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

In the paper

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

In the paper

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

In the paper

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

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

“In LOAD, age-associated changes in mitochondrial function, which mtDNA may mediate, will prove critical.”

In the paper

“In this respect, both mothers and fathers contribute to their offspring's AD risk, but because mitochondrial DNA (mtDNA) is maternally inherited mothers contribute more.”

• Also stated in: § 3. Support for the Hypothesis · plain

  “epidemiologic studies find that although both parents contribute to an individual's AD risk [112], mothers contribute more than fathers [113-116].”

What the sources say

• Not checked yetcites [112] Katzman R Alzheimer's disease N Engl J Med 1986 314 964 973 2870433 source
• Not checked yetcites [113] Edland SD Silverman JM Peskind ER Tsuang D Wijsman E Morris JC Increased risk of dementia in mothers of Alzheimer's disease cases: evidence for maternal inheritance Neurology 1996 47 254 256 8710088 source
• Not checked yetcites [114] Duara R Lopez-Alberola RF Barker WW Loewenstein DA Zatinsky M Eisdorfer CE Weinberg GB A comparison of familial and sporadic Alzheimer's disease Neurology 1993 43 1377 1384 8327141 source
• Not checked yetcites [115] Bassett SS Avramopoulos D Fallin D Evidence for parent of origin effect in late-onset Alzheimer disease Am J Med Genet 2002 114 679 686 12210287 source
• Not checked yetcites [116] Gomez-Tortosa E Barquero MS Baron M Sainz MJ Manzano S Payno M Ros R Almaraz C Gomez-Garre P Jimenez-Escrig A Variability of age at onset in siblings with familial Alzheimer disease Archives of neurology 2007 64 1743 1748 18071037 source

In the paper

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

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

“then greater mitochondrial durability should associate with slower brain aging and lesser mitochondrial durability should associate with faster brain aging.”

In the paper

“accumulating data certainly do suggest APP and Aβ, as well as the entire γ-secretase complex, physically associate with mitochondria and can effect changes in mitochondrial function [58-67].”

What the sources say

• Not checked yetcites [58] Caspersen C Wang N Yao J Sosunov A Chen X Lustbader JW Xu HW Stern D McKhann G Yan SD Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease FASEB J 2005 19 2040 2041 16210396 source
• Not checked yetcites [59] Lustbader JW Cirilli M Lin C Xu HW Takuma K Wang N Caspersen C Chen X Pollak S Chaney M Trinchese F Liu S Gunn-Moore F Lue LF Walker DG Kuppusamy P Zewier ZL Arancio O Stern D Yan SS Wu H ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease Science (New York, N.Y.) 2004 304 448 452 15087549 source
• Not checked yetcites [60] Manczak M Anekonda TS Henson E Park BS Quinn J Reddy PH Mitochondria are a direct site of A beta accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression Human molecular genetics 2006 15 1437 1449 16551656 source
• Not checked yetcites [61] Anandatheerthavarada HK Biswas G Robin MA Avadhani NG Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuronal cells J Cell Biol 2003 161 41 54 12695498 PMC2172865 source
• Not checked yetcites [62] Anandatheerthavarada HK Devi L Amyloid precursor protein and mitochondrial dysfunction in Alzheimer's disease Neuroscientist 2007 13 626 638 17911214 source
• Not checked yetcites [63] Devi L Prabhu BM Galati DF Avadhani NG Anandatheerthavarada HK Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer's disease brain is associated with mitochondrial dysfunction J Neurosci 2006 26 9057 9068 16943564 PMC6675337 source
• Not checked yetcites [64] Crouch PJ Blake R Duce JA Ciccotosto GD Li QX Barnham KJ Curtain CC Cherny RA Cappai R Dyrks T Masters CL Trounce IA Copper-dependent inhibition of human cytochrome c oxidase by a dimeric conformer of amyloid-beta1-42 J Neurosci 2005 25 672 679 15659604 PMC6725334 source
• Not checked yetcites [65] Hansson CA Frykman S Farmery MR Tjernberg LO Nilsberth C Pursglove SE Ito A Winblad B Cowburn RF Thyberg J Ankarcrona M Nicastrin, presenilin, APH-1, and PEN-2 form active gamma-secretase complexes in mitochondria J Biol Chem 2004 279 51654 51660 15456764 source
• Not checked yetcites [66] Hansson Petersen CA Alikhani N Behbahani H Wiehager B Pavlov PF Alafuzoff I Leinonen V Ito A Winblad B Glaser E Ankarcrona M The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae Proc Natl Acad Sci U S A 2008 105 13145 13150 18757748 PMC2527349 source
• Not checked yetcites [67] Teng FY Tang BL Widespread gamma-secretase activity in the cell, but do we need it at the mitochondria? Biochem Biophys Res Commun 2005 328 1 5 15670741 source

In the paper

“Existing data suggest mitochondrial function declines throughout much of adulthood and that adaptive changes, at least initially, mitigate this decline [47, 80-82].”

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 [80] Boveris A Navarro A Brain mitochondrial dysfunction in aging IUBMB Life 2008 60 308 314 18421773 source
• Not checked yetcites [81] Navarro A Boveris A The mitochondrial energy transduction system and the aging process Am J Physiol Cell Physiol 2007 292 C670 686 17020935 source
• Not checked yetcites [82] Barrientos A Casademont J Cardellach F Estivill X Urbano-Marquez A Nunes V Reduced steady-state levels of mitochondrial RNA and increased mitochondrial DNA amount in human brain with aging Brain Res Mol Brain Res 1997 52 284 289 9495550 source

In the paper

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

In the paper

“Subsequent studies found that the cognitively intact children of AD mothers, relative to the cognitively intact children of AD fathers, show greater degrees of age-associated brain atrophy, faster rates of longitudinal brain atrophy, increased Aβ plaque deposition, elevated cerebrospinal fluid (CSF) oxidative stress markers, and AD-like CSF Aβ changes [130-137].”

What the sources say

• Not checked yetcites [130] Berti V Mosconi L Glodzik L Li Y Murray J De Santi S Pupi A Tsui W De Leon MJ Structural brain changes in normal individuals with a maternal history of Alzheimer's Neurobiol Aging 2011 32 2325.e2317 2326 21316814 PMC3115436 source
• 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

In the paper

“These and other data in this section argue inheritance determines an individual's baseline mitochondrial function and durability, and maternal inheritance plays a greater role than paternal inheritance [30].”

What the sources say

• Not checked yetcites [30] Ross JM Stewart JB Hagstrom E Brene S Mourier A Coppotelli G Freyer C Lagouge M Hoffer BJ Olson L Larsson NG Germline mitochondrial DNA mutations aggravate ageing and can impair brain development Nature 2013 PMC3820420 23965628 source

In the paper

“Overall, we feel we can confidently state APP and Aβ homeostasis are exquisitely regulated processes, and bioenergetic metabolism regulates these processes.”

What the sources say

• Not checked yetcites [177] Brody DL Magnoni S Schwetye KE Spinner ML Esparza TJ Stocchetti N Zipfel GJ Holtzman DM Amyloid-beta dynamics correlate with neurological status in the injured human brain Science 2008 321 1221 1224 18755980 PMC2577829 source
• Not checked yetcites [178] Kang JE Lim MM Bateman RJ Lee JJ Smyth LP Cirrito JR Fujiki N Nishino S Holtzman DM Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle Science 2009 326 1005 1007 19779148 PMC2789838 source
• Not checked yetcites [179] Nitsch RM Farber SA Growdon JH Wurtman RJ Release of amyloid beta-protein precursor derivatives by electrical depolarization of rat hippocampal slices Proc Natl Acad Sci U S A 1993 90 5191 5193 8506366 PMC46681 source
• Not checked yetcites [180] Kamenetz F Tomita T Hsieh H Seabrook G Borchelt D Iwatsubo T Sisodia S Malinow R APP processing and synaptic function Neuron 2003 37 925 937 12670422 source
• Not checked yetcites [181] Cirrito JR Yamada KA Finn MB Sloviter RS Bales KR May PC Schoepp DD Paul SM Mennerick S Holtzman DM Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo Neuron 2005 48 913 922 16364896 source
• Not checked yetcites [182] Bero AW Yan P Roh JH Cirrito JR Stewart FR Raichle ME Lee JM Holtzman DM Neuronal activity regulates the regional vulnerability to amyloid-beta deposition Nat Neurosci 2011 14 750 756 21532579 PMC3102784 source
• Not checked yetcites [183] Bateman RJ Wen G Morris JC Holtzman DM Fluctuations of CSF amyloid-beta levels: implications for a diagnostic and therapeutic biomarker Neurology 2007 68 666 669 17325273 source
• Not checked yetcites [184] Jagust WJ Mormino EC Lifespan brain activity, beta-amyloid, and Alzheimer's disease Trends Cogn Sci 2011 15 520 526 21983147 PMC3206968 source

In the paper

“Regional reductions occur during aging, and become more pervasive with MCI and AD [195, 196].”

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

In the paper

“Relative to control subjects, MCI and AD subjects typically show low CSF Aβ, high total tau, and high phosphorylated tau levels [201, 202].”

What the sources say

• Not checked yetcites [201] Blennow K Hampel H Weiner M Zetterberg H Cerebrospinal fluid and plasma biomarkers in Alzheimer disease Nat Rev Neurol 2010 6 131 144 20157306 source
• Not checked yetcites [202] Blennow K Zetterberg H The application of cerebrospinal fluid biomarkers in early diagnosis of Alzheimer disease The Medical clinics of North America 2013 97 369 376 23642576 source

In the paper

“Regional reductions in brain glucose utilization occur with aging and to a greater extent in MCI and AD [185-193].”

What the sources say

• Not checked yetcites [185] De Santi S de Leon MJ Convit A Tarshish C Rusinek H Tsui WH Sinaiko E Wang GJ Bartlet E Volkow N Age-related changes in brain: II. Positron emission tomography of frontal and temporal lobe glucose metabolism in normal subjects The Psychiatric quarterly 1995 66 357 370 8584591 source
• Not checked yetcites [186] Marano CM Workman CI Kramer E Hermann CR Ma Y Dhawan V Chaly T Eidelberg D Smith GS Longitudinal studies of cerebral glucose metabolism in late-life depression and normal aging Int J Geriatr Psychiatry 2013 28 417 423 22740289 PMC3974580 source
• Not checked yetcites [187] Willis MW Ketter TA Kimbrell TA George MS Herscovitch P Danielson AL Benson BE Post RM Age, sex and laterality effects on cerebral glucose metabolism in healthy adults Psychiatry research 2002 114 23 37 11864807 source
• Not checked yetcites [188] Chetelat G Landeau B Salmon E Yakushev I Bahri MA Mezenge F Perrotin A Bastin C Manrique A Scheurich A Scheckenberger M Desgranges B Eustache F Fellgiebel A Relationships between brain metabolism decrease in normal aging and changes in structural and functional connectivity Neuroimage 2013 76 167 177 23518010 source
• Not checked yetcites [189] Kalpouzos G Chetelat G Baron JC Landeau B Mevel K Godeau C Barre L Constans JM Viader F Eustache F Desgranges B Voxel-based mapping of brain gray matter volume and glucose metabolism profiles in normal aging Neurobiol Aging 2009 30 112 124 17630048 source
• Not checked yetcites [190] Kantarci K Senjem ML Lowe VJ Wiste HJ Weigand SD Kemp BJ Frank AR Shiung MM Boeve BF Knopman DS Petersen RC Jack CR Jr. Effects of age on the glucose metabolic changes in mild cognitive impairment AJNR Am J Neuroradiol 2010 31 1247 1253 20299441 PMC2890033 source
• Not checked yetcites [191] Li Y Rinne JO Mosconi L Pirraglia E Rusinek H DeSanti S Kemppainen N Nagren K Kim BC Tsui W de Leon MJ Regional analysis of FDG and PIB-PET images in normal aging, mild cognitive impairment, and Alzheimer's disease European journal of nuclear medicine and molecular imaging 2008 35 2169 2181 18566819 PMC2693402 source
• Not checked yetcites [192] Mosconi L Mistur R Switalski R Tsui WH Glodzik L Li Y Pirraglia E De Santi S Reisberg B Wisniewski T de Leon MJ FDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer's disease European journal of nuclear medicine and molecular imaging 2009 36 811 822 19142633 PMC2774795 source
• Not checked yetcites [193] Scheef L Spottke A Daerr M Joe A Striepens N Kolsch H Popp J Daamen M Gorris D Heneka MT Boecker H Biersack HJ Maier W Schild HH Wagner M Jessen F Glucose metabolism, gray matter structure, and memory decline in subjective memory impairment Neurology 2012 79 1332 1339 22914828 source

In the paper

“Glucose utilization and synaptic density directly correlate, so to some extent FDG PET reflects synaptic integrity [194].”

What the sources say

• Not checked yetcites [194] Jacobs B Chugani HT Allada V Chen S Phelps ME Pollack DB Raleigh MJ Developmental changes in brain metabolism in sedated rhesus macaques and vervet monkeys revealed by positron emission tomography Cerebral cortex (New York, N.Y.: 1991) 1995 5 222 233 7613078 source

In the paper

“Their timeline states that in individuals who develop AD, Aβ plaque deposition and reduced CSF Aβ occur first. Next, CSF tau levels rise. These changes manifest years before clinical signs or symptoms develop. Later on hippocampal atrophy appears, followed shortly thereafter by memory decline and eventually dementia. Full progression from Aβ changes to clinical decline takes approximately 10 to 20”

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

In the paper

“Finally, we predict falling Aβ CSF levels reflect falling Aβ production more than it reflects decreased solubility or increased incorporation into plaques.”

In the paper

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

In the paper

“Also, the fact that Aβ accumulates for over a decade before symptoms arise [214], a finding that infers brains tolerate Aβ reasonably well, does not challenge our hypothesis.”

What the sources say

• Not checked yetcites [214] Villemagne VL Burnham S Bourgeat P Brown B Ellis KA Salvado O Szoeke C Macaulay SL Martins R Maruff P Ames D Rowe CC Masters CL Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study Lancet Neurol 2013 12 357 367 23477989 source

In the paper

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

In the paper

“Studies of non-demented individuals report that while CSF Aβ levels seem to decline during young adulthood, during late mid-life CSF Aβ levels may actually slightly increase [219, 220].”

What the sources say

• Not checked yetcites [219] Shoji M Kanai M Matsubara E Tomidokoro Y Shizuka M Ikeda Y Ikeda M Harigaya Y Okamoto K Hirai S The levels of cerebrospinal fluid Abeta40 and Abeta42(43) are regulated age-dependently Neurobiol Aging 2001 22 209 215 11182470 source
• Not checked yetcites [220] Peskind ER Li G Shofer J Quinn JF Kaye JA Clark CM Farlow MR DeCarli C Raskind MA Schellenberg GD Lee VM Galasko DR Age and apolipoprotein E*4 allele effects on cerebrospinal fluid beta-amyloid 42 in adults with normal cognition Arch Neurol 2006 63 936 939 16831961 source

In the paper

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

In the paper

“The brains of these mice show reduced plaque deposition, less fibrillar Aβ, and less oxidative stress than APP-PS1 mice that can freely produce COX [175, 176].”

What the sources say

• Not checked yetcites [175] Fukui H Diaz F Garcia S Moraes CT Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease Proc Natl Acad Sci U S A 2007 104 14163 14168 17715058 PMC1955773 source
• Not checked yetcites [176] Pinto M Pickrell AM Fukui H Moraes CT Mitochondrial DNA damage in a mouse model of Alzheimer's disease decreases amyloid beta plaque formation Neurobiol Aging 2013 34 2399 2407 23702344 PMC4020357 source

In the paper

“Plaque formation rates also vary over time [217]. After a period of rapid accumulation, plaque deposition gradually slows and by the time symptoms manifest plaque deposition is essentially done [20, 205, 218].”

What the sources say

• Not checked yetcites [217] Jack CR Jr. Wiste HJ Lesnick TG Weigand SD Knopman DS Vemuri P Pankratz VS Senjem ML Gunter JL Mielke MM Lowe VJ Boeve BF Petersen RC Brain beta-amyloid load approaches a plateau Neurology 2013 80 890 896 23446680 PMC3653215 source
• Not checked yetcites [20] Sperling RA Aisen PS Beckett LA Bennett DA Craft S Fagan AM Iwatsubo T Jack CR Jr. Kaye J Montine TJ Park DC Reiman EM Rowe CC Siemers E Stern Y Yaffe K Carrillo MC Thies B Morrison-Bogorad M Wagster MV Phelps CH Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease Alzheimers Dement 2011 7 280 292 21514248 PMC3220946 source
• Not checked yetcites [205] Jack CR Jr. Knopman DS Jagust WJ Shaw LM Aisen PS Weiner MW Petersen RC Trojanowski JQ Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade Lancet Neurol 2010 9 119 128 20083042 PMC2819840 source

In the paper

“one literature- based analysis concludes 85% of those over 85 meet at least one of the new AD criteria [26].”

What the sources say

• Not checked yetcites [26] Swerdlow RH Brain aging, Alzheimer's disease, and mitochondria Biochimica et biophysica acta 2011 1812 1630 1639 21920438 PMC3210037 source

In the paper

“Cognitive speed and multitasking abilities, for example, become less robust with advancing age.”

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

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

In the paper

“After all, many with plaques will remain asymptomatic for years or even decades, and perhaps some will never develop symptoms [241].”

What the sources say

• Not checked yetcites [241] Berlau DJ Corrada MM Head E Kawas CH APOE epsilon2 is associated with intact cognition but increased Alzheimer pathology in the oldest old Neurology 2009 72 829 834 19255410 PMC2667799 source

In the paper

“An agent claimed to inhibit Aβ oligomer formation did not meet its primary endpoint and further development was discontinued [257, 258].”

What the sources say

• Not checked yetcites [257] Aisen PS Gauthier S Ferris SH Saumier D Haine D Garceau D Duong A Suhy J Oh J Lau WC Sampalis J Tramiprosate in mild-to-moderate Alzheimer's disease - a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study) Archives of medical science: AMS 2011 7 102 111 22291741 PMC3258678 source
• Not checked yetcites [258] Sabbagh MN Drug development for Alzheimer's disease: where are we now and where are we headed? The American journal of geriatric pharmacotherapy 2009 7 167 185 19616185 PMC2948028 source

In the paper

“especially since inhibiting β secretase-mediated APP cleavage should change levels of APP and its α secretase-generated sAPPα product.”

In the paper

“A γ secretase inhibitor did make it to phase III testing, but safety issues and accelerated decline in the treatment group brought this trial to an early end [255].”

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

In the paper

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

In the paper

“despite the fact these approaches appear to accelerate, not impact, or at best very minimally slow symptomatic subject progression.”

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

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

In the paper

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

In the paper

“At the clinical level, it tends to lump rather than split age-associated and AD-associated cognitive changes.”

In the paper

“We believe manipulating mitochondrial function and cell bioenergetic pathways will ultimately achieve this goal.”

In the paper

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

In the paper

“According to our hypothesis, arresting brain aging will arrest both the development and progression of AD.”

In the paper

“We suspect the latter possibility will prove to be the case, and that removing Aβ will not actually remove the cause of AD but instead an epiphenomenon of aging.”

In the paper

“If correct, we believe, such approaches will benefit both asymptomatic and symptomatic individuals.”