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Cited by 755Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchMemory and Neural Mechanisms

Using mice to model Alzheimer's dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models

Open access
Webster, Scott J., Bachstetter, Adam D., Nelson, Peter T., Schmitt, Frederick A., Van Eldik, Linda J.·2014·Frontiers in Genetics
DOI 10.3389/fgene.2014.00088PMC PMC4005958
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Abstract

The goal of this review is to discuss how behavioral tests in mice relate to the pathological and neuropsychological features seen in human Alzheimer's disease (AD), and present a comprehensive analysis of the temporal progression of behavioral impairments in commonly used AD mouse models that contain mutations in amyloid precursor protein (APP). We begin with a brief overview of the neuropathological changes seen in the AD brain and an outline of some of the clinical neuropsychological assessments used to measure cognitive deficits associated with the disease. This is followed by a critical assessment of behavioral tasks that are used in AD mice to model the cognitive changes seen in the human disease. Behavioral tests discussed include spatial memory tests [Morris water maze (MWM), radial arm water maze (RAWM), Barnes maze], associative learning tasks (passive avoidance, fear conditioning), alternation tasks (Y-Maze/T-Maze), recognition memory tasks (Novel Object Recognition), attentional tasks (3 and 5 choice serial reaction time), set-shifting tasks, and reversal learning tasks. We discuss the strengths and weaknesses of each of these behavioral tasks, and how they may correlate with clinical assessments in humans. Finally, the temporal progression of both cognitive and non-cognitive deficits in 10 AD mouse models (PDAPP, TG2576, APP23, TgCRND8, J20, APP/PS1, TG2576 + PS1 (M146L), APP/PS1 KI, 5×FAD, and 3×Tg-AD) are discussed in detail. Mouse models of AD and the behavioral tasks used in conjunction with those models are immensely important in contributing to our knowledge of disease progression and are a useful tool to study AD pathophysiology and the resulting cognitive deficits. However, investigators need to be aware of the potential weaknesses of the available preclinical models in terms of their ability to model cognitive changes observed in human AD. It is our hope that this review will assist investigators in selecting an appropriate mouse model, and accompanying behavioral paradigms to investigate different aspects of AD pathology and disease progression.

AI snapshot

Written from the paper’s full text.

TL;DR

This review maps how behavioral tasks used in amyloid precursor protein (APP) mutant mice correspond to the neuropsychological assessments used clinically in Alzheimer's disease (AD), and tabulates the temporal onset of cognitive and non-cognitive deficits across 10 commonly used AD mouse models. It concludes that no single model recapitulates human AD, but that most models show spatial working memory deficits earlier than deficits in other cognitive domains.

Key findings

  • Across the reviewed models, the earliest observable cognitive impairment is consistently in spatial working memory (assessed by water maze tasks), generally followed by associative learning/reference memory deficits, with recognition memory deficits appearing later (e.g., PDAPP: working memory at 4 months, NOR at 6 months; Tg2576: spatial working memory at 5 months, NOR at 12 months; APP/PS1 KI: RAWM at 9 months, recognition memory at 15 months).
  • Onset varies substantially by model: J20 shows recognition memory deficits earliest (1–2 months), while APP/PS1 KI shows the latest onset (7–9 months for earliest deficits).
  • Non-cognitive abnormalities are also present in most models, including increased locomotor activity (J20 and TgCRND8 earliest at ~1 month; PDAPP and Tg2576 at ~3 months; PS1, 3×Tg-AD, and APP23 at ~6–9 months), anxiety, circadian/sleep disruption, and aggression (e.g., APP23 aggression by 6 months).
  • The review notes that increased aggression presents in as much as 65% of AD patients, and that depressive symptom prevalence in AD is reported to range from 2% to 85%, though little work has examined depressive-like behavior in AD mouse models.

Methods

  • Narrative review, not primary experimental work: it summarizes human AD neuropathology (ABC scoring of Amyloid, Braak, CERAD), clinical neuropsychological instruments (MMSE, MoCA, SBT, ADAS-cog, Logical Memory I/II, BVRT), and mouse behavioral tasks (MWM, RAWM, Barnes maze, Y-/T-maze, NOR, fear conditioning, passive/active avoidance, DMTP/DMTS, 3- and 5-CSRTT, set-shifting, reversal learning, WWWhich).
  • The core synthesis is two tables (Table 3 for five APP models: PDAPP, TG2576, APP23, TgCRND8, J20; Table 4 for five APP+PS1/Tau models: APP/PS1, TG2576+PS1(M146L), APP/PS1 KI, 5×FAD, 3×Tg-AD) coding impairment, no impairment, or no data by age, with an asterisk marking first appearance of diffuse amyloid plaques.
  • No new data, sample sizes, or statistical analyses are reported; findings are drawn from cited primary studies.

Limitations

  • Stated by the paper: no animal model recapitulates the entirety of AD; most models represent familial AD (FAD), which accounts for only a small percentage of total AD cases; background strain and likely overexpression of mutant human APP genes on brain development and function must always be considered; language-dependent domains (verbal acuity, verbal recall) cannot be modeled in rodents; the WWWhich episodic-like memory task is not comparable to human episodic memory tests because those rely on language; homology between rodent and human 5-CSRTT is "far from perfect."
  • Stated by the paper: the tables are not an all-encompassing list of mouse models, only examples of commonly used APP-mutation models.
  • Evident from the text: the tables contain many cells with no available data, and the review documents inconsistent reports across studies for several models (e.g., Tg2576 spatial memory deficits not replicated in some reports; PDAPP recognition memory findings inconsistent), indicating that model-by-model progression claims rest on heterogeneous and sometimes conflicting literature.

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

Integrity signals

Registry

Crossref · 10.3389/fgene.2014.00088

Cites

372 of 373 references verified1 citation errors · 0 not checkable

Statistics

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Claims the paper makes

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  • Findingcitation

    Circadian rhythm disruptions are observed in many AD mouse models.

    “Similar to the reported activity disturbances, circadian rhythm disruptions are also observed in many of the AD mouse models”
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  • Findingcitation

    The TG2576 model develops anxiety-like disturbances later, at 9-11 months of age.

    “Other models such as the TG2576 develop the anxiety-like disturbances later at the age of 9–11 months of age”
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  • Findingcitation

    Not all murine AD models exhibit anxiety disturbances.

    “not all murine AD models exhibit anxiety disturbances”
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  • Findingcitation

    Many AD mouse models display increased aggressive behavior.

    “Many AD mouse models also display increased aggressive behavior”
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  • Findingcitation

    Several mouse models of AD display sleep disruption.

    “Several mouse models of AD also display sleep disruption.”
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    Findingcitation

    The onset of activity disturbances differs among AD mouse models: J20 and TgCRND8 develop disruptions earliest (approximately 1 month of age), followed by PDAPP and TG2576 (approximately 3 months of age), and PS1 [Tg2576 + PS1 (M146L)], 3×TgAD, and APP23 mice developing last (approximately 6-9 months of age).

    “The onset of the disturbances is different for each model, with the J20 and the TgCRND8 mice developing disruptions earliest (approximately 1 month of age), followed by PDAPP and TG2576 (approximately 3 months of age), and the PS1 [Tg2576 + PS1 (M146L)], 3×TgAD, and APP23 mice developing last (approximately 6–9 months of age)”
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    Findingcitation

    Other AD mouse models that show activity disturbances are the PDAPP, TG2576, J20, APP + PS1 [Tg2576 + PS1 (M146L)], and 3×Tg-AD mouse models of AD.

    “Other AD mouse models that show activity disturbances are the PDAPP, TG2576, J20, APP + PS1 [Tg2576 + PS1 (M146L)], and 3×Tg-AD mouse models of AD.”
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    Findingcitation

    In both human AD and AD mouse models, greater sleep disruptions are associated with more severe cognitive decline.

    “the greater the sleep disruptions are, the more severe the cognitive decline seems to be”
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    Findingcitation

    In the TG2576 mouse, increased aggressive behaviors manifest as increased frequency of attacks on other home cage mice and altered latency to first attack when interacting with a novel mouse.

    “in the TG2576 mouse increased aggressive behaviors display themselves in both the frequency of attacks on other home cage mice as well as on the latency to first attack when interacting with a novel mouse”
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    Findingcitation

    In some AD mouse models, anxiety-like behavioral disturbances start early at 1-2 months of age (J20) or 3-6 months of age (APP/PS1).

    “in some models the behavioral disturbances start early at 1–2 months of age or 3–6 months of age for the J20 and the APP/PS1 models, respectively”
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    Findingnone given

    Most studies using mouse models of AD have focused on understanding/correcting the cognitive deficits associated with the disease.

    “most of the studies using mouse models of AD have focused on understanding/correcting the cognitive deficits associated with the disease.”
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    Premisecitation

    NFTs spread to the limbic and medial temporal lobe (Braak stage III-IV), and this stage correlates with early AD symptoms related to memory.

    “NFTs spread to the limbic and medial temporal lobe (Braak stage III-IV), and this stage correlates with early AD symptoms related to memory (Schmitt et al., 2000; Riley et al., 2011).”
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    Premisecitation

    The ADAS-cog has excellent test-retest reliability and is considered one of the most sensitive scales for assessing cognitive changes related to AD.

    “Because the ADAS-cog has an excellent test-retest reliability and is considered to be one of the most sensitive scales for assessing cognitive changes related to AD (Emilien et al., 2004), this test is extensively used in AD clinical trials as an outcome measure of cognitive change (Schmitt and Wichems, 2006; Connor and Sabbagh, 2008).”
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    The ADAS-cog is extensively used in AD clinical trials as an outcome measure of cognitive change.

    “Because the ADAS-cog has an excellent test-retest reliability and is considered to be one of the most sensitive scales for assessing cognitive changes related to AD (Emilien et al., 2004), this test is extensively used in AD clinical trials as an outcome measure of cognitive change (Schmitt and Wichems, 2006; Connor and Sabbagh, 2008).”
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    Premisecitation

    The MMSE has excellent reproducibility that lends itself well to longitudinal use in tracking progression of cognitive impairments associated with AD.

    “The MMSE has excellent reproducibility that lends itself well to longitudinal use in tracking the progression of the cognitive impairments associated with AD (Jacqmin-Gadda et al., 1997; Aevarsson and Skoog, 2000; Chatfield et al., 2007).”
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    Premisecitation

    The Short Blessed Test (SBT) consists of a six-item test designed to identify cognitive dysfunction seen in AD.

    “Another commonly used test battery is that of the Short Blessed Test (SBT) which consists of a six-item test designed to identify the cognitive dysfunction seen in AD (Katzman et al., 1983).”
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    Premisecitation

    The SBT results have demonstrated excellent reliability.

    “Despite the simplicity and brevity of the SBT, the results that it produces have demonstrated excellent reliability (Fuld, 1978).”
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    The SBT was the first mental status examination to be correlated with amyloid plaque burden at autopsy.

    “Similarly, the SBT was the first mental status examination to be correlated with amyloid plaque burden at autopsy (Carpenter et al., 2011).”
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    Premisecitation

    The MMSE is one of the most commonly used neuropsychological screening tools for cognitive impairments seen in AD.

    “The Mini-Mental Status Examination (MMSE) is one of the most commonly used neuropsychological screening tools for cognitive impairments seen in AD (Simard and Van Reekum, 1999; Snyderman and Rovner, 2009).”
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    Interpretationcitation

    The data support the Amyloid Cascade Hypothesis, which posits that beta-amyloid/plaque pathology kindles widespread tau/NFT pathology, with the tau/NFT pathology constituting the more direct cause of the cell loss and synapse elimination underlying clinical disease.

    “The data also support the “Amyloid Cascade Hypothesis”(Karran et al., 2011), a deceptively complex hypothesis which posits that beta-amyloid/plaque pathology kindles widespread tau/NFT pathology, with the tau/NFT pathology constituting the more direct cause of the cell loss and synapse elimination underlying clinical disease (Nelson et al., 2009b, 2012).”
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    Premisecitation

    The Alzheimer's Disease Assessment Scale (ADAS) was specifically developed to measure the severity of symptoms commonly seen in AD.

    “The Alzheimer's Disease Assessment Scale (ADAS) was specifically developed to measure the severity of symptoms commonly seen in AD (Rosen et al., 1984).”
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    Premisecitation

    T-maze and Y-maze alternation tasks rely on the natural exploratory behavior of rodents and are considered the most rudimentary tasks to assess spatial working memory.

    “These tasks rely on the natural exploratory behavior (tendency to choose an alternative arm over an arm which has been previously explored) of rodents and are considered the most rudimentary tasks to assess spatial working memory (Dudchenko, 2004).”
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    Premisecitation

    Once the AD patient progresses past MCI and into dementia, general cognition continues to decline with deficits appearing in all respective cognitive domains.

    “Once the AD patient progresses past MCI and into dementia, general cognition continues to decline with deficits appearing in all respective cognitive domains (Huff et al., 1987; Locascio et al., 1995; Lambon Ralph et al., 2003; Mckhann et al., 2011).”
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    Premisecitation

    Large numbers of AD mouse models have been tested in the MWM and most show AD related cognitive deficits.

    “Large numbers of AD mouse models have been tested in the MWM and most show AD related cognitive deficits (Webster et al., 2013).”
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    Premisecitation

    Spatial based working memory tasks are heavily employed in murine working memory testing and likely are more depictive of the visuospatial working memory tasks used clinically.

    “Instead, spatial based working memory tasks are heavily employed in murine working memory testing and likely are more depictive of the visuospatial working memory tasks used clinically (Benton, 1992; Benedict and Groninger, 1994).”
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    • Rests on an assumption: Working memory is perhaps one of the most well modeled aspects of the memory deficits in AD.

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    Interpretationnone given

    Some cognitive domains disrupted in AD have been extensively modeled in rodents (reference memory, working memory and executive function), some less so (attention), and some nearly not at all (episodic memory).

    “Some cognitive domains disrupted in AD have been extensively modeled (reference memory, working memory and executive function), some less so (attention), and some nearly not at all (episodic memory).”
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    • Rests on an assumption: Other cognitive domains impaired in human AD such as those involving language (i.e., verbal acuity tasks and verbal recall tasks) simply cannot be modeled in rodent models.

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    Premisecitation

    Clinically, many neuropsychological tests that assess working memory rely heavily on verbal tasks, employing language as a core construct, and thus are not feasible to model using mice.

    “Clinically, many of the neuropsychological tests that assess working memory rely heavily on the use of verbal tasks (Kaplan et al., 1978; Benedict et al., 1998; Spreen and Strauss, 1998; Delis et al., 2000), employing language as a core construct and thus are not feasible to model using mice.”
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    • Rests on an assumption: Other cognitive domains impaired in human AD such as those involving language (i.e., verbal acuity tasks and verbal recall tasks) simply cannot be modeled in rodent models.

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    Premisecitation

    Composite scores encompassing multiple neuropsychological tests can provide some of the most reliable assessments of global cognitive status relating to AD and serve as efficacy outcome measures in clinical trials.

    “Composite scores encompassing multiple neuropsychological tests are often used and can provide some of the most reliable assessments of global cognitive status relating to AD as well as serving as efficacy outcome measures in clinical trials (Bernick et al., 2012).”
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    Premisecitation

    Early deficits in episodic memory are followed closely by deficits in semantic memory, and both develop before deficits in attention, visuospatial memory, or executive function.

    “These early deficits in episodic memory are followed closely by deficits in semantic memory, and both are developed before other deficits in cognitive domains such as attention, visuospatial memory, or executive function (Bondi et al., 2008).”
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    Premisecitation

    The Morris Water Maze is perhaps the most widely employed spatial working memory task.

    “Perhaps the most widely employed spatial working memory task is that of the Morris Water Maze (MWM) (Morris et al., 1982).”
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    Premisecitation

    Other common tasks of murine spatial working memory are the Radial Arm Water Maze and the Barnes Maze.

    “Other common tasks of murine spatial working memory are the Radial Arm Water Maze (RAWM) and the Barnes Maze (Barnes, 1979; Diamond et al., 1999; Alamed et al., 2006).”
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    Premisecitation

    In the Radial Arm Maze, unimpaired rats and mice will quickly learn where the food reward is and which arms have previously been visited, and will avoid re-entering a previously entered arm.

    “Depending on the baiting paradigm, unimpaired rats and mice will quickly learn where the food reward is and which arms have previously been visited, and will avoid re-entering a previously entered arm.”
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    Premisecitation

    Response inhibition is required for the appropriate control of an individual's behavioral actions in response to a stimulus.

    “Response inhibition is required for the appropriate control of an individual's behavioral actions in response to a stimulus (Robbins, 1996; Humby et al., 1999; Perry and Hodges, 1999; Romberg et al., 2013a).”
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    Premisecitation

    Set-shifting tasks are similar to the Wisconsin Card Sorting Task in that they form the gold standard for assessing executive function.

    “In many ways, set-shifting tasks are similar to the Wisconsin Card Sorting Task in that they form the gold standard for assessing executive function (Drewe, 1974; Robinson et al., 1980; Arnett et al., 1994).”
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    Premisenone given

    All of the rodent behavioral tasks discussed in this section have been specifically developed to assess deficits in cognitive domains related to what is seen in human AD.

    “All of the rodent behavioral tasks discussed in this section have been specifically developed to assess deficits in cognitive domains related to what is seen in human AD.”
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    Premisecitation

    Cognitive decline is a defining feature of AD, and many mouse models have been developed that recapitulate aspects of the cognitive impairments seen in AD.

    “Cognitive decline is a defining feature of AD, and many mouse models have been developed that recapitulate aspects of the cognitive impairments seen in AD (Elder et al., 2010; Hochgrafe et al., 2013; Platt et al., 2013).”
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    Interpretationreasoning

    Caution should be used when attempting to correlate any preclinical finding concerning episodic memory in mice to that of human cognition.

    “Therefore, caution should be used when attempting to correlate any preclinical finding concerning episodic memory in mice to that of human cognition.”
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    Premisecitation

    Work over the past few decades on episodic-like memory across a number of animal species has suggested that episodic memory is not unique to humans, and several mouse behavioral tasks designed at assessing episodic-like memory have been developed.

    “However, work over the past few decades on episodic-like memory across a number of animal species has suggested otherwise, and several mouse behavioral tasks designed at assessing episodic-like memory have been developed (Clayton and Dickinson, 1998; Clayton et al., 2001; Griffiths and Clayton, 2001; Morris, 2001; Davis et al., 2013a,b).”
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    Premisereasoning

    The human episodic memory tasks rely on language as a foundational construct for assessment, and there is no such component in the WWWhich task for mice.

    “This is largely because the human tasks rely on language as a foundational construct for assessment. Obviously, there exists no such component in the WWWhich task for mice.”
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    Premisecitation

    Historically, episodic memory was thought to be unique to humans.

    “Historically, episodic memory was thought to be unique to humans (Tulving and Markowitsch, 1998).”
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    Premisenone given

    The NOR task itself is too simplistic to be considered a true episodic memory task; it is considered a task of recognition memory.

    “While the NOR task itself is too simplistic a task to be considered a true episodic memory task (rather it is considered a task of recognition memory), the WWWhich task is able to model episodic-like memory.”
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    Premisecitation

    Touchscreen versions of the 5-CSRTT are available in which the nose poke holes and stimulus lights are replaced with an LCD screen.

    “Touchscreen versions of this task are also available in which the nose poke holes and stimulus lights are replaced with an LCD screen (Romberg et al., 2011; Bussey et al., 2012).”
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    Interpretationnone given

    The contributions of both background strain and likely overexpression of mutant human APP genes on brain development and function must always be considered with regard to observed cognitive deficits in the various AD mouse models.

    “In addition, the contributions of both background strain and likely overexpression of mutant human APP genes on brain development and function must always be considered with regard to observed cognitive deficits in the various AD mouse models.”
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    Interpretationnone given

    No one animal model fully replicates the progression of cognitive impairments seen in the human disease, but AD mouse models have been invaluable in advancing our knowledge of the disease.

    “Although no one animal model fully replicates the progression of cognitive impairments seen in the human disease, AD mouse models have been invaluable in advancing our knowledge of the disease.”
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  • May combine two claims.

    Premisecitation

    In PDAPP, deficits in recognition memory appear after working memory deficits, with first reported deficits in the NOR task at 6 months old.

    “Deficits in recognition memory appear to develop after the working memory deficits in this model, as the first reported deficits in the NOR task are at 6 months old (Dodart et al., 1999).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dodart et al., 1999

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    Each transgenic mouse model of AD provides different insights into aspects of AD pathogenesis and the cognitive deficits associated with the disease.

    “Each transgenic mouse model of AD provides different insights into aspects of AD pathogenesis and the cognitive deficits associated with the disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    TgCRND8 are impaired on spatial working memory tasks starting at 3 months of age, and these deficits progress with age.

    “TgCRND8 are impaired on spatial working memory tasks starting at 3 months of age. These deficits are seen in the MWM and progress with age of the animal (Janus et al., 2000; Chishti et al., 2001; Gortz et al., 2008; Richter et al., 2008; Ambree et al., 2009).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Janus et al., 2000

      Not checked in the free run.

    • cites Chishti et al., 2001

      Not checked in the free run.

    • cites Gortz et al., 2008

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In APP23, deficits appear to be progressive with age, and at 12 months old animals also show cognitive deficits in a reference memory version of the Barnes maze.

    “The deficits appear to be progressive with age, and at 12 months old the animals also show cognitive deficits in a reference memory version of the Barnes maze (Prut et al., 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Prut et al., 2007

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In PDAPP, cognitive deficits in recognition memory do not appear as robust as those in working memory, with inconsistent reports in the literature.

    “The cognitive deficits in recognition memory do not appear as robust as those in working memory in this model as there are inconsistent reports in the literature (Dodart et al., 1999, 2002; Chen et al., 2000).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Dodart et al., 1999, 2002

      Not checked in the free run.

    • cites Chen et al., 2000

      Not checked in the free run.

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

    Premisecitation

    Most of the AD mouse models are representative of the familial form of AD (FAD), which accounts for only a small percentage of total AD cases each year.

    “It should be noted that most of the AD mouse models are representative of the familial form of AD (FAD) which accounts for only a small percentage of the total AD cases each year (Campion et al., 1999).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Campion et al., 1999

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In APP/PS1, impairments in reference memory develop by 6 months and persist through the rest of the life.

    “Impairments in reference memory develop by 6 months and persist through the rest of the life of this model (Reiserer et al., 2007; Bernardo et al., 2009; O'leary and Brown, 2009).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Reiserer et al., 2007

      Not checked in the free run.

    • cites Bernardo et al., 2009 source

      Not checked in the free run.

    • cites O'leary and Brown, 2009

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In APP/PS1, cognitive deficits are first seen at 3 months of age in the RAWM spatial working memory task and are also reported by 6 months of age in the MWM.

    “Cognitive deficits are first seen at 3 months of age in the RAWM spatial working memory task and are also reported by 6 months of age in the MWM (Cao et al., 2007; Ding et al., 2008).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Cao et al., 2007

      Not checked in the free run.

    • cites Ding et al., 2008

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    J20 recognition memory deficits do not appear to progress with age, and there has been a report of no recognition memory deficits in old animals in advanced stages of the disease.

    “However, they do not appear to progress with the age of the animal and there has even been a report of no recognition memory deficits in old animals in advanced stages of the disease (Karl et al., 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Karl et al., 2012

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    5×FAD working memory deficits are followed temporally by associative learning impairment in fear conditioning and deficits in a working memory version of the Y-maze.

    “These working memory deficits are followed temporally with the development of associative learning impairment in fear conditioning (Ohno et al., 2006; Devi and Ohno, 2010) as well as the development of deficits in a working memory version of the Y-maze (Oakley et al., 2006; Devi and Ohno, 2012; Shukla et al., 2013).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Ohno et al., 2006

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    • cites Devi and Ohno, 2010

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    • cites Oakley et al., 2006

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    APP/PS1 knock-in mouse model uses endogenous promoters to drive expression of humanized amyloid beta sequence, and AD-like pathology and cognitive deficits develop in the absence of APP or PS1 overexpression.

    “The APP/PS1 knock-in mouse model (first described in Flood et al., 2002) uses endogenous promoters to drive the expression of humanized amyloid beta sequence, and AD-like pathology and cognitive deficits develop in the absence of APP or PS1 overexpression (Flood et al., 2002).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Flood et al., 2002

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In APP + PS1, first observable deficits are shown in associative learning and present between 4 and 5 months of age.

    “The first observable deficits in this model are shown in associative learning and present themselves between 4 and 5 months of age (Dineley et al., 2002).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dineley et al., 2002

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  • May combine two claims.

    Premisecitation

    In APP/PS1 KI, these deficits are followed by impairments in associative memory (appearing by 14 months) and in recognition memory (not developing until 15 months).

    “These deficits are followed by impairments in associative memory (appearing by 14 months of age Thibault et al., 2012) and in recognition memory (not developing until 15 months of age Webster et al., 2013).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Thibault et al., 2012

      Not checked in the free run.

    • cites Webster et al., 2013

      Not checked in the free run.

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

    Premisecitation

    Non-cognitive neuropsychiatric symptoms are associated with AD and are seen as a very important concern among family members and caregivers.

    “Indeed, these non-cognitive symptoms are seen as a very important concern among the family members of the patients and caregivers alike (Tan et al., 2005).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Tan et al., 2005

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    These disturbances increase with the age of the animals and with the severity of the disease.

    “Further, these disturbances increase with the age of the animals and with the severity of the disease.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Non-cognitive symptoms are often more difficult to deal with, as they compose important sources of distress and psychological burden on family members/caregivers and can drastically affect quality of life by leading to institutionalization.

    “These non-cognitive symptoms are often more difficult to deal with, as they compose important sources of distress and psychological burden on the family members/caregivers and can drastically affect the quality of life of patients by leading to institutionalization (Hope et al., 1998; Shin et al., 2005).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Hope et al., 1998

      Not checked in the free run.

    • cites Shin et al., 2005

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Aggressive deficits correlate best with moderate to severe stages of the disease, as also observed clinically in human AD.

    “This suggests that perhaps aggressive deficits correlate best with moderate to severe stages of the disease, which is also what is observed clinically in human AD”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Senanarong et al., 2004

      Not checked in the free run.

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

    Premisecitation

    Numerous meta-analysis studies have linked depression and AD.

    “Numerous meta-analysis studies have linked depression and AD”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Chen et al., 1999

      Not checked in the free run.

    • cites Charlson and Peterson, 2002

      Not checked in the free run.

    • cites Ownby et al., 2006

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Human AD circadian rhythm disturbances are characterized by frequent awakenings during the nighttime and increased time slept during the day.

    “These disturbances are characterized by the AD patient's propensity to frequently awaken during the nighttime and to increase the amount of time slept during the day”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Ancoli-Israel et al., 1989 source

      Not checked in the free run.

    • cites Okawa et al., 1991

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    AD is not just a memory disorder; it is a complex disease with many different non-cognitive neuropsychiatric symptoms that are an important source of distress and a psychological burden on family members and caregivers.

    “AD is not just a memory disorder, rather it is a complex disease with many different non-cognitive neuropsychiatric symptoms which are an important source of distress and a psychological burden on family members and caregivers alike.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    No one animal model fully replicates the pathogenesis of AD; rather, models only model different aspects of the disease.

    “No one animal model fully replicates the pathogenesis of AD, but rather only model different aspects of the disease.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The anatomical makeup and cognitive ability of mice make it difficult to model all of the intricacies of higher-order cognitive function exclusive to humans.

    “the anatomical makeup and cognitive ability of mice make it difficult to model all of the intricacies of higher-order cognitive function exclusive to humans.”
    Quote in the paperNot a substantial claim
61 of 61

  • The paper relies on this without support.

    No animal model recapitulates the entirety of AD in humans.

    “However, no animal model recapitulates the entirety of AD in humans, and therefore it is important to understand both the utility and limitations of particular animal models.”

  • The paper relies on this without support.

    Outside of frontotemporal lobar degeneration (FTLD), one does not see widespread cortical NFTs without abundant plaque pathology.

    “It should be noted that outside of frontotemporal lobar degeneration (FTLD), one does not see widespread cortical NFTs without abundant plaque pathology.”

  • The paper relies on this without support.

    During late stages (Braak stage V–VI), NFTs increase in number and manifest in neocortical areas responsible for higher cognitive domains such as executive function, visuospatial capacities, and speech in synchrony with observed AD-related cognitive deficits in these respective cognitive domains.

    “During the late stages (Braak stage V–VI), NFTs increase in number and manifest in neocortical areas responsible for higher cognitive domains such as executive function, visuospatial capacities, and speech in synchrony with observed AD-related cognitive deficits in these respective cognitive domains.”

  • The paper relies on this without support.

    Some of the earliest neuropathological changes in AD are in the hippocampus and entorhinal cortex, followed by changes in the medial temporal lobe.

    “Some of the earliest neuropathological changes in AD are in the hippocampus and entorhinal cortex, followed by changes in the medial temporal lobe.”

  • The paper relies on this without support.

    Neuropsychological assessment is the most reliable means to clinically evaluate the cognitive deficits seen in humans.

    “Neuropsychological assessment is the most reliable means to clinically evaluate the cognitive deficits seen in humans.”

  • The paper relies on this without support.

    Other cognitive domains impaired in human AD such as those involving language (i.e., verbal acuity tasks and verbal recall tasks) simply cannot be modeled in rodent models.

    “Other cognitive domains impaired in human AD such as those involving language (i.e., verbal acuity tasks and verbal recall tasks) simply cannot be modeled in rodent models.”

  • The paper relies on this without support.

    Working memory is perhaps one of the most well modeled aspects of the memory deficits in AD.

    “Working memory is perhaps one of the most well modeled aspects of the memory deficits in AD.”

  • The paper relies on this without support.

    As the patient moves from the preclinical phase of AD into MCI, more cognitive domains begin to be affected.

    “As the patient moves from the preclinical phase of AD into MCI, more cognitive domains begin to be affected.”
8 of 8

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?

  • In preclinical Alzheimer's disease, mouse models that contain a mutation in amyloid precursor protein (APP) have been widely used as models of AD, and APP plays an essential role in cognitive function.

    “In preclinical AD, mouse models that contain a mutation in amyloid precursor protein (APP) have been widely used as models of AD, which play an essential role in cognitive function (Webster et al., 2014).”

    From Arbovirus infection increases the risk for the development of neurodegenerative disease pathology in the murine model (2024) · cites this paper as Webster et al., 2014

    The section on temporal progression of cognitive deficits (page not provided) describes APP-mutation mice as commonly used AD models. The APP/PS1 section reports cognitive deficits in one such model, but the paper does not establish that APP itself plays an essential role in cognitive function. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • 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].”

    From Alzheimer's disease: experimental models and reality (2017) · cites this paper as [169]

  • Numerous studies have documented a strong link between neocortical NFTs and cognitive loss.

    “On the other hand, numerous studies have documented a strong link between neocortical NFTs and cognitive loss[26, 46, 48, 97, 123, 160, 169].”

    From Alzheimer's disease: experimental models and reality (2017) · cites this paper as [169]

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Benedict, 1994, Preliminary standardization and validation of a multiple-form test for the assessment of visuospatial memory, Arch. Clin. Neuropsychol, 9, 109
  2. Benton, 1992, Benton Visual Retention Test, 5th Edn

Cited by

Sorted by citations

Related

Authors
Webster, S. J., Bachstetter, A. D., Nelson, P. T., Schmitt, F. A., & Van Eldik, L. J.
Affiliations
University of Kentucky (US)
ORCID
Venue
Frontiers in Genetics
Publisher
Frontiers Media SA
Published
2014-04-23
Volume
5
Pages
88-88
ISSN
1664-8021 (ISSN-L)
DOI
10.3389/fgene.2014.00088
PMC
PMC4005958
OpenAlex
W1982313782
Semantic Scholar
6bbaedb9f24f173e0fcdb0d6b5b0bfe9eb3f4679
Cited by
755
References
365
Citations by year
2026: 36 · 2025: 51 · 2024: 60 · 2023: 72 · 2022: 64 · 2021: 57 · 2020: 63 · 2019: 63 · 2018: 79 · 2017: 71 · 2016: 76 · 2015: 48 · 2014: 14
FWCI
8.15
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Genetics (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health
  • National Institute on Aging (P30AG028383)
  • National Institute of Nursing Research
  • National Institute of Child Health and Human Development
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 › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords
Alzheimer's disease, mouse models of Alzheimer's disease, amyloid precursor protein mutations, APP/PS1 mice, PDAPP mice, Tg2576 mice, APP23 mice, TgCRND8 mice, 5xFAD mice, 3xTg-AD mice, behavioral tests, cognitive impairment, spatial memory, recognition memory, associative learning, attention, set-shifting, reversal learning, neuropsychological assessment

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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.

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