Brain aging, Alzheimer's disease, and mitochondria

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [22] Goldman WP Morris JC Evidence that age-associated memory impairment is not a normal variant of aging Alzheimer Dis Assoc Disord 2001 15 72 79 11403335
• Not checked yetcites [23] Backman L Jones S Berger AK Laukka EJ Small BJ Cognitive impairment in preclinical Alzheimer's disease: a meta-analysis Neuropsychology 2005 19 520 531 16060827
• Not checked yetcites [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
• Not checked yetcites [25] Jacobs DM Sano M Dooneief G Marder K Bell KL Stern Y Neuropsychological detection and characterization of preclinical Alzheimer's disease Neurology 1995 45 957 962 7746414 source
• Not checked yetcites [26] Masur DM Sliwinski M Lipton RB Blau AD Crystal HA Neuropsychological prediction of dementia and the absence of dementia in healthy elderly persons Neurology 1994 44 1427 1432 8058143 source
• Not checked yetcites [27] Morris JC Storandt M Miller JP McKeel DW Price JL Rubin EH Berg L Mild cognitive impairment represents early-stage Alzheimer disease Arch Neurol 2001 58 397 405 11255443
• Not checked yetcites [28] Sacuiu S Sjogren M Johansson B Gustafson D Skoog I Prodromal cognitive signs of dementia in 85-year-olds using four sources of information Neurology 2005 65 1894 1900 16380609
• Not checked yetcites [29] Saxton J Lopez OL Ratcliff G Dulberg C Fried LP Carlson MC Newman AB Kuller L Preclinical Alzheimer disease: neuropsychological test performance 1.5 to 8 years prior to onset Neurology 2004 63 2341 2347 15623697 source
• Not checked yetcites [30] Small BJ Fratiglioni L Viitanen M Winblad B Backman L The course of cognitive impairment in preclinical Alzheimer disease: three- and 6-year follow-up of a population-based sample Arch Neurol 2000 57 839 844 10867781 source

In the paper

“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.”

What the sources say

• Not checked yetcites [15] 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 [16] Borson S Cognition, aging, and disabilities: conceptual issues Phys Med Rehabil Clin N Am 2010 21 375 382 20494283 PMC2876094 source
• Not checked yetcites [17] Folstein M Folstein S Functional expressions of the aging brain Nutr Rev 2010 68 Suppl 2 S70 S73 21091951 source
• Not checked yetcites [18] Salthouse TA Memory aging from 18 to 80 Alzheimer Dis Assoc Disord 2003 17 162 167 14512830

In the paper

“These neuroimaging studies show advancing age and prefrontal cortical atrophy positively correlate, while hippocampal volumes change to a lesser extent.”

What the sources say

• Not checked yetcites [15] Hedden T Gabrieli JD Insights into the ageing mind: a view from cognitive neuroscience Nat Rev Neurosci 2004 5 87 96 14735112 source

In the paper

“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].”

What the sources say

• Not checked yetcites [57] Braak H Braak E Staging of Alzheimer's disease-related neurofibrillary changes Neurobiol Aging 1995 16 271 278 discussion 278-284 7566337

In the paper

“Electron transport chain function declines, while free radical production increases.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“Several studies report mitochondrial DNA (mtDNA) mutation can initiate aging, or at least accelerate the progression of age-associated phenotypes [108, 109].”

What the sources say

• Not checked yetcites [108] Trifunovic A Wredenberg A Falkenberg M Spelbrink JN Rovio AT Bruder CE Bohlooly YM Gidlof S Oldfors A Wibom R Tornell J Jacobs HT Larsson NG Premature ageing in mice expressing defective mitochondrial DNA polymerase Nature 2004 429 417 423 15164064 source
• Not checked yetcites [109] Kujoth GC Hiona A Pugh TD Someya S Panzer K Wohlgemuth SE Hofer T Seo AY Sullivan R Jobling WA Morrow JD Van Remmen H Sedivy JM Yamasoba T Tanokura M Weindruch R Leeuwenburgh C Prolla TA Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging Science 2005 309 481 484 16020738 source

In the paper

“Soluble interstitial Aβ levels fall in the setting of trauma-induced coma, and rising levels signal clinical recovery [137].”

What the sources say

• Not checked yetcites [137] Brody DL Magnoni S Schwetye KE Spinner ML Esparza TJ Stocchetti N Zipfel GJ Holtzman DM Amyloid-beta dynamics correlate with neurological status in the injured human brain Science 2008 321 1221 1224 18755980 PMC2577829 source

In the paper

“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.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“Oxidative stress markers also increase in the aging brain. This manifests in the form of protein carbonylation, lipid oxidation, and mtDNA oxidation [117].”

What the sources say

• Not checked yetcites [117] Boveris A Navarro A Brain mitochondrial dysfunction in aging IUBMB Life 2008 60 308 314 18421773 source

In the paper

“Young adult APOE4 carriers, who also have an increased AD risk, have lower posterior cingulate COX activities than young adult non-APOE4 carriers [133].”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“Spectrophotometric analysis of the holoenzyme reveals the absence of its high affinity cytochrome c binding site and an altered Km [129].”

What the sources say

• Not checked yetcites [129] Parker WD Jr Parks JK Cytochrome c oxidase in Alzheimer’s disease brain: purification and characterization Neurology 1995 45 482 486 7898701

In the paper

“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].”

What the sources say

• Not checked yetcites [95] Gabuzda D Busciglio J Chen LB Matsudaira P Yankner BA Inhibition of energy metabolism alters the processing of amyloid precursor protein and induces a potentially amyloidogenic derivative J Biol Chem 1994 269 13623 13628 8175797 source
• Not checked yetcites [96] Gasparini L Racchi M Benussi L Curti D Binetti G Bianchetti A Trabucchi M Govoni S Effect of energy shortage and oxidative stress on amyloid precursor protein metabolism in COS cells Neurosci Lett 1997 231 113 117 9291153 source
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [145] Swerdlow RH Pathogenesis of Alzheimer's disease Clin Interv Aging 2007 2 347 359 18044185 PMC2685260

In the paper

“In one study, COX protein was increased in tangle-free neurons, and reduced in tangle-containing neurons [140].”

What the sources say

• Not checked yetcites [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

In the paper

“Large numbers of elderly individuals develop a dementia syndrome and have enough plaques and tangles to qualify for an AD diagnosis [3].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [2] Alzheimer's Association 2011 Alzheimer’s disease facts and figures Alzheimer's and Dementia 2011 7 208 244 21414557
• Not checked yetcites [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
• Not checked yetcites [7] Yaffe K Middleton LE Lui LY Spira AP Stone K Racine C Ensrud KE Kramer JH Mild cognitive impairment, dementia, and their subtypes in oldest old women Arch Neurol 2011 68 631 636 21555638 PMC3108074
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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
• Not checked yetcites [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

In the paper

“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).”

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [147] Swerdlow RH Khan SM A "mitochondrial cascade hypothesis" for sporadic Alzheimer's disease Med Hypotheses 2004 63 8 20 15193340
• Not checked yetcites [148] Swerdlow RH Khan SM The Alzheimer's disease mitochondrial cascade hypothesis: an update Exp Neurol 2009 218 308 315 19416677 PMC2710413

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [147] Swerdlow RH Khan SM A "mitochondrial cascade hypothesis" for sporadic Alzheimer's disease Med Hypotheses 2004 63 8 20 15193340
• Not checked yetcites [148] Swerdlow RH Khan SM The Alzheimer's disease mitochondrial cascade hypothesis: an update Exp Neurol 2009 218 308 315 19416677 PMC2710413

In the paper

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

In the paper

“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.”

In the paper

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

In the paper

“APP processing, though, is a highly regulated event.”

In the paper

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

In the paper

“- New definitions of Alzheimer’s disease infer most very elderly individuals have some form of it.”

In the paper

“- Whether Alzheimer’s disease and brain aging are mechanistically linked is contentious.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [147] Swerdlow RH Khan SM A "mitochondrial cascade hypothesis" for sporadic Alzheimer's disease Med Hypotheses 2004 63 8 20 15193340
• Not checked yetcites [148] Swerdlow RH Khan SM The Alzheimer's disease mitochondrial cascade hypothesis: an update Exp Neurol 2009 218 308 315 19416677 PMC2710413

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [147] Swerdlow RH Khan SM A "mitochondrial cascade hypothesis" for sporadic Alzheimer's disease Med Hypotheses 2004 63 8 20 15193340
• Not checked yetcites [148] Swerdlow RH Khan SM The Alzheimer's disease mitochondrial cascade hypothesis: an update Exp Neurol 2009 218 308 315 19416677 PMC2710413

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [147] Swerdlow RH Khan SM A "mitochondrial cascade hypothesis" for sporadic Alzheimer's disease Med Hypotheses 2004 63 8 20 15193340
• Not checked yetcites [148] Swerdlow RH Khan SM The Alzheimer's disease mitochondrial cascade hypothesis: an update Exp Neurol 2009 218 308 315 19416677 PMC2710413