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Alzheimer's disease: experimental models and reality
Open accessAbstract
Experimental models of Alzheimer's disease (AD) are critical to gaining a better understanding of pathogenesis and to assess the potential of novel therapeutic approaches. The most commonly used experimental animal models are transgenic mice that overexpress human genes associated with familial AD (FAD) that result in the formation of amyloid plaques. However, AD is defined by the presence and interplay of both amyloid plaques and neurofibrillary tangle pathology. The track record of success in AD clinical trials thus far has been very poor. In part, this high failure rate has been related to the premature translation of highly successful results in animal models that mirror only limited aspects of AD pathology to humans. A greater understanding of the strengths and weakness of each of the various models and the use of more than one model to evaluate potential therapies would help enhance the success of therapy translation from preclinical studies to patients. In this review, we summarize the pathological features and limitations of the major experimental models of AD, including transgenic mice, transgenic rats, various physiological models of sporadic AD and in vitro human cell culture models.
Overview
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TL;DR
This review argues that no current experimental model fully replicates human Alzheimer’s disease, because most models capture only limited aspects of AD pathology—usually amyloid-related changes—while AD is defined by both plaques and neurofibrillary tangles. It links the ~99.6% failure rate of AD clinical trials partly to premature translation from such models and recommends using multiple, better-characterized models, including more physiological and human-based systems.
Key findings
- AD is defined by both extracellular Aβ plaques/CAA and intraneuronal tau NFTs, but most animal models develop only amyloid accumulation and often lack widespread neuronal loss and NFTs; transgenic models are largely based on FAD mutations, whereas sAD afflicts >95% of AD patients.
- The paper reports an AD clinical trial failure rate of ~99.6%, many after success in preclinical animal models, and attributes this in part to models that mirror only limited AD pathology.
- Transgenic mouse examples: 5xFAD mice show intraneuronal Aβ at 6 weeks and plaques at 2 months; 3xTg mice show intraneuronal Aβ at 3–4 months, plaques at ~6 months, and NFTs at ~12 months, but NFT pathology is much less extensive than in AD. APP/PS1 models generally do not develop NFTs.
- Physiological models show age-related Aβ pathology but rare/limited tauopathy: ~40% of aged rhesus monkeys (25–31 years) had no plaques or CAA, while 100% of very old animals (33–39 years) had plaques; baboons show localized hippocampal tauopathy in 90% over age 26; aged dogs develop plaques from 8–9 years but typically no NFTs.
Methods
- Narrative review summarizing pathological features and limitations of major experimental AD models, including transgenic mice, transgenic rats, physiological models of sporadic AD, invertebrate models, and in vitro human cell culture models.
- No primary experimental data or systematic search is reported; the synthesis draws on cited literature and model comparisons, with a table detailing commonly used transgenic strains.
- Main analysis is qualitative comparison of how well each model replicates human AD neuropathology, especially plaques, tangles, neurodegeneration, and cognitive impairment.
Limitations
- The paper states that none of the available models replicate all features of human AD; transgenic models model FAD rather than sAD, use non-physiological overexpression, and generally lack NFTs and widespread neurodegeneration; physiological models have long lifespans, variable pathology, and little tauopathy; cell culture models lack the complex brain environment and have protocol, epigenetic, and phenotype-variation issues.
- The paper notes that absolute comparisons between transgenic models are difficult because characterization of cognitive testing, tau pathology, and synaptic pathology varies greatly.
- Evident from the text: as a narrative review, it does not provide a systematic search strategy, quantitative meta-analysis, or formal risk-of-bias assessment.
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Claims the paper makes
78 Not checked yet · 47 Own interpretation · 31 No basis given · 1 Supported
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In the paper
“While squirrel monkey Aβ also formed SDS stable dimers and trimers similar to humans, these oligomers likely have a different tertiary or quaternary structure from human species [125].”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
What the sources say
- Supportedcites [125] Rosen RF, Tomidokoro Y, Farberg AS, Dooyema J, Ciliax B, Preuss TM, Neubert TA, Ghiso JA, LeVine H 3rd, Walker LC (2016) Comparative pathobiology of beta-amyloid and the unique susceptibility of humans to Alzheimer’s disease. Neurobiol Aging 44:185–196. doi: 10.1016/j.neurobiolaging.2016.04.019 source
The Results (§3.1) report SDS-stable dimers and trimers in brain extracts from both humans with AD and older squirrel monkeys. The Discussion (§4) reiterates that finding. (LLM, conf=0.94)
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In the paper
“Overall, the general features of transgenic mice expressing human APP, with or without human PSEN1, are robust plaque formation, particularly in brain regions typically rich in plaques in AD such as the cortex and hippocampus.”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Transgenic mice expressing human APP and PSEN1 with FAD mutations
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In the paper
“CAA is mainly present in capillaries, in contrast to the prominent arteriolar CAA in AD.”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Unique transgenic mouse models useful for AD research
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In the paper
“For example, knock-in of the Swedish, London and Dutch mutations only results in the development of plaques if bred onto a PS1M146V knock-in background [93].”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Knock-in mouse models
What the sources say
- Not checked yetcites [93] Li H, Guo Q, Inoue T, Polito VA, Tabuchi K, Hammer RE, Pautler RG, Taffet GE, Zheng H (2014) Vascular and parenchymal amyloid pathology in an Alzheimer disease knock-in mouse model: interplay with cerebral blood flow. Mol Neurodegener 9:28. doi: 10.1186/1750-1326-9-28 source
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In the paper
“Tg-SwDI mice develop robust accumulation of fibrillar vascular Aβ and less prominent diffuse parenchymal plaques, starting at 3 months of age [29](see Figure 2).”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Unique transgenic mouse models useful for AD research
What the sources say
- Not checked yetcites [29] Davis J, Xu F, Deane R, Romanov G, Previti ML, Zeigler K, Zlokovic BV, van Nostrand WE (2004) Early-onset and robust cerebral microvascular accumulation of amyloid β-protein in transgenic mice expressing low levels of a vasculotropic Dutch/Iowa mutant form of amyloid β-protein precursor. J Biol Chem 279:20296–20306 source
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In the paper
“They all have evidence of cognitive impairment, particularly in spatial memory tasks.”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Transgenic mice expressing human APP and PSEN1 with FAD mutations
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In the paper
“However, it is important to note that the timing of cognitive impairment develops much earlier than in AD; typically coinciding with the onset of plaque development in transgenic mice in comparison to decades after plaque development in humans.”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Transgenic mice expressing human APP and PSEN1 with FAD mutations
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In the paper
“The other major limitation of these mouse models was that while some showed evidence of localized hyperphosphylated tau that may represent “pretangles”[107, 118, 151, 159], none developed neurofibrillary tangles.”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Transgenic mice expressing human APP and PSEN1 with FAD mutations
What the sources say
- Not checked yetcites [107] Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van EL et al (2006) Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci 26:10129–10140 source
- Not checked yetcites [118] Radde R, Bolmont T, Kaeser SA, Coomaraswamy J, Lindau D, Stoltze L, Calhoun ME, Jaggi F, Wolburg H, Gengler S et al (2006) Aβ42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep 7:940–946 source
- Not checked yetcites [151] Sturchler-Pierrat C, Abramowski D, Duke M, Wiederhold KH, Mistl C, Rothacher S, Ledermann B, Bürki K, Frey P, Paganetti PA et al (1997) Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci USA 94:13287–13292 source
- Not checked yetcites [159] Tomiyama T, Matsuyama S, Iso H, Umeda T, Takuma H, Ohnishi K, Ishibashi K, Teraoka R, Sakama N, Yamashita T et al (2010) A mouse model of amyloid β oligomers: their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo. J Neurosci 30:4845–4856 source
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In the paper
“Despite very high sequence homology between great ape and human tau (100% and 99.5% sequence homology between human tau and chimpanzee or gorilla tau respectively), tauopathy is rare.”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
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In the paper
“It is noteworthy that there is considerable variation in plaque pathology between animals.”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
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“Also, memory impairments appear to be mild; appearing more similar to typical age-related memory decline, rather than the extensive cognitive decline seen in AD[57].”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
What the sources say
- Not checked yetcites [57] Heuer E, Rosen RF, Cintron A, Walker LC (2012) Nonhuman primate models of Alzheimer-like cerebral proteopathy. Curr Pharm Des 18:1159–1169 source
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In the paper
“The two largest studies examining the presence of plaques in rhesus monkeys found that approximately 40% of aged animals (25–31 years) did not have any evidence of plaques or CAA after death of natural causes [164, 165].”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
What the sources say
- Not checked yetcites [164] Uno H, Alsum PB, Dong S, Richardson R, Zimbric ML, Thieme CS, Houser WD (1996) Cerebral amyloid angiopathy and plaques, and visceral amyloidosis in aged macaques. Neurobiol Aging 17:275–281 source
- Not checked yetcites [165] Uno H, Walker LC (1993) The age of biosenescence and the incidence of cerebral beta-amyloidosis in aged captive rhesus monkeys. Ann N Y Acad Sci 695:232–235 source
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In the paper
“The majority of animal models (both transgenic and physiological models) develop only the amyloid accumulation that defines AD.”
§ Alzheimer’s Disease: Experimental Models and Reality > Introduction
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In the paper
“On the other hand, numerous studies have documented a strong link between neocortical NFTs and cognitive loss[26, 46, 48, 97, 123, 160, 169].”
§ Alzheimer’s Disease: Experimental Models and Reality > AD neuropathology
What the sources say
- Not checked yetcites [26] Cummings BJ, Pike CJ, Shankle R, Cotman CW (1996) Beta-amyloid deposition and other measures of neuropathology predict cognitive status in Alzheimer’s disease. Neurobiol Aging 17:921–933 source
- Not checked yetcites [46] Giannakopoulos P, Kovari E, Gold G, von Gunten A, Hof PR, Bouras C (2009) Pathological substrates of cognitive decline in Alzheimer’s disease. Front Neurol Neurosci 24:20–29. doi: 10.1159/000197881 source
- Not checked yetcites [48] Gold G, Bouras C, Kovari E, Canuto A, Glaria BG, Malky A, Hof PR, Michel JP, Giannakopoulos P (2000) Clinical validity of Braak neuropathological staging in the oldest-old. Acta Neuropathol 99:579–582 (discussion 583–574) source
- Not checked yetcites [97] McKee AC, Kosik KS, Kowall NW (1991) Neuritic pathology and dementia in Alzheimer’s disease. Ann Neurol 30:156–165. doi: 10.1002/ana.410300206 source
- Not checked yetcites [123] Robinson JL, Geser F, Corrada MM, Berlau DJ, Arnold SE, Lee VM, Kawas CH, Trojanowski JQ (2011) Neocortical and hippocampal amyloid-beta and tau measures associate with dementia in the oldest-old. Brain 134:3708–3715. doi: 10.1093/brain/awr308 source
- Not checked yetcites [160] Tomlinson BE, Blessed G, Roth M (1970) Observations on the brains of demented old people. J Neurol Sci 11:205–242 source
- Not checked yetcites [169] Webster SJ, Bachstetter AD, Nelson PT, Schmitt FA, Van Eldik LJ (2014) Using mice to model Alzheimer’s dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models. Front Genet 5:88. doi: 10.3389/fgene.2014.00088 source
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In the paper
“It is suggested that oligomers are the most neurotoxic species in AD as levels of these species correlate much better with cognitive symptoms than presence of plaques or NFTs [166].”
§ Alzheimer’s Disease: Experimental Models and Reality > AD neuropathology
What the sources say
- Not checked yetcites [166] Viola KL, Klein WL (2015) Amyloid beta oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis. Acta Neuropathol 129:183–206 source
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In the paper
“For potential effects in established AD, a therapy would have to be shown to reduce pathology in models of AD with both Aβ and tau pathology.”
§ Alzheimer’s Disease: Experimental Models and Reality > AD neuropathology
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“Importantly however, these models often lack the widespread presence of other pathological features that define AD including neuronal loss and most importantly, neurofibrillary tangle development.”
§ Alzheimer’s Disease: Experimental Models and Reality > Introduction
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In the paper
“Importantly, sequence differences between mice and humans include 3 amino acids within the Aβ sequence (R5G, Y10F and H13R)[155, 174].”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models
What the sources say
- Not checked yetcites [155] Tanzi RE, Gusella JF, Watkins PC, Bruns GA, St. George Hyslop P, VanKeuren ML, Patterson D, Pagan S, Kurnit DM, Neve RL (1987) Amyloid & #x03B2;-protein gene: cDNA, mRNA distribution and genetic linkage near the Alzheimer’s locus. Science 235:880–884 source
- Not checked yetcites [174] Xu G, Ran Y, Fromholt SE, Fu C, Yachnis AT, Golde TE, Borchelt DR (2015) Murine Aβ over-production produces diffuse and compact Alzheimer-type amyloid deposits. Acta Neuropathol Commun 3:72. doi: 10.1186/s40478-015-0252-9 source
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In the paper
“the very high failure rate of clinical trials of AD therapeutics (of ~99.6%), many of which were successful in preclinical testing using these animal models [6, 27, 139]”
§ Alzheimer’s Disease: Experimental Models and Reality > Introduction
What the sources say
- Not checked yetcites [6] Banik A, Brown RE, Bamburg J, Lahiri DK, Khurana D, Friedland RP, Chen W, Ding Y, Mudher A, Padjen AL et al (2015) Translation of pre-clinical studies into successful clinical trials for Alzheimer’s disease: what are the roadblocks and how can they be overcome? J Alzheimers Dis 47:815–843. doi: 10.3233/JAD-150136 source
- Not checked yetcites [27] Cummings JL, Morstorf T, Zhong K (2014) Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther 6:37. doi: 10.1186/alzrt269 source
- Not checked yetcites [139] Schneider LS, Mangialasche F, Andreasen N, Feldman H, Giacobini E, Jones R, Mantua V, Mecocci P, Pani L, Winblad B et al (2014) Clinical trials and late-stage drug development for Alzheimer’s disease: an appraisal from 1984 to 2014. J Intern Med 275:251–283 source
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In the paper
“Wild-type mouse APP (695 isoform) has 97% sequence homology with human APP.”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models
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In the paper
“These differences between sAD and FAD may impact the translatability of therapeutic findings in transgenic mouse models that are largely based on over-expression of APP and PSEN1 containing FAD linked mutations.”
§ Alzheimer’s Disease: Experimental Models and Reality > AD neuropathology
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In the paper
“Therefore, expression of human APP is necessary for the formation of amyloid plaques in mice.”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models
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In the paper
“the very high failure rate of clinical trials of AD therapeutics (of ~99.6%), many of which were successful in preclinical testing using these animal models [6, 27, 139]”
§ Alzheimer’s Disease: Experimental Models and Reality > Introduction
What the sources say
- Not checked yetcites [6] Banik A, Brown RE, Bamburg J, Lahiri DK, Khurana D, Friedland RP, Chen W, Ding Y, Mudher A, Padjen AL et al (2015) Translation of pre-clinical studies into successful clinical trials for Alzheimer’s disease: what are the roadblocks and how can they be overcome? J Alzheimers Dis 47:815–843. doi: 10.3233/JAD-150136 source
- Not checked yetcites [27] Cummings JL, Morstorf T, Zhong K (2014) Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther 6:37. doi: 10.1186/alzrt269 source
- Not checked yetcites [139] Schneider LS, Mangialasche F, Andreasen N, Feldman H, Giacobini E, Jones R, Mantua V, Mecocci P, Pani L, Winblad B et al (2014) Clinical trials and late-stage drug development for Alzheimer’s disease: an appraisal from 1984 to 2014. J Intern Med 275:251–283 source
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In the paper
“This lack of additional AD associated pathology could at least partly account for the lack of translation between preclinical and clinical trials [6], although there have also been a few clinical trial failures for approaches not initially tested in transgenic models[69].”
§ Alzheimer’s Disease: Experimental Models and Reality > Introduction
What the sources say
- Not checked yetcites [6] Banik A, Brown RE, Bamburg J, Lahiri DK, Khurana D, Friedland RP, Chen W, Ding Y, Mudher A, Padjen AL et al (2015) Translation of pre-clinical studies into successful clinical trials for Alzheimer’s disease: what are the roadblocks and how can they be overcome? J Alzheimers Dis 47:815–843. doi: 10.3233/JAD-150136 source
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In the paper
“Therefore therapeutic approaches that have been shown to be successful only in Aβ models of AD, would only have the possible expectation of influencing the trajectory of AD pathology in the preclinical or MCI stages of the disease.”
§ Alzheimer’s Disease: Experimental Models and Reality > AD neuropathology
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In the paper
“Multiple transgenic strains have been generated and the exact phenotype for each transgenic strain strongly depends on the FAD mutation, the promoter used and the background mouse strain.”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models
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In the paper
“Wild-type mouse tau does not develop neurofibrillary tangles.”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Transgenic mice expressing tau
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In the paper
“In contrast, expression of human APP containing mutations associated with FAD resulted in consistent plaque pathology and varying amounts of consequent downstream AD-associated pathological features.”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models
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In the paper
“One major limitation of these transgenic mouse models is the lack of the widespread neurodegeneration and regional brain atrophy that occurs in AD.”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Transgenic mice expressing human APP and PSEN1 with FAD mutations
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“These mice are considered to be a much more physiological model of AD as they are designed to avoid the confounding effects of APP over-expression present in all other transgenic mouse models by humanizing mouse Aβ and knocking in specific APP FAD mutations.”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Knock-in mouse models
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In the paper
“For example, the Tg-SwDI transgenic mouse model is a particularly good model of CAA [29].”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Unique transgenic mouse models useful for AD research
What the sources say
- Not checked yetcites [29] Davis J, Xu F, Deane R, Romanov G, Previti ML, Zeigler K, Zlokovic BV, van Nostrand WE (2004) Early-onset and robust cerebral microvascular accumulation of amyloid β-protein in transgenic mice expressing low levels of a vasculotropic Dutch/Iowa mutant form of amyloid β-protein precursor. J Biol Chem 279:20296–20306 source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The major benefit of these two mouse models is that they replicate specific pathological features of AD more robustly than other models.”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Unique transgenic mouse models useful for AD research
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“A limited number of studies have reported the development of animal models that display both plaques and tangles [10, 51, 91, 109, 121].”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Transgenic mice with both plaques and tangles
What the sources say
- Not checked yetcites [10] Bolmont T, Clavaguera F, Meyer-Luehmann M, Herzig MC, Radde R, Staufenbiel M, Lewis J, Hutton M, Tolnay M, Jucker M (2007) Induction of tau pathology by intracerebral infusion of amyloid-β-containing brain extract and by amyloid-β deposition in APP x Tau transgenic mice. Am J Pathol 171:2012–2020 source
- Not checked yetcites [51] Grueninger F, Bohrmann B, Czech C, Ballard TM, Frey JR, Weidensteiner C, von Kienlin M, Ozmen L (2010) Phosphorylation of Tau at S422 is enhanced by Abeta in TauPS2APP triple transgenic mice. Neurobiol Dis 37:294–306. doi: 10.1016/j.nbd.2009.09.004 source
- Not checked yetcites [91] Lewis J, Dickson D, Lin WL, Chisholm L, Corral A, Jones G, Yen SH, Sahara N, Skipper L, Yager D et al (2001) Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293:1487–1491 source
- Not checked yetcites [109] Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Aβ and synaptic dysfunction. Neuron 39:409–421 source
- Not checked yetcites [121] Ribe EM, Perez M, Puig B, Gich I, Lim F, Cuadrado M, Sesma T, Catena S, Sanchez B, Nieto M et al (2005) Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice. Neurobiol Dis 20:814–822. doi: 10.1016/j.nbd.2005.05.027 source
plain- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The species with the most well characterized AD neuropathological features are non-human primates.”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Squirrel monkeys have extensive Aβ accumulation after 12 years of age, primarily in the form of CAA in arterioles and capillaries [22, 36, 167, 168].”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
What the sources say
- Not checked yetcites [22] Chambers JK, Kuribayashi H, Ikeda S, Une Y (2010) Distribution of neprilysin and deposit patterns of Abeta subtypes in the brains of aged squirrel monkeys (Saimiri sciureus). Amyloid 17:75–82. doi: 10.3109/13506129.2010.483119 source
- Not checked yetcites [36] Elfenbein HA, Rosen RF, Stephens SL, Switzer RC, Smith Y, Pare J, Mehta PD, Warzok R, Walker LC (2007) Cerebral beta-amyloid angiopathy in aged squirrel monkeys. Histol Histopathol 22:155–167
- Not checked yetcites [167] Walker LC, Kitt CA, Schwam E, Buckwald B, Garcia F, Sepinwall J, Price DL (1987) Senile plaques in aged squirrel monkeys. Neurobiol Aging 8:291–296 source
- Not checked yetcites [168] Walker LC, Masters C, Beyreuther K, Price DL (1990) Amyloid in the brains of aged squirrel monkeys. Acta Neuropathol 80:381–387 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“The prominence of CAA in squirrel monkeys makes this model particularly appropriate for the evaluation of whether a therapeutic approach might be associated with ARIA as a complication in patients [140, 141].”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
What the sources say
- Not checked yetcites [140] Scholtzova H, Nehete P, Nehete BP, Mallory M, Cho EH, Holmes A, Park J, Wren MS, Pardington P, Gupta G et al (2015) Toll-like receptor 9 stimulation via CpG ODN in a non-human primate model of sporadic cerebral amyloid angiopathy. Alz Dementia 11:P618 source
- Not checked yetcites [141] Scholtzova H, Williams L, Nehete P, Sabado R, Holmes A, Wisniewski T (2013) Innate immunity stimulation via TLR9 in a non-human primate model of sporadic cerebral amyloid angiopathy. Alz Dementia 9:p508 source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“A recent mass spectrometry study showed that squirrel monkeys have all major Aβ species that are present in the human brain (including Aβ1–40, Aβ1–42, Aβ1–34, Aβ4–40, Aβ4–42, AβN3pE and oxidized Aβ)[125].”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
What the sources say
- Not checked yetcites [125] Rosen RF, Tomidokoro Y, Farberg AS, Dooyema J, Ciliax B, Preuss TM, Neubert TA, Ghiso JA, LeVine H 3rd, Walker LC (2016) Comparative pathobiology of beta-amyloid and the unique susceptibility of humans to Alzheimer’s disease. Neurobiol Aging 44:185–196. doi: 10.1016/j.neurobiolaging.2016.04.019 source
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Great apes accumulate Aβ in the brain, resulting in the development of amyloid plaques and CAA in aged animals [43, 44, 78, 112, 113, 124].”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
What the sources say
- Not checked yetcites [43] Gearing M, Rebeck GW, Hyman BT, Tigges J, Mirra SS (1994) Neuropathology and apolipoprotein E profile of aged chimpanzees: implications for Alzheimer disease. Proc Natl Acad Sci USA 91:9382–9386 source
- Not checked yetcites [44] Gearing M, Tigges J, Mori H, Mirra SS (1997) β-Amyloid (Aβ) deposition in the brains of aged orangutans. Neurobiol Aging 18:139–146 source
- Not checked yetcites [78] Kimura N, Nakamura S, Goto N, Narushima E, Hara I, Shichiri S, Saitou K, Nose M, Hayashi T, Kawamura S et al (2001) Senile plaques in an aged western lowland gorilla. Exp Anim 50:77–81 source
- Not checked yetcites [112] Perez SE, Raghanti MA, Hof PR, Kramer L, Ikonomovic MD, Lacor PN, Erwin JM, Sherwood CC, Mufson EJ (2013) Alzheimer’s disease pathology in the neocortex and hippocampus of the western lowland gorilla (Gorilla gorilla gorilla). J Comp Neurol 521:4318–4338. doi: 10.1002/cne.23428 source
- Not checked yetcites [113] Perez SE, Sherwood CC, Cranfield MR, Erwin JM, Mudakikwa A, Hof PR, Mufson EJ (2016) Early Alzheimer’s disease-type pathology in the frontal cortex of wild mountain gorillas (Gorilla beringei beringei). Neurobiol Aging 39:195–201. doi: 10.1016/j.neurobiolaging.2015.12.017 source
- Not checked yetcites [124] Rosen RF, Farberg AS, Gearing M, Dooyema J, Long PM, Anderson DC, Davis-Turak J, Coppola G, Geschwind DH, Pare JF et al (2008) Tauopathy with paired helical filaments in an aged chimpanzee. J Comp Neurol 509:259–270. doi: 10.1002/cne.21744 source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This is likely due to the greater similarities between rat tau and human tau, in that there are also 6 isoforms of endogenous rat tau.”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic rat models
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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In the paper
“Neuritic plaques can be observed, some with phosphorylated tau immunoreactive dystrophic neurites [88].”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
What the sources say
- Not checked yetcites [88] Lemere CA, Beierschmitt A, Iglesias M, Spooner ET, Bloom JK, Leverone JF, Zheng JB, Seabrook TJ, Louard D, Li D et al (2004) Alzheimer’s disease aβ vaccine reduces central nervous system aβ levels in a non-human primate, the Caribbean vervet. Am J Pathol 165:283–297 source
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Again, there is 100% sequence homology between human and rhesus monkey Aβ.”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Vervets live to approximately 30 years in captivity and have evidence of Aβ deposition, gliosis and neuronal dystrophy with age [72, 88, 89].”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
What the sources say
- Not checked yetcites [72] Kalinin S, Willard SL, Shively CA, Kaplan JR, Register TC, Jorgensen MJ, Polak PE, Rubinstein I, Feinstein DL (2013) Development of amyloid burden in African Green monkeys. Neurobiol Aging 34:2361–2369. doi: 10.1016/j.neurobiolaging.2013.03.023 source
- Not checked yetcites [88] Lemere CA, Beierschmitt A, Iglesias M, Spooner ET, Bloom JK, Leverone JF, Zheng JB, Seabrook TJ, Louard D, Li D et al (2004) Alzheimer’s disease aβ vaccine reduces central nervous system aβ levels in a non-human primate, the Caribbean vervet. Am J Pathol 165:283–297 source
- Not checked yetcites [89] Lemere CA, Iglesias M, Spooner ET, Bloom JK, Leverone JF, Li D, Zheng JB, Seabrook TJ, Selkoe D, Ervin FR et al (2003) Aβ immunization in aged vervet monkeys reduces Aβ levels in brain and CSF. Soc Neurosci Abst 133(5):5
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This is the first time that plaques and tangles been replicated in vitro.”
§ Alzheimer’s Disease: Experimental Models and Reality > Cell culture models
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Very few models have both plaques and tangles, particularly ones that develop physiologically.”
§ Alzheimer’s Disease: Experimental Models and Reality > Factors to consider when choosing the best model
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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- Rests on an assumption: The presence of both plaques and tangles is required for diagnosis of AD.
In the paper
“While squirrel monkey Aβ also formed SDS stable dimers and trimers similar to humans, these oligomers likely have a different tertiary or quaternary structure from human species [125].”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
What the sources say
- Not checked yetcites [125] Rosen RF, Tomidokoro Y, Farberg AS, Dooyema J, Ciliax B, Preuss TM, Neubert TA, Ghiso JA, LeVine H 3rd, Walker LC (2016) Comparative pathobiology of beta-amyloid and the unique susceptibility of humans to Alzheimer’s disease. Neurobiol Aging 44:185–196. doi: 10.1016/j.neurobiolaging.2016.04.019 source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“It was recently shown that development of a 3D culture of human neural stem cells transfected with APPK670N/M671L/V717I and PS1ΔE9 in Matrigel scaffolding resulted in the extracellular aggregation of Aβ into plaques and the intracellular aggregation of tau in dystrophic neurites and the cell soma [23, 77].”
§ Alzheimer’s Disease: Experimental Models and Reality > Cell culture models
What the sources say
- Not checked yetcites [23] Choi SH, Kim YH, Hebisch M, Sliwinski C, Lee S, D’Avanzo C, Chen H, Hooli B, Asselin C, Muffat J et al (2014) A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature 515:274–278. doi: 10.1038/nature13800 source
- Not checked yetcites [77] Kim YH, Choi SH, D’Avanzo C, Hebisch M, Sliwinski C, Bylykbashi E, Washicosky KJ, Klee JB, Brustle O, Tanzi RE et al (2015) A 3D human neural cell culture system for modeling Alzheimer’s disease. Nat Protoc 10:985–1006. doi: 10.1038/nprot.2015.065 source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, invertebrates cannot be considered to model AD without genetic manipulation to express human transgenes of APP, Aβ and/or tau.”
§ Alzheimer’s Disease: Experimental Models and Reality > Drosophila, C. Elegans and zebrafish as AD models
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The use of such animals in AD research is limited by the lack of genetic homology with humans due to the much more simplified genetic make-up in these lower order animals.”
§ Alzheimer’s Disease: Experimental Models and Reality > Drosophila, C. Elegans and zebrafish as AD models
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Based on previous studies the rhesus monkey is the most practical non-human primate model to study AD because it is so well characterized and the squirrel monkey is the best available non-human primate model to study CAA.”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Based on previous studies the rhesus monkey is the most practical non-human primate model to study AD because it is so well characterized and the squirrel monkey is the best available non-human primate model to study CAA.”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“However this pathology appears to be inconsistent as other studies do report any AD associated pathology in aged animals [149].”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Other physiological models
What the sources say
- Not checked yetcites [149] Steffen J, Krohn M, Paarmann K, Schwitlick C, Bruning T, Marreiros R, Muller-Schiffmann A, Korth C, Braun K, Pahnke J (2016) Revisiting rodent models: octodon degus as Alzheimer’s disease model? Acta Neuropathol Commun 4:91. doi: 10.1186/s40478-016-0363-y source
hedged- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“The most notable example is the lack of Aβ in Drosophila and C. Elegans [1, 38].”
§ Alzheimer’s Disease: Experimental Models and Reality > Drosophila, C. Elegans and zebrafish as AD models
What the sources say
- Not checked yetcites [1] Alexander AG, Marfil V, Li C (2014) Use of Caenorhabditis elegans as a model to study Alzheimer’s disease and other neurodegenerative diseases. Front Genet 5:279. doi: 10.3389/fgene.2014.00279 source
- Not checked yetcites [38] Fernandez-Funez P, de Mena L, Rincon-Limas DE (2015) Modeling the complex pathology of Alzheimer’s disease in Drosophila. Exp Neurol 274:58–71. doi: 10.1016/j.expneurol.2015.05.013 source
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“An additional concern is that cell culture models do not accurately represent the complex environment that is found in the brain, which includes complex interactions between neurons and the presence other cell types besides neurons (e.g. glia) that are likely to have a very important role in the development of AD.”
§ Alzheimer’s Disease: Experimental Models and Reality > Cell culture models
hedged- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
In the paper
“For example, this approach has proven successful in identifying modifiers of tau toxicity using Drosophila as a model [53].”
§ Alzheimer’s Disease: Experimental Models and Reality > Drosophila, C. Elegans and zebrafish as AD models
What the sources say
- Not checked yetcites [53] Hannan SB, Drager NM, Rasse TM, Voigt A, Jahn TR (2016) Cellular and molecular modifier pathways in tauopathies: the big picture from screening invertebrate models. J Neurochem 137:12–25. doi: 10.1111/jnc.13532 source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Multiple groups have characterized iPSC lines from donor cells from FAD and sAD patients, which show increased production of Aβ, particularly Aβ42, and tau hyperphosphorylation in comparison to iPSCs derived from age-matched non-demented controls [66, 82, 101, 175].”
§ Alzheimer’s Disease: Experimental Models and Reality > Cell culture models
What the sources say
- Not checked yetcites [66] Israel MA, Yuan SH, Bardy C, Reyna SM, Mu Y, Herrera C, Hefferan MP, Van Gorp S, Nazor KL, Boscolo FS et al (2012) Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature 482:216–220. doi: 10.1038/nature10821 source
- Not checked yetcites [82] Kondo T, Asai M, Tsukita K, Kutoku Y, Ohsawa Y, Sunada Y, Imamura K, Egawa N, Yahata N, Okita K et al (2013) Modeling Alzheimer’s disease with iPSCs reveals stress phenotypes associated with intracellular Abeta and differential drug responsiveness. Cell Stem Cell 12:487–496. doi: 10.1016/j.stem.2013.01.009 source
- Not checked yetcites [101] Muratore CR, Rice HC, Srikanth P, Callahan DG, Shin T, Benjamin LN, Walsh DM, Selkoe DJ, Young-Pearse TL (2014) The familial Alzheimer’s disease APPV717I mutation alters APP processing and Tau expression in iPSC-derived neurons. Hum Mol Genet 23:3523–3536. doi: 10.1093/hmg/ddu064 source
- Not checked yetcites [175] Yagi T, Ito D, Okada Y, Akamatsu W, Nihei Y, Yoshizaki T, Yamanaka S, Okano H, Suzuki N (2011) Modeling familial Alzheimer’s disease with induced pluripotent stem cells. Hum Mol Genet 20:4530–4539. doi: 10.1093/hmg/ddr394 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In sum, physiological models represent the best available models of sAD.”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Other physiological models
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, there are still scientific and practical limitations that prevent widespread use of these models.”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Other physiological models
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“The very poor success rate of ~99.6% with AD targeting clinical trials can in part be explained by the premature translation of successful pathology reduction in transgenic mice to humans [6, 27, 139].”
§ Alzheimer’s Disease: Experimental Models and Reality > Conclusion
What the sources say
- Not checked yetcites [6] Banik A, Brown RE, Bamburg J, Lahiri DK, Khurana D, Friedland RP, Chen W, Ding Y, Mudher A, Padjen AL et al (2015) Translation of pre-clinical studies into successful clinical trials for Alzheimer’s disease: what are the roadblocks and how can they be overcome? J Alzheimers Dis 47:815–843. doi: 10.3233/JAD-150136 source
- Not checked yetcites [27] Cummings JL, Morstorf T, Zhong K (2014) Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther 6:37. doi: 10.1186/alzrt269 source
- Not checked yetcites [139] Schneider LS, Mangialasche F, Andreasen N, Feldman H, Giacobini E, Jones R, Mantua V, Mecocci P, Pani L, Winblad B et al (2014) Clinical trials and late-stage drug development for Alzheimer’s disease: an appraisal from 1984 to 2014. J Intern Med 275:251–283 source
plainconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, it is likely that the lack of NFT development in mouse models that overexpress Aβ is due to the endogenous differences between mouse and human tau.”
§ Alzheimer’s Disease: Experimental Models and Reality > Factors to consider when choosing the best model
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Endogenous species differences between rodents and humans affect the cleavage and biochemistry of human Aβ in transgenic rodents.”
§ Alzheimer’s Disease: Experimental Models and Reality > Factors to consider when choosing the best model
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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In the paper
“Currently it is known that the distribution of Aβ and tau accumulation is different in FAD and sAD, with more present in subcortical regions in FAD [147].”
§ Alzheimer’s Disease: Experimental Models and Reality > Factors to consider when choosing the best model
What the sources say
- Not checked yetcites [147] Shinohara M, Fujioka S, Murray ME, Wojtas A, Baker M, Rovelet-Lecrux A, Rademakers R, Das P, Parisi JE, Graff-Radford NR et al (2014) Regional distribution of synaptic markers and APP correlate with distinct clinicopathological features in sporadic and familial Alzheimer’s disease. Brain 137:1533–1549. doi: 10.1093/brain/awu046 source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“These additional APP cleavage products are also capable of causing toxicity independent of Aβ [45, 105].”
§ Alzheimer’s Disease: Experimental Models and Reality > Factors to consider when choosing the best model
What the sources say
- Not checked yetcites [45] Ghosal K, Vogt DL, Liang M, Shen Y, Lamb BT, Pimplikar SW (2009) Alzheimer’s disease-like pathological features in transgenic mice expressing the APP intracellular domain. Proc Natl Acad Sci USA 106:18367–18372. doi: 10.1073/pnas.0907652106 source
- Not checked yetcites [105] Nikolaev A, McLaughlin T, O’Leary DD, Tessier-Lavigne M (2009) APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 457:981–989. doi: 10.1038/nature07767 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Furthermore, APP overexpression was recently suggested to be the underlying cause of two prominent AD phenotypes, rather than a downstream response to Aβ as was initially suggested based on studies using transgenic mice, calling into question whether this may also be the case for other interpreted examples of downstream AD pathology observed in transgenic mouse models [130].”
§ Alzheimer’s Disease: Experimental Models and Reality > Factors to consider when choosing the best model
What the sources say
- Not checked yetcites [130] Saito T, Matsuba Y, Yamazaki N, Hashimoto S, Saido TC (2016) Calpain activation in Alzheimer’s model mice is an artifact of APP and presenilin over-expression. J Neurosci 36:9933–9936. doi: 10.1523/JNEUROSCI.1907-16.2016 source
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In the paper
“This is an important factor to consider as this increased solubility could contribute to amyloid clearing drugs working much better in transgenic mice than humans.”
§ Alzheimer’s Disease: Experimental Models and Reality > Factors to consider when choosing the best model
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In the paper
“and atypical cognitive symptoms are more likely to be present in FAD [147].”
§ Alzheimer’s Disease: Experimental Models and Reality > Factors to consider when choosing the best model
What the sources say
- Not checked yetcites [147] Shinohara M, Fujioka S, Murray ME, Wojtas A, Baker M, Rovelet-Lecrux A, Rademakers R, Das P, Parisi JE, Graff-Radford NR et al (2014) Regional distribution of synaptic markers and APP correlate with distinct clinicopathological features in sporadic and familial Alzheimer’s disease. Brain 137:1533–1549. doi: 10.1093/brain/awu046 source
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In the paper
“This is further complicated by the fact that expression of different isoforms of human ApoE in transgenic mice results in different levels of plaque and CAA burden with apoE4 expression enhancing amyloid deposition compared to apoE3 or apoE2 [3, 21, 40, 59, 86, 178].”
§ Alzheimer’s Disease: Experimental Models and Reality > Factors to consider when choosing the best model
What the sources say
- Not checked yetcites [3] Bales KR, Liu F, Wu S, Lin S, Koger D, DeLong C, Hansen JC, Sullivan PM, Paul SM (2009) Human APOE isoform-dependent effects on brain beta-amyloid levels in PDAPP transgenic mice. J Neurosci 29:6771–6779 source
- Not checked yetcites [21] Castellano JM, Kim J, Stewart FR, Jiang H, De Mattos RB, Patterson BW, Fagan AM, Morris JC, Mawuenyega KG, Cruchaga C et al (2011) Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci Transl Med 3:89ra57 source
- Not checked yetcites [40] Fryer JD, Simmons K, Parsadanian M, Bales KR, Paul SM, Sullivan PM, Holtzman DM (2005) Human apolipoprotein E4 alters the amyloid-beta 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model. J Neurosci 25:2803–2810 source
- Not checked yetcites [59] Holtzman DM, Bales KR, Tenkova T, Fagan AM, Parsadanian M, Sartorius LJ, Mackey B, Olney J, McKeel D, Wozniak D et al (2000) Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer’s disease. PNAS 97:2892–2897 source
- Not checked yetcites [86] Kuszczyk MA, Sanchez S, Pankiewicz J, Kim J, Duszczyk M, Guridi M, Asuni AA, Sullivan PM, Holtzman DM, Sadowski MJ (2013) Blocking the interaction between apolipoprotein E and Aβ reduces intraneuronal accumulation of Aβ and inhibits synaptic degeneration. Am J Pathol 182:1750–1768 source
- Not checked yetcites [178] Youmans KL, Tai LM, Nwabuisi-Heath E, Jungbauer L, Kanekiyo T, Gan M, Kim J, Eimer WA, Estus S, Rebeck GW et al (2012) APOE4-specific changes in Abeta accumulation in a new transgenic mouse model of Alzheimer disease. J Biol Chem 287:41774–41786. doi: 10.1074/jbc.M112.407957 source
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In the paper
“Careful examination of neuropathology and cognitive impairment in multiple species, including those closest to humans, shows that AD is a uniquely human disease.”
§ Alzheimer’s Disease: Experimental Models and Reality > Conclusion
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In the paper
“Transgenic mouse studies confirmed that ApoE was necessary for the formation of fibrillar amyloid plaques and CAA [4, 5, 41, 61], however they also identified important differences between mouse and human ApoE.”
§ Alzheimer’s Disease: Experimental Models and Reality > Factors to consider when choosing the best model
What the sources say
- Not checked yetcites [4] Bales KR, Verina T, Cummins DJ, Du Y, Dodel RC, Saura J, Fishman CE, DeLong CA, Piccardo P, Petegnief V et al (1999) Apolipoprotein E is essential for amyloid deposition in the APPV717F transgenic mouse model of Alzheimer’s disease. PNAS 96:15233–15238 source
- Not checked yetcites [5] Bales KR, Verina T, Dodel RC, Du YS, Altstiel L, Bender M, Hyslop P, Johnstone EM, Little SP, Cummins DJ et al (1997) Lack of apolipoprotein E dramatically reduces amyloid β-peptide deposition. Nature Gen 17:263–264 source
- Not checked yetcites [41] Fryer JD, Taylor JW, DeMattos RB, Bales KR, Paul SM, Parsadanian M, Holtzman DM (2003) Apolipoprotein E markedly facilitates age-dependent cerebral amyloid angiopathy and spontaneous hemorrhage in amyloid precursor protein Transgenic mice. J Neurosci 23:7889–7896 source
- Not checked yetcites [61] Holtzman DM, Fagan AM, Mackey B, Tenkova T, Sartorius L, Paul SM, Bales KR, Hsiao Ashe K, Irizarry MC, Hyman BT (2000) Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer’s disease model. Ann Neurol 47:739–747 source
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In the paper
“The consistent lack of translation between animal models and human studies has resulted in the development of more human-centric approaches.”
§ Alzheimer’s Disease: Experimental Models and Reality > Conclusion
plaindirect- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 87
- Probably not a substantial claim. 3
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“While there is evidence for minor neurodegeneration in most of these mouse models, it only occurred in very old animals and was localized to very specific brain regions.”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Transgenic mice expressing human APP and PSEN1 with FAD mutations
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In the paper
“NFTs form at approximately 12 months, initially in CA1 and then in the cortex; however, they are much less extensive compared to AD tissue (see Figure 2).”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Transgenic mice with both plaques and tangles
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“However, the consistent and abundant expression of both plaques and tangles has proven troublesome, and development of both plaques and tangles is typically not observed until old age in these models.”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Transgenic mice with both plaques and tangles
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Additional knock-in of the Arctic mutation into these mice results in more rapid pathology development including plaque development beginning at 2 months that is more widespread throughout the brain and memory impairment from 6 months [129].”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Knock-in mouse models
What the sources say
- Not checked yetcites [129] Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, Iwata N, Saido TC (2014) Single App knock-in mouse models of Alzheimer’s disease. Nat Neurosci 17:661–663. doi: 10.1038/nn.3697 source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Mice also have minor, localized neurodegeneration, evidence of synaptic impairment and cognitive deficits from 6 months (Table 1).”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Transgenic mice with both plaques and tangles
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Furthermore, over-expression of mutated tau results in significant motor deficits that are not seen in AD and interfere with cognitive testing.”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Transgenic mice expressing tau
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“These mice develop NFTs, neurodegeneration, atrophy and motor deficits.”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Transgenic mice expressing tau
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“As a result, knock-in mice have the same expression of APP and AICD as wild-type mice and APP expression occurs in a physiological manner in the correct brain regions and cell types.”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Knock-in mouse models
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“3xTg mice first develop intraneuronal Aβ at 3–4 months, followed by plaque development at approximately 6 months in the cortex and hippocampus.”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Transgenic mice with both plaques and tangles
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“All have plaque associated gliosis, similar to that in AD, and the majority have localized pathology associated with synaptic impairment such as decreased long-term potentiation and decreased levels of synaptic markers such as synaptophysin.”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Transgenic mice expressing human APP and PSEN1 with FAD mutations
plaincorrelational- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Tg-SwDI mice also have localized neurodegeneration of cholinergic neurons and cognitive impairment (Table 1).”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Unique transgenic mouse models useful for AD research
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In contrast, knock-in of Swedish and Iberian mutations results in plaque development beginning at 6 months, and gliosis, synaptic alterations and memory impairment from 18 months [129].”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Knock-in mouse models
What the sources say
- Not checked yetcites [129] Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, Iwata N, Saido TC (2014) Single App knock-in mouse models of Alzheimer’s disease. Nat Neurosci 17:661–663. doi: 10.1038/nn.3697 source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“The APP E693Δ-Tg model expresses the Osaka (APPE693Δ) mutation, which results in a unique phenotype of significantly increased expression of Aβ oligomers, synaptic impairment and cognitive impairments from 8 months of age, but no plaque or tau pathology formation [159].”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Unique transgenic mouse models useful for AD research
What the sources say
- Not checked yetcites [159] Tomiyama T, Matsuyama S, Iso H, Umeda T, Takuma H, Ohnishi K, Ishibashi K, Teraoka R, Sakama N, Yamashita T et al (2010) A mouse model of amyloid β oligomers: their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo. J Neurosci 30:4845–4856 source
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Furthermore, widespread presence of plaques and tangles are typically not observed until old age in these mice and even then the pathology is less then typically seen in AD (see Figure 2).”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Transgenic mice with both plaques and tangles
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Plaques are typically found in rhesus monkeys that are older than 25 years and they have a similar distribution that that observed in humans; more being present in the cortex than the hippocampus [54, 56, 96, 134, 146, 150, 164, 165].”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
What the sources say
- Not checked yetcites [54] Hartig W, Bruckner G, Schmidt C, Brauer K, Bodewitz G, Turner JD, Bigl V (1997) Co-localization of beta-amyloid peptides, apolipoprotein E and glial markers in senile plaques in the prefrontal cortex of old rhesus monkeys. Brain Res 751:315–322 source
- Not checked yetcites [56] Heilbroner PL, Kemper TL (1990) The cytoarchitectonic distribution of senile plaques in three aged monkeys. Acta Neuropathol 81:60–65 source
- Not checked yetcites [96] Martin LJ, Pardo CA, Cork LC, Price DL (1994) Synaptic pathology and glial responses to neuronal injury precede the formation of senile plaques and amyloid deposits in the aging cerebral cortex. Am J Pathol 145:1358–1381
- Not checked yetcites [134] Sani S, Traul D, Klink A, Niaraki N, Gonzalo-Ruiz A, Wu CK, Geula C (2003) Distribution, progression and chemical composition of cortical amyloid-beta deposits in aged rhesus monkeys: similarities to the human. Acta Neuropathol 105:145–156. doi: 10.1007/s00401-002-0626-5 source
- Not checked yetcites [146] Shah P, Lal N, Leung E, Traul DE, Gonzalo-Ruiz A, Geula C (2010) Neuronal and axonal loss are selectively linked to fibrillar amyloid-β within plaques of the aged primate cerebral cortex. Am J Pathol 177:325–333. doi: 10.2353/ajpath.2010.090937 source
- Not checked yetcites [150] Struble RG, Price DL Jr, Cork LC, Price DL (1985) Senile plaques in cortex of aged normal monkeys. Brain Res 361:267–275 source
- Not checked yetcites [164] Uno H, Alsum PB, Dong S, Richardson R, Zimbric ML, Thieme CS, Houser WD (1996) Cerebral amyloid angiopathy and plaques, and visceral amyloidosis in aged macaques. Neurobiol Aging 17:275–281 source
- Not checked yetcites [165] Uno H, Walker LC (1993) The age of biosenescence and the incidence of cerebral beta-amyloidosis in aged captive rhesus monkeys. Ann N Y Acad Sci 695:232–235 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Minor neuronal loss is observed immediately around compact plaques; however, there is no evidence of widespread neuronal loss, even in brain regions with a high plaque load [146].”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
What the sources say
- Not checked yetcites [146] Shah P, Lal N, Leung E, Traul DE, Gonzalo-Ruiz A, Geula C (2010) Neuronal and axonal loss are selectively linked to fibrillar amyloid-β within plaques of the aged primate cerebral cortex. Am J Pathol 177:325–333. doi: 10.2353/ajpath.2010.090937 source
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Great apes are capable of forming NFTs [124], but this is a rare event that has only been observed in one chimpanzee studied.”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
What the sources say
- Not checked yetcites [124] Rosen RF, Farberg AS, Gearing M, Dooyema J, Long PM, Anderson DC, Davis-Turak J, Coppola G, Geschwind DH, Pare JF et al (2008) Tauopathy with paired helical filaments in an aged chimpanzee. J Comp Neurol 509:259–270. doi: 10.1002/cne.21744 source
plainSingle case- Asserted: passes — The authors put it forward as true.
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In the paper
“Aβ levels accumulate with age, reaching similar levels in the cortex to that observed in human AD, and there is often more Aβ42 than Aβ40 [126].”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
What the sources say
- Not checked yetcites [126] Rosen RF, Walker LC, Levine H 3rd (2011) PIB binding in aged primate brain: enrichment of high-affinity sites in humans with Alzheimer’s disease. Neurobiol Aging 32:223–234. doi: 10.1016/j.neurobiolaging.2009.02.011 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“All rat models have some degree of cognitive impairment; however, the degree of impairment has only been extensively characterized in the McGill-R-Thy1-APP rats [90].”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic rat models
What the sources say
- Not checked yetcites [90] Leon WC, Canneva F, Partridge V, Allard S, Ferretti MT, DeWilde A, Vercauteren F, Atifeh R, Ducatenzeiler A, Klein W et al (2010) A novel transgenic rat model with a full Alzheimer’s-like amyloid pathology displays pre-plaque intracellular amyloid-beta-associated cognitive impairment. J Alzheimer’s Dis 20:113–126. doi: 10.3233/JAD-2010-1349 source
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The majority of plaques are diffuse; only approximately 20% contained fibrillar Aβ [134, 146].”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
What the sources say
- Not checked yetcites [134] Sani S, Traul D, Klink A, Niaraki N, Gonzalo-Ruiz A, Wu CK, Geula C (2003) Distribution, progression and chemical composition of cortical amyloid-beta deposits in aged rhesus monkeys: similarities to the human. Acta Neuropathol 105:145–156. doi: 10.1007/s00401-002-0626-5 source
- Not checked yetcites [146] Shah P, Lal N, Leung E, Traul DE, Gonzalo-Ruiz A, Geula C (2010) Neuronal and axonal loss are selectively linked to fibrillar amyloid-β within plaques of the aged primate cerebral cortex. Am J Pathol 177:325–333. doi: 10.2353/ajpath.2010.090937 source
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“Focal neurons and glia containing phosphorylated tau have been observed in gorillas, but NFTs and tau positive dystrophic neurites are not present [112].”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
What the sources say
- Not checked yetcites [112] Perez SE, Raghanti MA, Hof PR, Kramer L, Ikonomovic MD, Lacor PN, Erwin JM, Sherwood CC, Mufson EJ (2013) Alzheimer’s disease pathology in the neocortex and hippocampus of the western lowland gorilla (Gorilla gorilla gorilla). J Comp Neurol 521:4318–4338. doi: 10.1002/cne.23428 source
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“All models have robust amyloid plaque expression (albeit at lower levels than in transgenic mice) and interestingly, TgF344-AD rats have NFTs [24], despite expression of only endogenous rat tau, not human tau.”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic rat models
What the sources say
- Not checked yetcites [24] Cohen RM, Rezai-Zadeh K, Weitz TM, Rentsendorj A, Gate D, Spivak I, Bholat Y, Vasilevko V, Glabe CG, Breunig JJ et al (2013) A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric abeta, and frank neuronal loss. J Neurosci 33:6245–6256. doi: 10.1523/JNEUROSCI.3672-12.2013 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Plaques are predominantly diffuse and less abundant than that found in human AD.”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Typically, great apes have more prevalent CAA, which is more likely to contain fibrillar Aβ than plaques.”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In contrast to great apes, parenchymal plaques are more prevalent than CAA in rhesus monkeys, with CAA present in approximately one third of aged rhesus monkeys [164, 165].”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
What the sources say
- Not checked yetcites [164] Uno H, Alsum PB, Dong S, Richardson R, Zimbric ML, Thieme CS, Houser WD (1996) Cerebral amyloid angiopathy and plaques, and visceral amyloidosis in aged macaques. Neurobiol Aging 17:275–281 source
- Not checked yetcites [165] Uno H, Walker LC (1993) The age of biosenescence and the incidence of cerebral beta-amyloidosis in aged captive rhesus monkeys. Ann N Y Acad Sci 695:232–235 source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“This data is consistent with the amyloid cascade hypothesis that suggests that Aβ plaques /Aβ oligomers kindle widespread tau/NFT pathology, with the latter representing the more direct cause of neuronal and synaptic loss that underlie the clinical disease[144].”
§ Alzheimer’s Disease: Experimental Models and Reality > AD neuropathology
What the sources say
- Not checked yetcites [144] Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 8:595–608. doi: 10.15252/emmm.201606210 source
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In the paper
“AD is defined in the brain by pathological accumulation of amyloid β (Aβ) into extracellular plaques in the brain parenchyma and in the vasculature (known as congophilic amyloid angiopathy [CAA]), and abnormally phosphorylated tau that accumulates intraneuronally forming neurofibrillary tangles (NFTs) [102, 136].”
§ Alzheimer’s Disease: Experimental Models and Reality > AD neuropathology
What the sources say
- Not checked yetcites [102] Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns N, Davies P, Tredici KD, Duyckaerts C, Frosch MP et al (2012) Correlation of Alzheimer’s disease neuropathologic changes with cognitive status: a review of the literature. JNEN 71:362–381
- Not checked yetcites [136] Scheltens P, Blennow K, Breteler MM, de Strooper B, Frisoni GB, Salloway S, Van der Flier WM (2016) Alzheimer’s disease. Lancet 388:505–517. doi: 10.1016/S0140-6736(15)01124-1 source
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In the paper
“FAD shows disproportionate subcortical Aβ42 accumulation, associated with enhanced striatal tau pathology [147].”
§ Alzheimer’s Disease: Experimental Models and Reality > AD neuropathology
What the sources say
- Not checked yetcites [147] Shinohara M, Fujioka S, Murray ME, Wojtas A, Baker M, Rovelet-Lecrux A, Rademakers R, Das P, Parisi JE, Graff-Radford NR et al (2014) Regional distribution of synaptic markers and APP correlate with distinct clinicopathological features in sporadic and familial Alzheimer’s disease. Brain 137:1533–1549. doi: 10.1093/brain/awu046 source
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In the paper
“These differences impair Aβ aggregation and prevent the formation of amyloid plaques in wild-type mice.”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models
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In the paper
“Initial transgenic models expressed wild-type human APP in mice, however while these transgenic mice had increased Aβ production, they failed to consistently show extensive AD associated neuropathology [14, 34, 117, 172, 173].”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models
What the sources say
- Not checked yetcites [14] Boutajangout A, Wisniewski T (2014) Tau-based therapeutic approaches for Alzheimer’s disease—a mini-review. Gerontology 60:381–385. doi: 10.1159/000358875 source
- Not checked yetcites [34] Dujardin S, Colin M, Buee L (2015) Invited review: animal models of tauopathies and their implications for research/translation into the clinic. Neuropathol Appl Neurobiol 41:59–80. doi: 10.1111/nan.12200 source
- Not checked yetcites [117] Puzzo D, Gulisano W, Palmeri A, Arancio O (2015) Rodent models for Alzheimer’s disease drug discovery. Expert Opin Drug Discov 10:703–711. doi: 10.1517/17460441.2015.1041913 source
- Not checked yetcites [172] Wisniewski T, Goni F (2015) Immunotherapeutic Approaches for Alzheimer’s Disease. Neuron 85:1162–1176 source
- Not checked yetcites [173] Wisniewski T, Sigurdsson EM (2010) Murine models of Alzheimer’s disease and their use in developing immunotherapies. Biochim Biophys Acta Mol Basis Dis 1802:847–859 source
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In the paper
“These results highlight the often overlooked fact that these animal models do not have AD, they only recapitulate specific pathological features, most commonly in a non-physiological manner designed to allow for efficient experiments.”
§ Alzheimer’s Disease: Experimental Models and Reality > Introduction
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In the paper
“Familial AD (FAD) results in an earlier age of onset and different neuropathological and clinical features compared to sAD [80, 127, 147, 156].”
§ Alzheimer’s Disease: Experimental Models and Reality > AD neuropathology
What the sources say
- Not checked yetcites [80] Knopman DS (2015) Is dominantly inherited Alzheimer disease a clone of sporadic Alzheimer disease? Neurology 85:750–751. doi: 10.1212/WNL.0000000000001897 source
- Not checked yetcites [127] Ryman DC, Acosta-Baena N, Aisen PS, Bird T, Danek A, Fox NC, Goate A, Frommelt P, Ghetti B, Langbaum JB et al (2014) Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology 83:253–260. doi: 10.1212/WNL.0000000000000596 source
- Not checked yetcites [147] Shinohara M, Fujioka S, Murray ME, Wojtas A, Baker M, Rovelet-Lecrux A, Rademakers R, Das P, Parisi JE, Graff-Radford NR et al (2014) Regional distribution of synaptic markers and APP correlate with distinct clinicopathological features in sporadic and familial Alzheimer’s disease. Brain 137:1533–1549. doi: 10.1093/brain/awu046 source
- Not checked yetcites [156] Tellechea P, Pujol N, Esteve-Belloch P, Echeveste B, Garcia-Eulate MR, Arbizu J, Riverol M (2015) Early- and late-onset Alzheimer disease: are they the same entity? Neurologia. doi: 10.1016/j.nrl.2015.08.002 source
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In the paper
“Definitive diagnosis of AD still depends on postmortem neuropathological assessment of both amyloid plaques and tau pathology, which are present together in very few AD models.”
§ Alzheimer’s Disease: Experimental Models and Reality > AD neuropathology
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In the paper
“However, in this scenario accumulation of Aβ pathology only has a prominent role in the preclinical and MCI stages of AD, while tau pathology is already prominent in early clinical AD.”
§ Alzheimer’s Disease: Experimental Models and Reality > AD neuropathology
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In the paper
“There have been many clinicopathological studies that have correlated amyloid plaques with cognitive deficits in AD, with an emerging picture that the strongest correlation exists in the earliest stages of the disease and this association greatly weakens as NFTs and neocortical degeneration become more widespread [9, 102, 103, 157, 160, 169].”
§ Alzheimer’s Disease: Experimental Models and Reality > AD neuropathology
What the sources say
- Not checked yetcites [9] Blessed G, Tomlinson BE (1968) The association between quantitative measures of dementia and senile change in the gray matter of elderly subjects. Br J Psychiatry 114:797–811 source
- Not checked yetcites [102] Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns N, Davies P, Tredici KD, Duyckaerts C, Frosch MP et al (2012) Correlation of Alzheimer’s disease neuropathologic changes with cognitive status: a review of the literature. JNEN 71:362–381
- Not checked yetcites [103] Nelson PT, Braak H, Markesbery WR (2009) Neuropathology and cognitive impairment in Alzheimer disease: a complex but coherent relationship. J Neuropathol Exp Neurol 68:1–14. doi: 10.1097/NEN.0b013e3181919a48 source
- Not checked yetcites [157] Thal DR, Rub U, Orantes M, Braak H (2002) Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58:1791–1800 source
- Not checked yetcites [160] Tomlinson BE, Blessed G, Roth M (1970) Observations on the brains of demented old people. J Neurol Sci 11:205–242 source
- Not checked yetcites [169] Webster SJ, Bachstetter AD, Nelson PT, Schmitt FA, Van Eldik LJ (2014) Using mice to model Alzheimer’s dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models. Front Genet 5:88. doi: 10.3389/fgene.2014.00088 source
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In the paper
“In addition, FAD shows significantly different development of associated neuropathology such as TDP-43 and argyrophilic grain disease compared to sAD; in the ADNI sAD cohort the latter two pathologies occurred in about 20% of subjects, while in the FAD DIAN cohort these pathologies were absent [18].”
§ Alzheimer’s Disease: Experimental Models and Reality > AD neuropathology
What the sources say
- Not checked yetcites [18] Cairns NJ, Perrin RJ, Franklin EE, Carter D, Vincent B, Xie M, Bateman RJ, Benzinger T, Friedrichsen K, Brooks WS et al (2015) Neuropathologic assessment of participants in two multi-center longitudinal observational studies: the Alzheimer Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN). Neuropathology 35:390–400. doi: 10.1111/neup.12205 source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“The necessity of these mutations for NFT development is an obvious limitation of these transgenic mouse models, as these mutations are not associated with AD in humans and the development of mutated tau may influence its toxicity or interaction with Aβ in a way that is not representative of what occurs in AD.”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Transgenic mice expressing tau
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In the paper
“However, 3xTg mice are still limited by the production of mutated Aβ and tau that is not representative of that in sAD and is highly over-expressed in a non-physiological manner.”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Transgenic mice with both plaques and tangles
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In the paper
“The limitation of these models is that they do not replicate all features of AD and therefore cannot be used as a complete model of AD.”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Unique transgenic mouse models useful for AD research
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In the paper
“Transgenic rats have a number of potential advantages over transgenic mice; they are more similar to humans in their physiological, morphological and genetic characteristics, their larger brain makes CSF collection, electrophysiology and imaging easier and they have a richer behavioral phenotype, making more complex behavioral testing possible [32].”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic rat models
What the sources say
- Not checked yetcites [32] Do Carmo S, Cuello AC (2013) Modeling Alzheimer’s disease in transgenic rats. Mol Neurodegener 8:37. doi: 10.1186/1750-1326-8-37 source
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In the paper
“Since the vast majority of AD transgenic models have pathology that is dependent on the expression of FAD mutations and most AD clinical trials are conducted in sAD patients, in whom AD pathogenesis has significant distinctions from FAD, this represents one stumbling block for the translatability of success in these models.”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models
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In the paper
“Of all of the models reported, only the 3xTg mouse model has been widely used in AD studies and is considered the most complete transgenic mouse model of AD pathology available[108].”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Transgenic mice with both plaques and tangles
What the sources say
- Not checked yetcites [108] Oddo S, Caccamo A, Kitazawa M, Tseng BP, LaFerla FM (2003) Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer’s disease. Neurobiol Aging 24:1063–1070 source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“This is likely due to the sequence differences between mouse and human tau (share only 88% sequence homology) and the fact that adult mice only express 4R isoforms, not a mixture of 3R and 4R isoforms that are present in humans.”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Transgenic mice expressing tau
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In the paper
“In contrast, NFTs readily form in transgenic mice that express human tau containing mutations associated with FTLD; the most commonly used models being those that express 4R tau with P301L or P301S mutations[49, 91, 92, 135, 177].”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Transgenic mice expressing tau
What the sources say
- Not checked yetcites [49] Gotz J, Ittner LM (2008) Animal models of Alzheimer’s disease and frontotemporal dementia. Nat Rev Neurosci 9:532–544 source
- Not checked yetcites [91] Lewis J, Dickson D, Lin WL, Chisholm L, Corral A, Jones G, Yen SH, Sahara N, Skipper L, Yager D et al (2001) Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293:1487–1491 source
- Not checked yetcites [92] Lewis J, McGowan E, Rockwood J, Melrose H, Nacharaju P, Van Slegtenhorst M, Gwinn-Hardy K, Murphy MP, Baker M, Yu X et al (2000) Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet 25:402–405 source
- Not checked yetcites [135] Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, Guimaraes A, DeTure M, Ramsden M, McGowan E et al (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309:476–481 source
- Not checked yetcites [177] Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, Maeda J, Suhara T, Trojanowski JQ, Lee VM (2007) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53:337–351 source
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In the paper
“which virtually all individuals with AD and about a third of aged cognitively normal individuals have) [68, 179]”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Unique transgenic mouse models useful for AD research
What the sources say
- Not checked yetcites [68] Jellinger KA (2002) Alzheimer disease and cerebrovascular pathology: an update. J Neural Transm 109:813–836 source
- Not checked yetcites [179] Zhang-Nunes SX, Maat-Schieman ML, Van Duinen SG, Roos RA, Frosch MP, Greenberg SM (2006) The cerebral beta-amyloid angiopathies: hereditary and sporadic. Brain Pathol 16:30–39 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Importantly, expression of all 6 isoforms of human tau only results in tangle formation in mice lacking endogenous tau, showing that endogenous mouse tau inhibits the aggregation of human tau [2].”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic mouse models > Transgenic mice expressing tau
What the sources say
- Not checked yetcites [2] Andorfer C, Kress Y, Espinoza M, de Silva R, Tucker KL, Barde YA, Duff K, Davies P (2003) Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J Neurochem 86:582–590 source
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In the paper
“Two of the major limitations of transgenic rodent models is that they model FAD and not sAD and that the pathology development in these models is typically non-physiological.”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models
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In the paper
“In sum, transgenic rats are potentially useful in AD research and offer specific advantages over transgenic mice; however the comparatively minimal use of these models means that greater characterization needs to be done to properly determine their suitability as models of AD.”
§ Alzheimer’s Disease: Experimental Models and Reality > Transgenic rat models
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In the paper
“Multiple species naturally develop neuropathological features similar to those seen in AD brain, and their potential as naturally occurring models of sAD has been examined.”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models
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In the paper
“Interestingly, aged baboons show heavy, but highly localized tauopathy in the hippocampus, which increases with age and is observed in 90% of animals over the age of 26 years [142].”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
What the sources say
- Not checked yetcites [142] Schultz C, Hubbard GB, Rub U, Braak E, Braak H (2000) Age-related progression of tau pathology in brains of baboons. Neurobiol Aging 21:905–912 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Both diffuse and compact plaques are present and AβN3pE is present in newly developed CAA and plaques at a ratio of approximately 1:1 with general Aβ [39].”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
What the sources say
- Not checked yetcites [39] Frost JL, Le KX, Cynis H, Ekpo E, Kleinschmidt M, Palmour RM, Ervin FR, Snigdha S, Cotman CW, Saido TC et al (2013) Pyroglutamate-3 amyloid-beta deposition in the brains of humans, non-human primates, canines, and Alzheimer disease-like transgenic mouse models. Am J Pathol 183:369–381 source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“However, limitations include lack of NFTs, lack of compact plaques, long lifespan and the lack of consistent pathology in all animals.”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Other physiological models
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In the paper
“Other neuropathological features present in aged dogs include cortical atrophy, declined ratio of CSF Aβ42:40, increased Aβ oligomers, and presence of oxidative damage and mitochondrial dysfunction [16].”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Other physiological models
What the sources say
- Not checked yetcites [16] Braidy N, Poljak A, Jayasena T, Mansour H, Inestrosa NC, Sachdev PS (2015) Accelerating Alzheimer’s research through ‘natural’ animal models. Curr Opin Psychiatry 28:155–164. doi: 10.1097/YCO.0000000000000137 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Plaques have been observed in grey mouse lemurs that are as young as 8 years old and both diffuse and compact plaques can be observed, predominantly in the cortex[11].”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
What the sources say
- Not checked yetcites [11] Bons N, Mestre N, Ritchie K, Petter A, Podlisny M, Selkoe D (1994) Identification of amyloid β protein in the brain of the small, short-lived lemurian primate Microcebus murinus. Neurobiol Aging 15:215–220 source
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In the paper
“It is evident that crosstalk between Aβ and tau can significantly influence toxicity; increased Aβ production results in NFT formation in FAD and Down Syndrome, while there is also evidence to show that tau increases Aβ-associated toxicity (particularly synaptotoxcity), suggesting that the presence of both pathological features are important to replicate the toxicity that occurs in human AD [106].”
§ Alzheimer’s Disease: Experimental Models and Reality > Factors to consider when choosing the best model
What the sources say
- Not checked yetcites [106] Nisbet RM, Polanco JC, Ittner LM, Gotz J (2015) Tau aggregation and its interplay with amyloid-beta. Acta Neuropathol 129:207–220. doi: 10.1007/s00401-014-1371-2 source
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In the paper
“Grey mouse lemurs have accumulation of intraneuronal phosphorylated tau, which increases with age, however this is predominantly observed in the cortex and not in the hippocampus (unlike in AD) [12, 47, 83].”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
What the sources say
- Not checked yetcites [12] Bons N, Rieger F, Prudhomme D, Fisher A, Krause KH (2006) Microcebus murinus: a useful primate model for human cerebral aging and Alzheimer’s disease? Genes Brain Behav 5:120–130. doi: 10.1111/j.1601-183X.2005.00149.x source
- Not checked yetcites [47] Giannakopoulos P, Silhol S, Jallageas V, Mallet J, Bons N, Bouras C, Delaère P (1997) Quantitative analysis of tau protein-immunoreactive accumulations and β amyloid protein deposits in the cerebral cortex of the mouse lemur, Microcebus murinus. Acta Neuropathol 94:131–139 source
- Not checked yetcites [83] Kraska A, Dorieux O, Picq JL, Petit F, Bourrin E, Chenu E, Volk A, Perret M, Hantraye P, Mestre-Frances N et al (2011) Age-associated cerebral atrophy in mouse lemur primates. Neurobiol Aging 32:894–906. doi: 10.1016/j.neurobiolaging.2009.05.018 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This is important because previous studies have shown that specific FAD mutations are associated with specific iPSC phenotypes and therefore sAD iPSC lines are likely to differ further.”
§ Alzheimer’s Disease: Experimental Models and Reality > Cell culture models
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Minimal phosphorylated tau is observed in occasional neurons, but no NFTs are present, even in aged animals [36].”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
What the sources say
- Not checked yetcites [36] Elfenbein HA, Rosen RF, Stephens SL, Switzer RC, Smith Y, Pare J, Mehta PD, Warzok R, Walker LC (2007) Cerebral beta-amyloid angiopathy in aged squirrel monkeys. Histol Histopathol 22:155–167
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Finally, despite greater sequence homology with human tau, very few physiological models have evidence of tauopathy and none have widespread presence of NFTs similar to that in AD.”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Other physiological models
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“One of the main advantages of using invertebrates is the ease of genetic manipulation and multiple transgenic lines expressing human APP, Aβ and tau have been developed for each species [1, 38, 111].”
§ Alzheimer’s Disease: Experimental Models and Reality > Drosophila, C. Elegans and zebrafish as AD models
What the sources say
- Not checked yetcites [1] Alexander AG, Marfil V, Li C (2014) Use of Caenorhabditis elegans as a model to study Alzheimer’s disease and other neurodegenerative diseases. Front Genet 5:279. doi: 10.3389/fgene.2014.00279 source
- Not checked yetcites [38] Fernandez-Funez P, de Mena L, Rincon-Limas DE (2015) Modeling the complex pathology of Alzheimer’s disease in Drosophila. Exp Neurol 274:58–71. doi: 10.1016/j.expneurol.2015.05.013 source
- Not checked yetcites [111] Paquet D, Bhat R, Sydow A, Mandelkow EM, Berg S, Hellberg S, Falting J, Distel M, Koster RW, Schmid B et al (2009) A zebrafish model of tauopathy allows in vivo imaging of neuronal cell death and drug evaluation. J Clin Invest 119:1382–1395. doi: 10.1172/JCI37537 source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In sum, non-human primates typically have age related Aβ pathology, but tauopathy is rare and/or very limited.”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
plain- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Rhesus monkeys do not have tauopathy despite a high sequence homology between human and rhesus monkey tau.
- Rests on an assumption: Vervets do not have NFTs.
None of the sources cited for this claim have been checked yet.
In the paper
“NFTs are typically not observed; however, pretangles and possible NFTs have been observed in a very limited number of aged, demented dogs [137, 148].”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Other physiological models
What the sources say
- Not checked yetcites [137] Schmidt F, Boltze J, Jager C, Hofmann S, Willems N, Seeger J, Hartig W, Stolzing A (2015) Detection and quantification of β-amyloid, pyroglutamyl Aβ, and tau in aged canines. J Neuropathol Exp Neurol 74:912–923. doi: 10.1097/NEN.0000000000000230 source
- Not checked yetcites [148] Smolek T, Madari A, Farbakova J, Kandrac O, Jadhav S, Cente M, Brezovakova V, Novak M, Zilka N (2016) Tau hyperphosphorylation in synaptosomes and neuroinflammation are associated with canine cognitive impairment. J Comp Neurol 524:874–895. doi: 10.1002/cne.23877 source
hedged- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“In addition, synaptosomes from demented dogs contain increased total and phosphorylated tau than non-demented dogs, suggesting that cognitive impairment in aged dogs may result from synaptic impairment [148].”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Other physiological models
What the sources say
- Not checked yetcites [148] Smolek T, Madari A, Farbakova J, Kandrac O, Jadhav S, Cente M, Brezovakova V, Novak M, Zilka N (2016) Tau hyperphosphorylation in synaptosomes and neuroinflammation are associated with canine cognitive impairment. J Comp Neurol 524:874–895. doi: 10.1002/cne.23877 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Some studies have found that Octodon degu have intracellular and extracellular accumulation of Aβ, plaques at old ages, intracellular tau accumulation, astrocytosis, synaptic changes and memory impairment that correlates with increased levels of oligomers (reviewed in [16, 131]).”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Other physiological models
What the sources say
- Not checked yetcites [16] Braidy N, Poljak A, Jayasena T, Mansour H, Inestrosa NC, Sachdev PS (2015) Accelerating Alzheimer’s research through ‘natural’ animal models. Curr Opin Psychiatry 28:155–164. doi: 10.1097/YCO.0000000000000137 source
- Not checked yetcites [131] Salazar C, Valdivia G, Ardiles AO, Ewer J, Palacios AG (2016) Genetic variants associated with neurodegenerative Alzheimer disease in natural models. Biol Res 49:14. doi: 10.1186/s40659-016-0072-9 source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It is important to note that the majority of these cell culture models have been generated from FAD donor cells and it will be necessary to increase the number of sAD lines available going forward to compare the different phenotypes between FAD and sAD.”
§ Alzheimer’s Disease: Experimental Models and Reality > Cell culture models
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It must be considered that downstream pathology may be artifacts that result from overexpression of APP, PS1 or tau, or from other APP cleavage products besides Aβ (eg N-APP, APP C-terminal fragments, AICD).”
§ Alzheimer’s Disease: Experimental Models and Reality > Factors to consider when choosing the best model
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Plaques are more commonly observed than CAA and plaques predominantly consist of Aβ42, while CAA consists of both Aβ40 and Aβ42 [98].”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
What the sources say
- Not checked yetcites [98] Mestre-Frances N, Keller E, Calenda A, Barelli H, Checler F, Bons N (2000) Immunohistochemical analysis of cerebral cortical and vascular lesions in the primate Microcebus murinus reveal distinct amyloid β1–42 and β1–40 immunoreactivity profiles. Neurobiol Dis 7:1–8. doi: 10.1006/nbdi.1999.0270 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Aged dogs have the same Aβ sequence as humans and they develop plaques and CAA starting at 8–9 years of age[137, 143, 148].”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Other physiological models
What the sources say
- Not checked yetcites [137] Schmidt F, Boltze J, Jager C, Hofmann S, Willems N, Seeger J, Hartig W, Stolzing A (2015) Detection and quantification of β-amyloid, pyroglutamyl Aβ, and tau in aged canines. J Neuropathol Exp Neurol 74:912–923. doi: 10.1097/NEN.0000000000000230 source
- Not checked yetcites [143] Schutt T, Helboe L, Pedersen LO, Waldemar G, Berendt M, Pedersen JT (2016) Dogs with cognitive dysfunction as a spontaneous model for early Alzheimer’s disease: a translational study of neuropathological and inflammatory markers. J Alzheimers Dis 52:433–449. doi: 10.3233/JAD-151085 source
- Not checked yetcites [148] Smolek T, Madari A, Farbakova J, Kandrac O, Jadhav S, Cente M, Brezovakova V, Novak M, Zilka N (2016) Tau hyperphosphorylation in synaptosomes and neuroinflammation are associated with canine cognitive impairment. J Comp Neurol 524:874–895. doi: 10.1002/cne.23877 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Cortical atrophy is observed a subpopulation of animals aged over 3 years[31, 83], which correlates with age-associated cognitive decline[114].”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Non-human primates
What the sources say
- Not checked yetcites [31] Dhenain M, Michot JL, Privat N, Picq JL, Boller F, Duyckaerts C, Volk A (2000) MRI description of cerebral atrophy in mouse lemur primates. Neurobiol Aging 21:81–88 source
- Not checked yetcites [83] Kraska A, Dorieux O, Picq JL, Petit F, Bourrin E, Chenu E, Volk A, Perret M, Hantraye P, Mestre-Frances N et al (2011) Age-associated cerebral atrophy in mouse lemur primates. Neurobiol Aging 32:894–906. doi: 10.1016/j.neurobiolaging.2009.05.018 source
- Not checked yetcites [114] Picq JL, Aujard F, Volk A, Dhenain M (2012) Age-related cerebral atrophy in nonhuman primates predicts cognitive impairments. Neurobiol Aging 33:1096–1109. doi: 10.1016/j.neurobiolaging.2010.09.009 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Overall, the sequence homology in genes of interest in AD is minimal between invertebrates and humans and these invertebrate orthologues often lack regions of these genes that are important in AD pathophysiology.”
§ Alzheimer’s Disease: Experimental Models and Reality > Drosophila, C. Elegans and zebrafish as AD models
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, these plaques differ from those in human AD as they are primarily diffuse, and therefore may represent an earlier stage of plaque development.”
§ Alzheimer’s Disease: Experimental Models and Reality > Physiological models > Other physiological models
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It is exceptionally important to acknowledge that none of the available models replicate all features of human AD, and therefore cannot be considered to be representative models of AD as a complete disease.”
§ Alzheimer’s Disease: Experimental Models and Reality > Factors to consider when choosing the best model
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Some iPSC lines also have evidence of additional AD-associated pathology such as increased activation of GSK3β [66], increased number of large endosomes [66], and accumulation of intraneuronal Aβ oligomers [82].”
§ Alzheimer’s Disease: Experimental Models and Reality > Cell culture models
What the sources say
- Not checked yetcites [66] Israel MA, Yuan SH, Bardy C, Reyna SM, Mu Y, Herrera C, Hefferan MP, Van Gorp S, Nazor KL, Boscolo FS et al (2012) Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature 482:216–220. doi: 10.1038/nature10821 source
- Not checked yetcites [82] Kondo T, Asai M, Tsukita K, Kutoku Y, Ohsawa Y, Sunada Y, Imamura K, Egawa N, Yahata N, Okita K et al (2013) Modeling Alzheimer’s disease with iPSCs reveals stress phenotypes associated with intracellular Abeta and differential drug responsiveness. Cell Stem Cell 12:487–496. doi: 10.1016/j.stem.2013.01.009 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Expression of mouse ApoE resulted in greater plaque formation than expression of human ApoE, and mouse ApoE preferentially promoted the formation of parenchymal plaques, while human ApoE promoted the formation of CAA [59, 60, 94].”
§ Alzheimer’s Disease: Experimental Models and Reality > Factors to consider when choosing the best model
What the sources say
- Not checked yetcites [59] Holtzman DM, Bales KR, Tenkova T, Fagan AM, Parsadanian M, Sartorius LJ, Mackey B, Olney J, McKeel D, Wozniak D et al (2000) Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer’s disease. PNAS 97:2892–2897 source
- Not checked yetcites [60] Holtzman DM, Bales KR, Wu S, Bhat P, Parsadanian M, Fagan AM, Chang LK, Sun Y, Paul SM (1999) Expression of human apolipoprotein E reduces amyloid-beta deposition in a mouse model of Alzheimer’s disease. J Clin Invest 103:R15–R21 source
- Not checked yetcites [94] Liao F, Zhang TJ, Jiang H, Lefton KB, Robinson GO, Vassar R, Sullivan PM, Holtzman DM (2015) Murine versus human apolipoprotein E4: differential facilitation of and co-localization in cerebral amyloid angiopathy and amyloid plaques in APP transgenic mouse models. Acta Neuropathol Commun 3:70. doi: 10.1186/s40478-015-0250-y source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“New human cell culture models have the advantage of allowing high-throughput screening of novel therapeutics directly using human cells; however these models obviously cannot replace in vivo models for preclinical testing.”
§ Alzheimer’s Disease: Experimental Models and Reality > Conclusion
boosted- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Non-human primates offer the unique advantages of greater genetic similarity to humans and a more physiological relevant development of pathology that better resembles that in found in sAD compared to transgenic models, but studies are limited by availability, costs, time until onset of phenotype and the inconsistent presence of pathology in all animals.”
§ Alzheimer’s Disease: Experimental Models and Reality > Conclusion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Despite some mutations in PS1 causing the earliest onset of FAD in humans, sole expression of human PS1 with FAD mutations doesn’t result development of plaques in transgenic mice [138, 154], showing that the response of endogenous mouse proteins to human PS1 is different from that in humans.”
§ Alzheimer’s Disease: Experimental Models and Reality > Factors to consider when choosing the best model
What the sources say
- Not checked yetcites [138] Schneider I, Reverse D, Dewachter I, Ris L, Caluwaerts N, Kuiperi C, Gilis M, Geerts H, Kretzschmar H, Godaux E et al (2001) Mutant presenilins disturb neuronal calcium homeostasis in the brain of transgenic mice, decreasing the threshold for excitotoxicity and facilitating long-term potentiation. J Biol Chem 276:11539–11544. doi: 10.1074/jbc.M010977200 source
- Not checked yetcites [154] Takeuchi A, Irizarry MC, Duff K, Saido T, Hsiao Ashe K, Hasegawa H, Mann DM, Hyman BT, Iwatsubo T (2000) Age-related amyloid & #x03B2; deposition in transgenic mice overexpressing both Alzheimer mutant presenilin 1 and amylo β precursor protein swedish mutant is not associated with global neuronal loss. AJP 157:331–339
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“In contrast, initial studies show that more physiological knock-in mouse models develop cognitive impairment many months after plaque development [129], which is more similar to humans.”
§ Alzheimer’s Disease: Experimental Models and Reality > Factors to consider when choosing the best model
What the sources say
- Not checked yetcites [129] Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, Iwata N, Saido TC (2014) Single App knock-in mouse models of Alzheimer’s disease. Nat Neurosci 17:661–663. doi: 10.1038/nn.3697 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As mentioned above, cognitive impairment occurs at a different stage of pathology development in transgenic mouse and rat models in comparison to humans; occurring at or before the onset of plaque development in rodents and many decades after plaque development in humans.”
§ Alzheimer’s Disease: Experimental Models and Reality > Factors to consider when choosing the best model
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It must also be considered that endogenous rodent proteins and/or protein pathways may react differently in response to non-physiological expression of specific human proteins and as such, downstream effects cannot be assumed to also occur in humans.”
§ Alzheimer’s Disease: Experimental Models and Reality > Factors to consider when choosing the best model
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Animal models have the obvious advantage of providing the option to do preclinical testing in vivo, allowing the testing of general toxicity of new therapeutics and providing a system in which cognitive testing can be done.”
§ Alzheimer’s Disease: Experimental Models and Reality > Conclusion
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, despite similarities between FAD and sAD, the underlying cause of the two subtypes of AD are very different; FAD directly resulting from Aβ over-expression and sAD likely resulting from multiple factors that contribute to poor clearance of Aβ from the brain.”
§ Alzheimer’s Disease: Experimental Models and Reality > Factors to consider when choosing the best model
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
- Rests on an assumption: FAD directly results from Aβ over-expression and sAD likely results from multiple factors that contribute to poor clearance of Aβ from the brain.
In the paper
“An elegant study supporting this hypothesis showed that crossing the APP E693Δ-Tg model with wild-type human tau mice resulted in robust formation of NFTs, which never developed in mice with endogenous mouse tau [163].”
§ Alzheimer’s Disease: Experimental Models and Reality > Factors to consider when choosing the best model
What the sources say
- Not checked yetcites [163] Umeda T, Maekawa S, Kimura T, Takashima A, Tomiyama T, Mori H (2014) Neurofibrillary tangle formation by introducing wild-type human tau into APP transgenic mice. Acta Neuropathol 127:685–698. doi: 10.1007/s00401-014-1259-1 source
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“New knock-in mouse models are potentially more representative and physiological models of AD; however, they still need to be further validated in future studies.”
§ Alzheimer’s Disease: Experimental Models and Reality > Conclusion
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Transgenic animal models represent partial models of FAD and not sAD.”
§ Alzheimer’s Disease: Experimental Models and Reality > Factors to consider when choosing the best model
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Ultimately, this raises the concern that other human transgenes of interest (e.g. other loci identified in GWAS studies) may also have to be co-expressed in AD transgenic models in order to replicate the protein interactions that occur in AD.”
§ Alzheimer’s Disease: Experimental Models and Reality > Factors to consider when choosing the best model
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“For example, transgenic mice expressing human APP on the C57BL6 background produce much less of the CT99 and CT83 fragments that are most prominent in humans [37, 64], which potentially complicates the translation of results from studies testing β- or γ-secretase targeting therapeutics in these transgenic mice to humans.”
§ Alzheimer’s Disease: Experimental Models and Reality > Factors to consider when choosing the best model
What the sources say
- Not checked yetcites [37] Esh C, Patton L, Kalback W, Kokjohn TA, Lopez J, Brune D, Newell AJ, Beach T, Schenk D, Games D et al (2005) Altered APP processing in PDAPP (Val717 –>Phe) transgenic mice yields extended-length Aβ peptides. Biochemistry 44:13807–13819. doi: 10.1021/bi051213+ source
- Not checked yetcites [64] Hunter JM, Bowers WJ, Maarouf CL, Mastrangelo MA, Daugs ID, Kokjohn TA, Kalback WM, Luehrs DC, Valla J, Beach TG et al (2011) Biochemical and morphological characterization of the AβPP/PS/tau triple transgenic mouse model and its relevance to sporadic Alzheimer’s disease. J Alzheimers Dis 27:361–376 source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“For example, plaque cores from transgenic mice are much more soluble than those in human AD, which has been suggested to result from the lack of Aβ post-translational modifications in transgenic mice (such as N-terminal degradation, isomerization, racemization, pyrogluamyl formation and oxidation) [37, 71, 85].”
§ Alzheimer’s Disease: Experimental Models and Reality > Factors to consider when choosing the best model
What the sources say
- Not checked yetcites [37] Esh C, Patton L, Kalback W, Kokjohn TA, Lopez J, Brune D, Newell AJ, Beach T, Schenk D, Games D et al (2005) Altered APP processing in PDAPP (Val717 –>Phe) transgenic mice yields extended-length Aβ peptides. Biochemistry 44:13807–13819. doi: 10.1021/bi051213+ source
- Not checked yetcites [71] Kalback W, Watson MD, Kokjohn TA, Kuo YM, Weiss N, Luehrs DC, Lopez J, Brune D, Sisodia SS, Staufenbiel M et al (2002) APP transgenic mice Tg2576 accumulate Aβ peptides that are distinct from the chemically modified and insoluble peptides deposited in Alzheimer’s disease senile plaques. Biochemistry 41:922–928 source
- Not checked yetcites [85] Kuo YM, Kokjohn TA, Beach TG, Sue LI, Brune D, Lopez JC, Kalback WM, Abramowski D, Sturchler-Pierrat C, Staufenbiel M et al (2001) Comparitive analysis of amyloid-beta chemical structure and amyloid plaque morphology of transgenic mouse and Alzheimer’s disease brains. JBC 276:12991–12998 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
AD is unique to humans.
“AD is a complex, multi-factorial disease, and one that appears to be unique to humans.”
The paper relies on this without support.
The presence of both plaques and tangles is required for diagnosis of AD.
“The presence of both plaques and tangles is required for diagnosis of AD”
The paper relies on this without support.
Rhesus monkeys do not have tauopathy despite a high sequence homology between human and rhesus monkey tau.
“Rhesus monkeys do not have tauopathy, despite a high sequence homology between human and rhesus monkey tau.”
The paper relies on this without support.
Vervets do not have NFTs.
“No NFTs are present.”
The paper relies on this without support.
Squirrel monkey plaques are typically smaller than plaques in human AD.
“Plaques are also present, which can be either diffuse or compact and are typically smaller than plaques in human AD.”
The paper relies on this without support.
Aβ deposition in squirrel monkeys is mostly observed in the cortex and amygdala with little deposition in the hippocampus.
“Aβ deposition is mostly observed in the cortex and amygdala with little deposition in the hippocampus.”
The paper relies on this without support.
The maximum lifespan of grey mouse lemurs is 18 years in captivity.
“The maximum lifespan of these prosimians is 18 years in captivity.”
The paper relies on this without support.
The most prevalent symptom of AD in humans is cognitive impairment.
“The most prevalent symptom of AD in humans is cognitive impairment.”
The paper relies on this without support.
ApoE4 is the strongest identified genetic risk factor linked to sAD.
“ApoE4, which is the strongest identified genetic risk factor linked to sAD”
The paper relies on this without support.
FAD directly results from Aβ over-expression and sAD likely results from multiple factors that contribute to poor clearance of Aβ from the brain.
“FAD directly resulting from Aβ over-expression and sAD likely resulting from multiple factors that contribute to poor clearance of Aβ from the brain.”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The high failure rate of agents in clinical trials and relatively limited drug development for AD reflect the biological disconnect and thus restricted translatability between mouse models and human pathology.”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [86]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Modelling all aspects of AD pathology in an experimental animal setting is difficult. This can be attributed in part to (1) the disease being unique to humans, as far as we know, (2) the multifactorial nature of AD having both genetic and environmental etiologies, and (3) the high variability in disease onset, development and progression among patients [86]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [86]
The cited source says what the claim attributes to it.
In the citing paper
“These transgenic mice express human genes that result in the formation of amyloid plaques (APP or PSEN1) and/or neurofibrillary tangles (MAPT), with other aspects of human pathology incompletely represented, such as memory-associated cognitive impairments, contribution of aging, neuronal loss, widespread neurodegeneration and regional brain atrophy [86, 325]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [86]
The cited source says what the claim attributes to it.
In the citing paper
“However, we also acknowledge that our analysis of AD-specific validation was limited by the lack of existing comprehensive experimental models for AD (Drummond and Wisniewski, 2017).”
From Drug repurposing for Alzheimer’s disease from 2012–2022—a 10-year literature review (2023) · cites this paper as Drummond and Wisniewski, 2017
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“This is further exacerbated by the limited availability of human biomarkers, longer trial durations and prohibitively high trial costs [68, 86, 102]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [86]
Experimental — accuracy not yet measured
In the citing paper
“Familial neurodegenerative disease is rare and the pathological processes driving it may be substantially different than those driving sporadic disease (100).”
From The Transcriptional Landscape of Microglial Genes in Aging and Neurodegenerative Disease (2019) · cites this paper as [100]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Alzheimer’s Disease: Experimental Models and Reality > Conclusion
“The very poor success rate of ~99.6% with AD targeting clinical trials”
§ Alzheimer’s Disease: Experimental Models and Reality > Introduction
“the very high failure rate of clinical trials of AD therapeutics (of ~99.6%)”
Citations
Cites
1 retracted
RETRACTED ARTICLE: APP binds DR6 to trigger axon pruning and neuron death via distinct caspases
Nikolaev, A., McLaughlin, T., O’Leary, D. D. M., & Tessier-Lavigne, M. (2009) · Nature · doi:10.1038/nature07767 · Cited by 992
RetractedNeuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123 · cited 1×
“A further complication is that there is extensive evidence showing medial temporal tauopathy predates Aβ deposition [15, 25, 35], presumably Fig.”
BackgroundAmyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359
The amyloid hypothesis of Alzheimer's disease at 25 years
Selkoe, D. J., & Hardy, J. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201606210 · Cited by 6,164
Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice
Hsiao, K., Chapman, P., Nilsen, S., Eckman, C., Harigaya, Y., Younkin, S., Yang, F., & Cole, G. (1996) · Science · doi:10.1126/science.274.5284.99 · Cited by 4,210
Triple-Transgenic Model of Alzheimer’s Disease with Plaques and Tangles
Oddo, S., Caccamo, A., Shepherd, J. D., Murphy, M. P., Golde, T. E., Kayed, R., Metherate, R., Mattson, M. P., Akbari, Y., & LaFerla, F. M. (2003) · Neuron · doi:10.1016/s0896-6273(03)00434-3 · Cited by 4,126
Blessed, G., Tomlinson, B. E., & Roth, M. (1968) · British Journal of Psychiatry · doi:10.1192/bjp.114.512.797 · Cited by 4,117
Oakley, H., Cole, S. L., Logan, S., Maus, E., Shao, P., Craft, J., Guillozet-Bongaarts, A., Ohno, M., Disterhoft, J., Van Eldik, L., et al. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.1202-06.2006 · Cited by 3,530 · cited 2×
“The other major limitation of these mouse models was that while some showed evidence of localized hyperphosphorylated tau that may represent “pretangles” [107, 118, 151, 159], none developed neurofibrillary tangles.”
BackgroundPhases of Aβ-deposition in the human brain and its relevance for the development of AD
Thal, D. R., Rüb, U., Orantes, M., & Braak, H. (2002) · Neurology · doi:10.1212/wnl.58.12.1791 · Cited by 3,490
Scheltens, P., Blennow, K., Breteler, M. M. B., de Strooper, B., Frisoni, G. B., Salloway, S., & Van der Flier, W. M. (2016) · The Lancet · doi:10.1016/s0140-6736(15)01124-1 · Cited by 3,125
Research works printed but not linked: 1
- Lemere CA, Iglesias M, Spooner ET, Bloom JK, Leverone JF, Li D, Zheng JB, Seabrook TJ, Selkoe D, Ervin FR et al (2003) Aβ immunization in aged vervet monkeys reduces Aβ levels in brain and CSF. Soc Neurosci Abst 133(5):5
Cited by
Sorted by citations
Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future
Zhang, Y., Chen, H., Li, R., Sterling, K., & Song, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01484-7 · Cited by 988
“In order to study Alzheimer’s pathogenesis and therapeutic strategies, better animal models to recapitulate the natural process of the disease are required.(443,444) Many transgenic mouse models have been developed and commonly used, including the mice containing mutations in the APP (e.”
BackgroundAPP mouse models for Alzheimer’s disease preclinical studies.
Sasaguri, H., Nilsson, P., Hashimoto, S., Nagata, K., Saito, T., De Strooper, B., Hardy, J., Vassar, R., Winblad, B., & Saido, T. C. (2017) · The EMBO Journal · doi:10.15252/embj.201797397 · Cited by 793
Savelieff, M. G., Nam, G., Kang, J., Lee, H. J., Lee, M., & Lim, M. H. (2018) · Chemical Reviews · doi:10.1021/acs.chemrev.8b00138 · Cited by 612
Systematic phenotyping and characterization of the 5xFAD mouse model of Alzheimer’s disease.
Forner, S., Kawauchi, S., Balderrama-Gutierrez, G., Kramár, E. A., Matheos, D. P., Phan, J., Javonillo, D. I., Tran, K. M., Hingco, E., da Cunha, C., et al. (2021) · Scientific Data · doi:10.1038/s41597-021-01054-y · Cited by 501
Molecular characterization of selectively vulnerable neurons in Alzheimer’s disease
Leng, K., Li, E., Eser, R., Piergies, A., Sit, R., Tan, M., Neff, N., Li, S. H., Rodriguez, R. D., Suemoto, C. K., et al. (2021) · Nature Neuroscience · doi:10.1038/s41593-020-00764-7 · Cited by 485
Metadata
- Authors
- Drummond, E., & Wisniewski, T.
- Affiliations
- NYU Langone Health (US)
- ORCID
- Drummond, Eleanor
- Venue
- Acta Neuropathologica
- Published
- 2016-12-26
- Volume
- 133
- Issue
- 2
- Pages
- 155-175
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC5253109
- OpenAlex
- W2563078526
- Semantic Scholar
- 14b0f96edcf55616021a5539c0bde2ef324c0a5c
- Cited by
- 810
- References
- 182
- Citations by year
- 2026: 81 · 2025: 93 · 2024: 123 · 2023: 115 · 2022: 117 · 2021: 111 · 2020: 84 · 2019: 36 · 2018: 31 · 2017: 18
- FWCI
- 3.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Acta Neuropathologica (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (AG08051)
- National Institute of Neurological Disorders and Stroke (NS073502)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, animal models of Alzheimer's disease, transgenic mice, familial Alzheimer's disease, amyloid plaques, neurofibrillary tangles, sporadic Alzheimer's disease, transgenic rats, in vitro cell culture model, translational failure, clinical trial failure, drug target validation
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Humans, Animals, Genetically Modified
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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