CoChat
Sign Up
Cited by 811Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Alzheimer's disease: experimental models and reality

Open access
Drummond, Eleanor, Wisniewski, Thomas·2017·Acta Neuropathologica
DOI 10.1007/s00401-016-1662-xPMC PMC5253109
Open this paper in CoChat — free account

Abstract

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.

AI snapshot

Written from the paper’s full text.

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.

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

Integrity signals

Registry

Crossref · 10.1007/s00401-016-1662-x

Cites

182 of 182 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 168 cited sources checked · 0 supported · 0 flagged

  • Findingnone given

    Overall, transgenic mice expressing human APP, with or without human PSEN1, have robust plaque formation, particularly in brain regions typically rich in plaques in AD such as the cortex and hippocampus.

    “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.”
    Quote in the paperSubstantial claim
  • Findingnone given

    CAA in Tg-SwDI mice is mainly present in capillaries, in contrast to the prominent arteriolar CAA in AD.

    “CAA is mainly present in capillaries, in contrast to the prominent arteriolar CAA in AD.”
    Quote in the paperNot a substantial claim
  • Findingcitation

    Knock-in of the Swedish, London and Dutch mutations only results in the development of plaques if bred onto a PS1M146V knock-in background.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Findingcitation

    Tg-SwDI mice develop robust accumulation of fibrillar vascular Aβ and less prominent diffuse parenchymal plaques, starting at 3 months of age.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Findingnone given

    These transgenic mice all have evidence of cognitive impairment, particularly in spatial memory tasks.

    “They all have evidence of cognitive impairment, particularly in spatial memory tasks.”
    Quote in the paperSubstantial claim
  • May combine two claims. 87
  • Classified as probably not a substantial claim. 3

  • May combine two claims.

    Findingnone given

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    3xTg mice form NFTs at approximately 12 months, initially in CA1 and then in the cortex; however, they are much less extensive compared to AD tissue.

    “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).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Findingnone given

    3xTg mice also have minor, localized neurodegeneration, evidence of synaptic impairment and cognitive deficits from 6 months.

    “Mice also have minor, localized neurodegeneration, evidence of synaptic impairment and cognitive deficits from 6 months (Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    Over-expression of mutated tau results in significant motor deficits that are not seen in AD and interfere with cognitive testing.

    “Furthermore, over-expression of mutated tau results in significant motor deficits that are not seen in AD and interfere with cognitive testing.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    These tau transgenic mice develop NFTs, neurodegeneration, atrophy and motor deficits.

    “These mice develop NFTs, neurodegeneration, atrophy and motor deficits.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    3xTg mice first develop intraneuronal Aβ at 3-4 months, followed by plaque development at approximately 6 months in the cortex and hippocampus.

    “3xTg mice first develop intraneuronal Aβ at 3–4 months, followed by plaque development at approximately 6 months in the cortex and hippocampus.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    All transgenic mice expressing human APP, with or without human PSEN1, 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.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    Tg-SwDI mice also have localized neurodegeneration of cholinergic neurons and cognitive impairment.

    “Tg-SwDI mice also have localized neurodegeneration of cholinergic neurons and cognitive impairment (Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    The APP E693Δ-Tg model expresses the Osaka (APPE693Δ) mutation, which results in significantly increased expression of Aβ oligomers, synaptic impairment and cognitive impairments from 8 months of age, but no plaque or tau pathology formation.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Findingreasoning

    In 3xTg mice, widespread presence of plaques and tangles is typically not observed until old age and even then the pathology is less than typically seen in AD.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Plaques are typically found in rhesus monkeys older than 25 years and have a similar distribution to humans, with more present in the cortex than the hippocampus.

    “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].”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [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 in the free run.

    • cites [56] Heilbroner PL, Kemper TL (1990) The cytoarchitectonic distribution of senile plaques in three aged monkeys. Acta Neuropathol 81:60–65 source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Minor neuronal loss is observed immediately around compact plaques in rhesus monkeys; however, there is no evidence of widespread neuronal loss, even in brain regions with a high plaque load.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Findingcitation

    Great apes are capable of forming NFTs, but this is a rare event that has only been observed in one chimpanzee studied.

    “Great apes are capable of forming NFTs [124], but this is a rare event that has only been observed in one chimpanzee studied.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Aβ levels accumulate with age in rhesus monkeys, reaching similar levels in the cortex to that observed in human AD, and there is often more Aβ42 than Aβ40.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    All transgenic 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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    The majority of plaques in rhesus monkeys are diffuse; only approximately 20% contained fibrillar Aβ.

    “The majority of plaques are diffuse; only approximately 20% contained fibrillar Aβ [134, 146].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Findingcitation

    Focal neurons and glia containing phosphorylated tau have been observed in gorillas, but NFTs and tau positive dystrophic neurites are not present.

    “Focal neurons and glia containing phosphorylated tau have been observed in gorillas, but NFTs and tau positive dystrophic neurites are not present [112].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Findingcitation

    All transgenic rat models have robust amyloid plaque expression (albeit at lower levels than in transgenic mice) and TgF344-AD rats have NFTs despite expression of only endogenous rat tau, not human tau.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Findingnone given

    In great apes, plaques are predominantly diffuse and less abundant than in human AD.

    “Plaques are predominantly diffuse and less abundant than that found in human AD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    Typically, great apes have more prevalent CAA, which is more likely to contain fibrillar Aβ than plaques.

    “Typically, great apes have more prevalent CAA, which is more likely to contain fibrillar Aβ than plaques.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The data are consistent with the amyloid cascade hypothesis 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.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

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

    Premisecitation

    AD is defined in the brain by pathological accumulation of Aβ into extracellular plaques in brain parenchyma and vasculature (CAA), and abnormally phosphorylated tau that accumulates intraneuronally forming neurofibrillary tangles.

    “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].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FAD shows disproportionate subcortical Aβ42 accumulation, associated with enhanced striatal tau pathology.

    “FAD shows disproportionate subcortical Aβ42 accumulation, associated with enhanced striatal tau pathology [147].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisereasoning

    These sequence differences impair Aβ aggregation and prevent the formation of amyloid plaques in wild-type mice.

    “These differences impair Aβ aggregation and prevent the formation of amyloid plaques in wild-type mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Initial transgenic models expressing wild-type human APP in mice had increased Aβ production but failed to consistently show extensive AD-associated neuropathology.

    “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].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [172] Wisniewski T, Goni F (2015) Immunotherapeutic Approaches for Alzheimer’s Disease. Neuron 85:1162–1176 source

      Not checked in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Animal models of AD do not have AD; they only recapitulate specific pathological features, most commonly in a non-physiological manner designed to allow efficient experiments.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Familial AD results in an earlier age of onset and different neuropathological and clinical features compared to sporadic AD.

    “Familial AD (FAD) results in an earlier age of onset and different neuropathological and clinical features compared to sAD [80, 127, 147, 156].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    In the amyloid cascade 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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Many clinicopathological studies have correlated amyloid plaques with cognitive deficits in AD, with the strongest correlation in the earliest stages of the disease and this association greatly weakens as NFTs and neocortical degeneration become more widespread.

    “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].”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The necessity of FTLD mutations for NFT development is a limitation because these mutations are not associated with AD in humans and mutated tau may influence its toxicity or interaction with Aβ in a way not representative of AD.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    3xTg mice are limited by production of mutated Aβ and tau that is not representative of sAD and is highly over-expressed in a non-physiological manner.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The limitation of Tg-SwDI and APP E693Δ-Tg models is that they do not replicate all features of AD and therefore cannot be used as a complete model of AD.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Transgenic rats have potential advantages over transgenic mice: they are more similar to humans in 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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Since the vast majority of AD transgenic models have pathology dependent on 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 translatability of success in these models.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Of all reported models, 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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The failure of wild-type mouse tau to develop neurofibrillary tangles is likely due to sequence differences between mouse and human tau (88% sequence homology) and the fact that adult mice only express 4R isoforms, not a mixture of 3R and 4R isoforms present in humans.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    NFTs readily form in transgenic mice that express human tau containing mutations associated with FTLD; the most commonly used models express 4R tau with P301L or P301S mutations.

    “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].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [49] Gotz J, Ittner LM (2008) Animal models of Alzheimer’s disease and frontotemporal dementia. Nat Rev Neurosci 9:532–544 source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Virtually all individuals with AD and about a third of aged cognitively normal individuals have CAA.

    “which virtually all individuals with AD and about a third of aged cognitively normal individuals have) [68, 179]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [68] Jellinger KA (2002) Alzheimer disease and cerebrovascular pathology: an update. J Neural Transm 109:813–836 source

      Not checked in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Two major limitations of transgenic rodent models are that they model FAD and not sAD and that pathology development in these models is typically non-physiological.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vervets, 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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Limitations of aged dogs include lack of NFTs, lack of compact plaques, long lifespan and lack of consistent pathology in all animals.

    “However, limitations include lack of NFTs, lack of compact plaques, long lifespan and the lack of consistent pathology in all animals.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    Plaques have been observed in grey mouse lemurs as young as 8 years old and both diffuse and compact plaques can be observed, predominantly in the cortex.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Crosstalk between Aβ and tau can significantly influence toxicity; increased Aβ production results in NFT formation in FAD and Down Syndrome, while tau increases Aβ-associated toxicity, suggesting that the presence of both pathological features is important to replicate the toxicity that occurs in human AD.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Grey mouse lemurs have accumulation of intraneuronal phosphorylated tau, which increases with age, predominantly in the cortex and not in the hippocampus (unlike in AD).

    “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].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Premisenone given

    Previous studies have shown that specific FAD mutations are associated with specific iPSC phenotypes and therefore sAD iPSC lines are likely to differ further.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Minimal phosphorylated tau is observed in occasional neurons in squirrel monkeys, but no NFTs are present, even in aged animals.

    “Minimal phosphorylated tau is observed in occasional neurons, but no NFTs are present, even in aged animals [36].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Non-human primates typically have age related Aβ pathology, but tauopathy is rare and/or very limited.

    “In sum, non-human primates typically have age related Aβ pathology, but tauopathy is rare and/or very limited.”
    Quote in the paperSubstantial claim
    • 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.

  • May combine two claims.

    Premisecitation

    NFTs are typically not observed in aged dogs; however, pretangles and possible NFTs have been observed in a very limited number of aged, demented dogs.

    “NFTs are typically not observed; however, pretangles and possible NFTs have been observed in a very limited number of aged, demented dogs [137, 148].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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]).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

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

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    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).

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In grey mouse lemurs, plaques are more commonly observed than CAA and plaques predominantly consist of Aβ42, while CAA consists of both Aβ40 and Aβ42.

    “Plaques are more commonly observed than CAA and plaques predominantly consist of Aβ42, while CAA consists of both Aβ40 and Aβ42 [98].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aged dogs have the same Aβ sequence as humans and they develop plaques and CAA starting at 8-9 years of age.

    “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].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cortical atrophy is observed in a subpopulation of grey mouse lemurs aged over 3 years, which correlates with age-associated cognitive decline.

    “Cortical atrophy is observed a subpopulation of animals aged over 3 years[31, 83], which correlates with age-associated cognitive decline[114].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Dog plaques differ from those in human AD as they are primarily diffuse, and therefore may represent an earlier stage of plaque development.

    “However, these plaques differ from those in human AD as they are primarily diffuse, and therefore may represent an earlier stage of plaque development.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Some iPSC lines have evidence of additional AD-associated pathology such as increased activation of GSK3β, increased number of large endosomes, and accumulation of intraneuronal Aβ oligomers.

    “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].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    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 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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Sole expression of human PS1 with FAD mutations does not result in development of plaques in transgenic mice, despite some mutations in PS1 causing the earliest onset of FAD in humans.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Initial studies show that more physiological knock-in mouse models develop cognitive impairment many months after plaque development, which is more similar to humans.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Despite similarities between FAD and sAD, the underlying cause of the two subtypes of AD are very different; FAD directly results from Aβ over-expression and sAD likely results from multiple factors that contribute to poor clearance of Aβ from the brain.

    “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.”
    Quote in the paperNot a substantial claim
    • 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.

  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Transgenic animal models represent partial models of FAD and not sAD.

    “Transgenic animal models represent partial models of FAD and not sAD.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Transgenic mice expressing human APP on the C57BL6 background produce much less of the CT99 and CT83 fragments that are most prominent in humans, which potentially complicates the translation of results from studies testing β- or γ-secretase targeting therapeutics in these transgenic mice to humans.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

88 of 88

  • 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.”
10 of 10

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?

  • High failure rate and limited drug development reflect biological disconnect and restricted translatability between mouse models and human pathology.

    “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]

    The Introduction and Conclusion report a roughly 99.6% failure rate in AD clinical trials and say that differences between animal models and human pathology may partly explain poor translation. The paper does not establish that this disconnect accounts for relatively limited drug development, and it presents the explanation for trial failures as partial rather than definitive. No page numbers are available in our copy. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Modelling all aspects of AD pathology in animals is difficult due to disease being unique to humans, multifactorial, and variable.

    “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]

  • Transgenic AD mice express human genes causing amyloid plaques and/or tangles, with other aspects incompletely represented.

    “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 analysis of AD-specific validation was limited by the lack of existing comprehensive experimental models for AD.

    “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

  • Limited availability of human biomarkers, longer trial durations, and high trial costs exacerbate the disconnect.

    “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]

    The Conclusion says non-human primate studies are limited by cost and time until disease features appear, but it does not make those claims about human clinical trials. The AD neuropathology section describes human biomarker assays without saying they are scarce. Searches for limited human biomarkers and clinical-trial duration and costs found no passage supporting the attributed factors. (LLM, conf=0.74)

    Experimental — accuracy not yet measured

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.

  • 99.6% is called both a success rate and a failure rate

    Minor

    The conclusion calls 99.6% the clinical-trial success rate, while the introduction identifies the same figure as the failure rate. This reverses the meaning of a conclusion-bearing statistic.

1 of 1

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 1

  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

Related

Authors
Drummond, E., & Wisniewski, T.
Affiliations
NYU Langone Health (US)
ORCID
Drummond, Eleanor
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2016-12-26
Volume
133
Issue
2
Pages
155-175
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
DOI
10.1007/s00401-016-1662-x
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 · 2012: 1
FWCI
3.29
Type
journal article
Language
en
Open access
Licence
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
  • Health Sciences › Medicine › Physiology › 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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review