    • cites [147] Swerdlow RH Khan SM A "mitochondrial cascade hypothesis" for sporadic Alzheimer's disease Med Hypotheses 2004 63 8 20 15193340

      Not checked in the free run.

    • cites [148] Swerdlow RH Khan SM The Alzheimer's disease mitochondrial cascade hypothesis: an update Exp Neurol 2009 218 308 315 19416677 PMC2710413

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted), S4 (based).

    Interpretationreasoning

    Reducing Aβ will only benefit patients if Aβ itself also induces neurodysfunction.

    “The other paradigm alternatively postulates in late-onset, non-autosomal dominant AD Aβ accumulates because of a more upstream physiologic process, Aβ accumulation marks this upstream process, and reducing Aβ will only benefit patients if Aβ itself also induces neurodysfunction.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted).

    Interpretationnone given

    In late-onset, non-autosomal dominant Alzheimer's disease, Aβ accumulates because of a more upstream physiologic process.

    “The other paradigm alternatively postulates in late-onset, non-autosomal dominant AD Aβ accumulates because of a more upstream physiologic process, Aβ accumulation marks this upstream process, and reducing Aβ will only benefit patients if Aβ itself also induces neurodysfunction.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [123] Swerdlow RH Mitochondria and cell bioenergetics: Increasingly recognized components and a possible etiologic cause of Alzheimer’s disease Antioxid Redox Signal 2011 in press PMC3329949 21902597

      Not checked in the free run.

    • cites [146] Swerdlow RH Burns JM Khan SM The Alzheimer's disease mitochondrial cascade hypothesis J Alzheimers Dis 2010 20 Suppl 2 S265 S279 20442494 PMC2883665

      Not checked in the free run.

    • cites [147] Swerdlow RH Khan SM A "mitochondrial cascade hypothesis" for sporadic Alzheimer's disease Med Hypotheses 2004 63 8 20 15193340

      Not checked in the free run.

    • cites [148] Swerdlow RH Khan SM The Alzheimer's disease mitochondrial cascade hypothesis: an update Exp Neurol 2009 218 308 315 19416677 PMC2710413

      Not checked in the free run.

45 of 45

  • The authors state this as an assumption.

    Brain aging and Alzheimer’s disease are mechanistically related.

    “Rather than assuming brain aging and AD are mechanistically divergent phenomena, the mitochondrial cascade hypothesis assumes brain aging and AD are mechanistically related.”
1 of 1

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?

Cites

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5 of the 157 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. White, 2011, Dissonance in diagnoses of dementia type during life with attribution determined at autopsy in the Honolulu-Asia Aging Study; impact of high prevalence of mixed pathology and specificity/non-specificity of clinical manifestations in the very old, Neurology, PL01.002
  2. Rentz, 2006, Amyloid imaging with Pittsburgh Compound-B (PIB) in AD, MCI, and highly intelligent older adults, Neurology, 66, A66

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Related

Authors
Swerdlow, R. H.
Affiliations
University of Kansas (US)
Corresponding author
Swerdlow, Russell H.
ORCID
Swerdlow, Russell H.
Venue
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
Publisher
Elsevier BV
Published
2011-12
Volume
1812
Issue
12
Pages
1630-1639
ISSN
0925-4439 (ISSN-L)
DOI
10.1016/j.bbadis.2011.08.012
PMC
PMC3210037
OpenAlex
W2107600848
Semantic Scholar
27fa4335f66ebc5c5884c9fe5844e2bb4ba32ecb
Cited by
306
References
157
Citations by year
2026: 3 · 2025: 10 · 2024: 17 · 2023: 14 · 2022: 23 · 2021: 27 · 2020: 27 · 2019: 28 · 2018: 26 · 2017: 17 · 2016: 24 · 2015: 17 · 2014: 20 · 2013: 29 · 2012: 22
FWCI
2.50
Type
journal article
Language
en
Open access
Licence
Locations
  • Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • P30AG035982
  • Morgan Family Foundation
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
Alzheimer's disease, brain aging, mitochondria, amyloid-beta, bioenergetic stress, mitochondrial dysfunction, disease definition, molecular mechanisms, threshold hypothesis
MeSH terms
Aging, Alzheimer Disease, Brain, Humans, Mitochondria, Amyloid beta-Peptides

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.

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