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

In the paper

“Interestingly, AD cybrid Aβ levels also increased.”

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].”

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

In the paper

“NAD+/NADH ratios in AD and MCI cybrids were lower than they were in control cybrids”

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].”

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

In the paper

“This was despite the fact that AD and MCI respiration was relatively uncoupled, or less efficient, than control cybrid respiration.”

In the paper

“The AD and MCI lines showed reduced basal oxygen consumption, which suggests reduced respiratory flux.”

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

In the paper

“AD and MCI cybrid glycolysis fluxes were also relatively lower”

In the paper

“Mean COX activity was lower in subjects with AD-affected mothers than it was in the other two groups.”

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

In the paper

“Among 27 individuals in which the exons of each COX gene were sequenced, no two individuals exhibited an identical composite genotype.”

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

In the paper

“First, the mitochondrial cascade hypothesis maintains gene inheritance defines an individual's baseline mitochondrial function.”

In the paper

“Those with low baseline function and fast rates of mitochondrial decline will develop symptoms and AD histology changes at younger ages than those with high baseline function and slow rates of mitochondrial decline.”

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.”

In the paper

“and argues if an amyloid cascade truly exists, mitochondrial function triggers it.”

In the paper

“In autosomal dominant AD, changes in APP or its processing will prove critical.”

In the paper

“Those with less extreme combinations, for example those with low baseline function and slow rates of mitochondrial decline, or with high baseline function and fast rates of mitochondrial decline, will develop symptoms and AD histology changes at intermediate ages.”

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.”

In the paper

“Third, an individual's baseline mitochondrial function and functional change rate influences their AD chronology.”

In the paper

“Second, inherited and environmental factors determine the rate at which age-associated mitochondrial changes develop and manifest.”

In the paper

“AD and MCI cybrid cell lines successfully model numerous pathologies observed in AD and MCI subject brains (Table 1).”

In the paper

“This suggests that compared to cognitively intact individuals, individuals in the earliest clinically detectable stage of AD already show reduced mitochondrial function.”

In the paper

“First, in AD and MCI cybrids the observed changes most likely arise from changes in mitochondrial function.”

In the paper

“this probably reflects compromised respiratory function.”

In the paper

“Therefore, two types of brain aging likely exist, compensated brain aging and uncompensated brain aging.”

In the paper

“In aggregate, AD subject brains and blood cells contain less PCR-amplifiable mtDNA [47, 105, 109-111].”

What the sources say

• Not checked yetcites [47] Hirai K Aliev G Nunomura A Fujioka H Russell RL Atwood CS Johnson AB Kress Y Vinters HV Tabaton M Shimohama S Cash AD Siedlak SL Harris PL Jones PK Petersen RB Perry G Smith MA Mitochondrial abnormalities in Alzheimer's disease J Neurosci 2001 21 3017 3023 11312286 PMC6762571 source
• Not checked yetcites [105] de la Monte SM Luong T Neely TR Robinson D Wands JR Mitochondrial DNA damage as a mechanism of cell loss in Alzheimer's disease Laboratory investigation; a journal of technical methods and pathology 2000 80 1323 1335 10950123 source
• Not checked yetcites [109] Brown AM Sheu RK Mohs R Haroutunian V Blass JP Correlation of the clinical severity of Alzheimer's disease with an aberration in mitochondrial DNA (mtDNA) Journal of molecular neuroscience: MN 2001 16 41 48 11345519 source
• Not checked yetcites [110] Davis RE Miller S Herrnstadt C Ghosh SS Fahy E Shinobu LA Galasko D Thal LJ Beal MF Howell N Parker WD Jr. Mutations in mitochondrial cytochrome c oxidase genes segregate with late-onset Alzheimer disease Proc Natl Acad Sci U S A 1997 94 4526 4531 9114023 PMC20756 source
• Not checked yetcites [111] Rodriguez-Santiago B Casademont J Nunes V Is mitochondrial DNA depletion involved in Alzheimer's disease? European journal of human genetics: EJHG 2001 9 279 285 11313772 source

In the paper

“MtDNA from AD subject brains exhibits excess oxidative damage and deletions [47, 102-105].”

What the sources say

• Not checked yetcites [47] Hirai K Aliev G Nunomura A Fujioka H Russell RL Atwood CS Johnson AB Kress Y Vinters HV Tabaton M Shimohama S Cash AD Siedlak SL Harris PL Jones PK Petersen RB Perry G Smith MA Mitochondrial abnormalities in Alzheimer's disease J Neurosci 2001 21 3017 3023 11312286 PMC6762571 source
• Not checked yetcites [102] Mecocci P MacGarvey U Beal MF Oxidative damage to mitochondrial DNA is increased in Alzheimer's disease Ann Neurol 1994 36 747 751 7979220 source
• Not checked yetcites [103] Corral-Debrinski M Horton T Lott MT Shoffner JM McKee AC Beal MF Graham BH Wallace DC Marked changes in mitochondrial DNA deletion levels in Alzheimer brains Genomics 1994 23 471 476 7835898 source
• Not checked yetcites [104] Hamblet NS Castora FJ Elevated levels of the Kearns-Sayre syndrome mitochondrial DNA deletion in temporal cortex of Alzheimer's patients Mutat Res 1997 379 253 262 9357554 source
• Not checked yetcites [105] de la Monte SM Luong T Neely TR Robinson D Wands JR Mitochondrial DNA damage as a mechanism of cell loss in Alzheimer's disease Laboratory investigation; a journal of technical methods and pathology 2000 80 1323 1335 10950123 source

In the paper

“Based on this, we concluded mtDNA at least partly determines low COX activity in AD.”

In the paper

“the mitochondria used to generate these cybrid lines derive not from subject brains, but from subject platelets, which implies mitochondrial dysfunction in AD and MCI subjects exists independent of Aβ or neurodegeneration.”

In the paper

“According to our hypothesis, symptomatic AD coincides temporally with the stage of uncompensated brain aging.”

In the paper

“This study found that cognitively normal, middle-aged children of AD mothers, but not AD fathers, show reduced cerebral glucose utilization on fluorodeoxyglucose positron emission tomography (FDG PET).”

What the sources say

• Not checked yetcites [129] Mosconi L Brys M Switalski R Mistur R Glodzik L Pirraglia E Tsui W De Santi S de Leon MJ Maternal family history of Alzheimer's disease predisposes to reduced brain glucose metabolism Proc Natl Acad Sci U S A 2007 104 19067 19072 18003925 PMC2141909 source

In the paper

“from a strict association perspective it does appear that the TOMM40 gene, and by extension its protein product, could potentially impact LOAD.”

What the sources say

• Not checked yetcites [143] Roses AD An inherited variable poly-T repeat genotype in TOMM40 in Alzheimer disease Arch Neurol 2010 67 536 541 20457951 PMC3140162 source
• Not checked yetcites [144] Caselli RJ Dueck AC Huentelman MJ Lutz MW Saunders AM Reiman EM Roses AD Longitudinal modeling of cognitive aging and the TOMM40 effect Alzheimers Dement 2012 8 490 495 23102119 PMC3483561 source
• Not checked yetcites [145] Maruszak A Peplonska B Safranow K Chodakowska-Zebrowska M Barcikowska M Zekanowski C TOMM40 rs10524523 polymorphism's role in late-onset Alzheimer's disease and in longevity J Alzheimers Dis 2012 28 309 322 22008263 source
• Not checked yetcites [146] Hayden KM McEvoy JM Linnertz C Attix D Kuchibhatla M Saunders AM Lutz MW Welsh-Bohmer KA Roses AD Chiba-Falek O A homopolymer polymorphism in the TOMM40 gene contributes to cognitive performance in aging Alzheimers Dement 2012 8 381 388 22863908 PMC3438346 source
• Not checked yetcites [147] Johnson SC La Rue A Hermann BP Xu G Koscik RL Jonaitis EM Bendlin BB Hogan KJ Roses AD Saunders AM Lutz MW Asthana S Green RC Sager MA The effect of TOMM40 poly-T length on gray matter volume and cognition in middle-aged persons with APOE epsilon3/epsilon3 genotype Alzheimers Dement 2011 7 456 465 21784354 PMC3143375 source
• Not checked yetcites [148] Potkin SG Guffanti G Lakatos A Turner JA Kruggel F Fallon JH Saykin AJ Orro A Lupoli S Salvi E Weiner M Macciardi F Hippocampal atrophy as a quantitative trait in a genome-wide association study identifying novel susceptibility genes for Alzheimer's disease PLoS One 2009 4 e6501 19668339 PMC2719581 source
• Not checked yetcites [149] Beekman M Blanche H Perola M Hervonen A Bezrukov V Sikora E Flachsbart F Christiansen L De Craen AJ Kirkwood TB Rea IM Poulain M Robine JM Valensin S Stazi MA Passarino G Deiana L Gonos ES Paternoster L Sorensen TI Tan Q Helmer Q van den Akker EB Deelen J Martella F Cordell HJ Ayers KL Vaupel JW Tornwall O Johnson TE Schreiber S Lathrop M Skytthe A Westendorp RG Christensen K Gampe J Nebel A Houwing-Duistermaat JJ Slagboom PE Franceschi C Genome-wide linkage analysis for human longevity: Genetics of Healthy Aging Study Aging Cell 2013 12 184 193 23286790 PMC3725963 source
• Not checked yetcites [150] Elias-Sonnenschein LS Helisalmi S Natunen T Hall A Paajanen T Herukka SK Laitinen M Remes AM Koivisto AM Mattila KM Lehtimaki T Verhey FR Visser PJ Soininen H Hiltunen M Genetic loci associated with Alzheimer's disease and cerebrospinal fluid biomarkers in a Finnish case-control cohort PLoS One 2013 8 e59676 23573206 PMC3616106 source
• Not checked yetcites [151] Crenshaw DG Gottschalk WK Lutz MW Grossman I Saunders AM Burke JR Welsh-Bohmer KA Brannan SK Burns DK Roses AD Using genetics to enable studies on the prevention of Alzheimer's disease Clinical pharmacology and therapeutics 2013 93 177 185 23249780 PMC4131283 source
• Not checked yetcites [152] Roses AD Lutz MW Crenshaw DG Grossman I Saunders AM Gottschalk WK TOMM40 and APOE: Requirements for replication studies of association with age of disease onset and enrichment of a clinical trial Alzheimers Dement 2013 9 132 136 23333464 source

In the paper

“Maternal inheritance appears to determine several AD endophenotypes.”

What the sources say

• Not checked yetcites [129] Mosconi L Brys M Switalski R Mistur R Glodzik L Pirraglia E Tsui W De Santi S de Leon MJ Maternal family history of Alzheimer's disease predisposes to reduced brain glucose metabolism Proc Natl Acad Sci U S A 2007 104 19067 19072 18003925 PMC2141909 source
• 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
• Not checked yetcites [131] Mosconi L Berti V Swerdlow RH Pupi A Duara R de Leon M Maternal transmission of Alzheimer's disease: prodromal metabolic phenotype and the search for genes Hum Genomics 2010 4 170 193 20368139 PMC3033750 source
• Not checked yetcites [132] Mosconi L Glodzik L Mistur R McHugh P Rich KE Javier E Williams S Pirraglia E De Santi S Mehta PD Zinkowski R Blennow K Pratico D de Leon MJ Oxidative stress and amyloid-beta pathology in normal individuals with a maternal history of Alzheimer's Biol Psychiatry 2010 68 913 921 20817151 PMC2967599 source
• Not checked yetcites [133] Mosconi L Mistur R Switalski R Brys M Glodzik L Rich K Pirraglia E Tsui W De Santi S de Leon MJ Declining brain glucose metabolism in normal individuals with a maternal history of Alzheimer disease Neurology 2009 72 513 520 19005175 PMC2677512 source
• Not checked yetcites [134] Mosconi L Rinne JO Tsui WH Berti V Li Y Wang H Murray J Scheinin N Nagren K Williams S Glodzik L De Santi S Vallabhajosula S de Leon MJ Increased fibrillar amyloid-{beta} burden in normal individuals with a family history of late-onset Alzheimer's Proc Natl Acad Sci U S A 2010 107 5949 5954 20231448 PMC2851906 source
• Not checked yetcites [135] Honea RA Swerdlow RH Vidoni E Burns JM Progressive regional atrophy in normaladults with a maternal history of Alzheimer disease Neurology 2011 76 822 829 21357834 PMC3053329 source
• Not checked yetcites [136] Honea RA Swerdlow RH Vidoni ED Goodwin J Burns JM Reduced gray matter volume in normal adults with a maternal family history of Alzheimer disease Neurology 2010 74 113 120 20065246 PMC2809030 source
• Not checked yetcites [137] Honea RA Vidoni ED Swerdlow RH Burns JM Maternal family history is associated with Alzheimer's disease biomarkers J Alzheimers Dis 2012 31 659 668 22669011 PMC3608420 source
• Not checked yetcites [138] Andrawis JP Hwang KS Green AE Kotlerman J Elashoff D Morra JH Cummings JL Toga AW Thompson PM Apostolova LG Effects of ApoE4 and maternal history of dementia on hippocampal atrophy Neurobiology of aging 2012 33 856 866 20833446 PMC3010297 source

In the paper

“Maternal inheritance, therefore, also associates with a systemic biochemical endophenotype.”

In the paper

“The APOE gene product, interestingly, also appears to influence mitochondrial function [164-167].”

What the sources say

• Not checked yetcites [164] Chang S ran Ma T Miranda RD Balestra ME Mahley RW Huang Y Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity Proc Natl Acad Sci U S A 2005 102 18694 18699 16344479 PMC1311737 source
• Not checked yetcites [165] Mahley RW Huang Y Apolipoprotein e sets the stage: response to injury triggers neuropathology Neuron 2012 76 871 885 23217737 PMC4891195 source
• Not checked yetcites [166] Chen HK Ji ZS Dodson SE Miranda RD Rosenblum CI Reynolds IJ Freedman SB Weisgraber KH Huang Y Mahley RW Apolipoprotein E4 domain interaction mediates detrimental effects on mitochondria and is a potential therapeutic target for Alzheimer disease J Biol Chem 2011 286 5215 5221 21118811 PMC3037634 source
• Not checked yetcites [167] Nakamura T Watanabe A Fujino T Hosono T Michikawa M Apolipoprotein E4 (1-272) fragment is associated with mitochondrial proteins and affects mitochondrial function in neuronal cells Mol Neurodegener 2009 4 35 19695092 PMC2739857 source

In the paper

“Data also argue mitochondria directly influence other AD-associated pathologies, and particularly APP and Aβ homeostasis.”

What the sources say

• Not checked yetcites [49] 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
• Not checked yetcites [50] 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
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• Not checked yetcites [52] Khan SM Cassarino DS Abramova NN Keeney PM Borland MK Trimmer PA Krebs CT Bennett JC Parks JK Swerdlow RH Parker WD Jr. Bennett JP Jr. Alzheimer's disease cybrids replicate beta-amyloid abnormalities through cell death pathways Annals of neurology 2000 48 148 155 10939564 source
• Not checked yetcites [172] Onyango IG Ahn JY Tuttle JB Bennett JP Jr. Swerdlow RH Nerve growth factor attenuates oxidant-induced beta-amyloid neurotoxicity in sporadic Alzheimer's disease cybrids J Neurochem 2010 114 1605 1618 20561151 source

In the paper

“Polymorphisms in other nuclear genes, for example transcription factor A of the mitochondria (TFAM), associate with AD risk in some studies [168-170].”

What the sources say

• Not checked yetcites [168] Alvarez V Corao AI Alonso-Montes C Sanchez-Ferrero E De Mena L Morales B Garcia-Castro M Coto E Mitochondrial transcription factor A (TFAM) gene variation and risk of late-onset Alzheimer's disease J Alzheimers Dis 2008 13 275 280 18430995 source
• Not checked yetcites [169] Belin AC Bjork BF Westerlund M Galter D Sydow O Lind C Pernold K Rosvall L Hakansson A Winblad B Nissbrandt H Graff C Olson L Association study of two genetic variants in mitochondrial transcription factor A (TFAM) in Alzheimer's and Parkinson's disease Neurosci Lett 2007 420 257 262 17537576 source
• Not checked yetcites [170] Gunther C von Hadeln K Muller-Thomsen T Alberici A Binetti G Hock C Nitsch RM Stoppe G Reiss J Gal A Finckh U Possible association of mitochondrial transcription factor A (TFAM) genotype with sporadic Alzheimer disease Neurosci Lett 2004 369 219 223 15464268 source

In the paper

“The mitochondrial cascade hypothesis, on the other hand, does not assume Aβ drives the other biomarker changes.”

In the paper

“Recent data indicate plaque deposition essentially occurs during the run-up to clinical AD [216, 217].”

What the sources say

• Not checked yetcites [216] Burns JM Swerdlow RH Backwaters and rapids on the amyloid river Neurology 2013 80 878 879 23446682 source
• 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

In the paper

“According to our hypothesis, Aβ deposition temporally coincides with an asymptomatic stage of compensated brain aging”

In the paper

“we believe it makes sense to view Aβ biomarkers primarily as biomarkers of brain aging.”

In the paper

“Also, emerging data from FDG PET and cerebral perfusion studies show glucose utilization and cerebral blood flow may regionally increase around the time that plaque deposition begins [221, 222].”

What the sources say

• Not checked yetcites [221] Schultz A McLaren D Chhatwal J Evans K K. J Sperling R Increased cerebral blood flow in cognitively normal older adults with amyloid Alzheimer Dement 2013 3 089
• Not checked yetcites [222] Oh H Madison C Baker S Jagust WJ Region-specific associations of brain glucose metabolism with age and beta-amyloid deposition in normal aging. Alzheimer Dement 2013 2 129

In the paper

“Our hypothesis, therefore, can accommodate a growing realization that for many subjects with suspected AD, or who have an increased risk of developing AD, what are currently considered downstream biomarker changes potentially precede upstream biomarker changes [206-213].”

What the sources say

• Not checked yetcites [206] Knopman DS Jack CR Jr. Wiste HJ Weigand SD Vemuri P Lowe VJ Kantarci K Gunter JL Senjem ML Mielke MM Roberts RO Boeve BF Petersen RC Brain injury biomarkers are not dependent on beta-amyloid in normal elderly Ann Neurol 2012 PMC3660408 23424032 source
• Not checked yetcites [207] Chetelat G Alzheimer disease: Abeta-independent processes-rethinking preclinical AD Nat Rev Neurol 2013 9 123 124 23399647 PMC3935395 source
• Not checked yetcites [208] 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
• Not checked yetcites [209] Reiman EM Caselli RJ Yun LS Chen K Bandy D Minoshima S Thibodeau SN Osborne D Preclinical evidence of Alzheimer's disease in persons homozygous for the epsilon 4 allele for apolipoprotein E N Engl J Med 1996 334 752 758 8592548 source
• Not checked yetcites [210] Small GW Mazziotta JC Collins MT Baxter LR Phelps ME Mandelkern MA Kaplan A La Rue A Adamson CF Chang L Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease JAMA 1995 273 942 947 7884953 source
• Not checked yetcites [211] Wirth M Madison CM Rabinovici GD Oh H Landau SM Jagust WJ Alzheimer's disease neurodegenerative biomarkers are associated with decreased cognitive function but not beta-amyloid in cognitively normal older individuals J Neurosci 2013 33 5553 5563 23536070 PMC3687777 source
• Not checked yetcites [212] Jack CR Jr. Knopman DS Weigand SD Wiste HJ Vemuri P Lowe V Kantarci K Gunter JL Senjem ML Ivnik RJ Roberts RO Rocca WA Boeve BF Petersen RC An operational approach to National Institute on Aging-Alzheimer's Association criteria for preclinical Alzheimer disease Ann Neurol 2012 71 765 775 22488240 PMC3586223 source
• Not checked yetcites [213] Podlesniy P Figueiro-Silva J Llado A Antonell A Sanchez-Valle R Alcolea D Lleo A Molinuevo JL Serra N Trullas R Low cerebrospinal fluid concentration of mitochondrial DNA in preclinical Alzheimer disease Annals of neurology 2013 23794434 source

In the paper

“Lastly, it is worth noting that at least some elements of cognitive decline evolve throughout adulthood [195, 242-245].”

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

In the paper

“data argue symptoms generally manifest only after plaques stop forming (Figure 5) [205, 216, 217].”

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
• Not checked yetcites [216] Burns JM Swerdlow RH Backwaters and rapids on the amyloid river Neurology 2013 80 878 879 23446682 source
• 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

In the paper

“In essence, the mitochondrial cascade hypothesis sees plaque deposition as technically marking one's passage through brain aging, as opposed to one's passage into AD.”

In the paper

“Under the mitochondrial cascade hypothesis, pre-plaque and post-plaque cognitive changes can potentially share a common etiology.”

In the paper

“These changes typically manifest at ages younger than those at which plaque deposition typically begins.”

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

In the paper

“Autopsy studies reveal at the time of death, brains from cognitively normal individuals frequently contain plaques [77, 234-237].”

What the sources say

• Not checked yetcites [77] 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
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In the paper

“The amyloid cascade hypothesis [14, 15], in conjunction with the newly designated preclinical AD category [20], necessarily infers cognitive changes that arise before plaques appear are etiologically unrelated to cognitive changes that arise after plaques appear.”

What the sources say

• Not checked yetcites [14] Hardy J Allsop D Amyloid deposition as the central event in the aetiology of Alzheimer's disease Trends in pharmacological sciences 1991 12 383 388 1763432 source
• Not checked yetcites [15] Hardy JA Higgins GA Alzheimer's disease: the amyloid cascade hypothesis Science (New York, N.Y.) 1992 256 184 185 1566067 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

In the paper

“Further, our hypothesis predicts that even if Aβ-based interventions turn out to benefit FAD patients, benefits may not extrapolate well to LOAD because LOAD and FAD cascades potentially differ.”

In the paper

“For this reason, we believe our hypothesis better accommodates data that argue early adult cognitive markers predict AD risk long before plaques and probably Aβ changes occur [246, 247].”

What the sources say

• Not checked yetcites [246] Snowdon DA Kemper SJ Mortimer JA Greiner LH Wekstein DR Markesbery WR Linguistic ability in early life and cognitive function and Alzheimer's disease in late life. Findings from the Nun Study JAMA 1996 275 528 532 8606473 source
• Not checked yetcites [247] Smyth KA Fritsch T Cook TB McClendon MJ Santillan CE Friedland RP Worker functions and traits associated with occupations and the development of AD Neurology 2004 63 498 503 15304581 source

In the paper

“An alternative design will test Aβ-based interventions in asymptomatic FAD subjects with presenilin 1 mutations, as their age of symptomatic onset is reasonably predictable [259, 260].”

What the sources say

• Not checked yetcites [259] Bateman RJ Xiong C Benzinger TL Fagan AM Goate A Fox NC Marcus DS Cairns NJ Xie X Blazey TM Holtzman DM Santacruz A Buckles V Oliver A Moulder K Aisen PS Ghetti B Klunk WE McDade E Martins RN Masters CL Mayeux R Ringman JM Rossor MN Schofield PR Sperling RA Salloway S Morris JC Clinical and biomarker changes in dominantly inherited Alzheimer's disease N Engl J Med 2012 367 795 804 22784036 PMC3474597 source
• Not checked yetcites [260] Colombia at the centre of preclinical AD research Lancet Neurol 2012 11 567 22710749 source

In the paper

“Trials featuring intravenous infusions of antibodies to Aβ failed to meet their primary endpoints [252].”

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

In the paper

“The fact that the amyloid tap turns itself off before clinical changes appreciably manifest, we feel, also argues against the idea that Aβ perpetuates itself in a prion-like fashion [261].”

What the sources say

• Not checked yetcites [261] Jucker M Walker LC Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders Ann Neurol 2011 70 532 540 22028219 PMC3203752 source

In the paper

“One of these antibodies, which to date has not yet reported any post-hoc evidence of clinical efficacy in its phase 3 trials, appears to reduce plaque burden [253].”

What the sources say

• Not checked yetcites [253] Rinne JO Brooks DJ Rossor MN Fox NC Bullock R Klunk WE Mathis CA Blennow K Barakos J Okello AA Rodriguez Martinez de Liano S Liu E Koller M Gregg KM Schenk D Black R Grundman M 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer's disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study Lancet Neurol 2010 9 363 372 20189881 source

In the paper

“As people meeting preclinical AD criteria may remain cognitively stable for many years [205, 214], these trials will take a long time to complete.”

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
• 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

In the paper

“In one human study, a vaccine to Aβ did reduce plaque burden, a remarkable technical achievement [248, 249].”

What the sources say

• Not checked yetcites [248] Boche D Denham N Holmes C Nicoll JA Neuropathology after active Abeta42 immunotherapy: implications for Alzheimer's disease pathogenesis Acta Neuropathol 2010 120 369 384 20632020 source
• Not checked yetcites [249] Nicoll JA Barton E Boche D Neal JW Ferrer I Thompson P Vlachouli C Wilkinson D Bayer A Games D Seubert P Schenk D Holmes C Abeta species removal after abeta42 immunization J Neuropathol Exp Neurol 2006 65 1040 1048 17086100 source

In the paper

“A drug intended to modify γ secretase activity similarly failed [256].”

What the sources say

• Not checked yetcites [256] Green RC Schneider LS Amato DA Beelen AP Wilcock G Swabb EA Zavitz KH Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial JAMA 2009 302 2557 2564 20009055 PMC2902875 source

In the paper

“γ secretase inhibition, after all, did accelerate cognitive decline [255].”

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

In the paper

“The other did not show a straightforward reduction in plaque burden, but despite this a subsequent alternative analysis argued clinical effects should not be ruled out and called for further studies [254].”

What the sources say

• Not checked yetcites [254] Tayeb HO Murray ED Price BH Tarazi FI Bapineuzumab and solanezumab for Alzheimer's disease: is the ‘amyloid cascade hypothesis’ still alive? Expert opinion on biological therapy 2013 13 1075 1084 23574434 source

In the paper

“We now know from biomarker studies that brain amyloidosis burns itself out before clinical signs and symptoms emerge [217].”

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

In the paper

“While safety concerns caused this trial to terminate prematurely, subsequent clinical analyses were at best unimpressive [250, 251].”

What the sources say

• Not checked yetcites [250] Gilman S Koller M Black RS Jenkins L Griffith SG Fox NC Eisner L Kirby L Rovira MB Forette F Orgogozo JM Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial Neurology 2005 64 1553 1562 15883316 source
• Not checked yetcites [251] Holmes C Boche D Wilkinson D Yadegarfar G Hopkins V Bayer A Jones RW Bullock R Love S Neal JW Zotova E Nicoll JA Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial Lancet 2008 372 216 223 18640458 source

In the paper

“Because Aβ is considered a consequence of brain aging as opposed to the cause of a disease, we predict targeted removal of brain Aβ will only benefit AD patients to the extent Aβ mediates brain damage.”

In the paper

“Accordingly, we believe FAD's unique genetics etiologically distinguishes FAD from LOAD more than it links FAD to LOAD.”

In the paper

“Altering levels of APP and of sAPPα, a growth factor [262], may impact AD more than altering Aβ levels.”

What the sources say

• Not checked yetcites [262] Mattson MP Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives Physiol Rev 1997 77 1081 1132 9354812 source

In the paper

“According to our hypothesis, Aβ marks a continuum between brain aging and AD, as opposed to a unique and age-unrelated event.”

In the paper

“Later on, as mitochondrial dysfunction surpasses a threshold Aβ production and accumulation declines.”

In the paper

“The mitochondrial cascade hypothesis proposes changes in mitochondrial function change Aβ homeostasis.”

In the paper

“We further predict targeted Aβ removal will benefit asymptomatic subjects to the same extent it benefits symptomatic subjects.”

In the paper

“Finally, as we believe mitochondrial dysfunction initiates LOAD, we would instead advocate developing mitochondrial or bioenergetic medicine approaches for the treatment of LOAD [263-266].”

What the sources say

• Not checked yetcites [263] Swerdlow RH Treating neurodegeneration by modifying mitochondria: potential solutions to a “complex” problem Antioxid Redox Signal 2007 9 1591 1603 17663643 source
• Not checked yetcites [264] Swerdlow RH Mitochondrial medicine and the neurodegenerative mitochondriopathies. Pharmaceuticals 2009 2 150 167 21814473 PMC3148068 source
• Not checked yetcites [265] Swerdlow RH Role and treatment of mitochondrial DNA-related mitochondrial dysfunction in sporadic neurodegenerative diseases Current pharmaceutical design 2011 17 3356 3373 21902672 PMC3351798 source
• Not checked yetcites [266] Swerdlow RH Bioenergetic Medicine British journal of pharmacology 2013 PMC3976609 24004341

In the paper

“In general, we feel removing Aβ from the brains of LOAD patients will only help to the extent that Aβ toxicity contributes to LOAD.”

In the paper

“At the etiological level, our hypothesis tends to split rather than lump LOAD and FAD.”

In the paper

“In some ways, therefore, brain aging and LOAD also represent a continuum.”