Aop: 429


Each AOP should be given a descriptive title that takes the form “MIE leading to AO”. For example, “Aromatase inhibition [MIE] leading to reproductive dysfunction [AO]” or “Thyroperoxidase inhibition [MIE] leading to decreased cognitive function [AO]”. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

A cholesterol/glucose dysmetabolism initiated Tau-driven AOP toward memory loss (AO) in sporadic Alzheimer's Disease with plausible MIE's plug-ins for environmental neurotoxicants

Short name
A short name should also be provided that succinctly summarises the information from the title. This name should not exceed 90 characters. More help

Graphical Representation

A graphical summary of the AOP listing all the KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs should be provided. This is easily achieved using the standard box and arrow AOP diagram (see this page for example). The graphical summary is prepared and uploaded by the user (templates are available) and is often included as part of the proposal when AOP development projects are submitted to the OECD AOP Development Workplan. The graphical representation or AOP diagram provides a useful and concise overview of the KEs that are included in the AOP, and the sequence in which they are linked together. This can aid both the process of development, as well as review and use of the AOP (for more information please see page 19 of the Users' Handbook).If you already have a graphical representation of your AOP in electronic format, simple save it in a standard image format (e.g. jpeg, png) then click ‘Choose File’ under the “Graphical Representation” heading, which is part of the Summary of the AOP section, to select the file that you have just edited. Files must be in jpeg, jpg, gif, png, or bmp format. Click ‘Upload’ to upload the file. You should see the AOP page with the image displayed under the “Graphical Representation” heading. To remove a graphical representation file, click 'Remove' and then click 'OK.'  Your graphic should no longer be displayed on the AOP page. If you do not have a graphical representation of your AOP in electronic format, a template is available to assist you.  Under “Summary of the AOP”, under the “Graphical Representation” heading click on the link “Click to download template for graphical representation.” A Powerpoint template file should download via the default download mechanism for your browser. Click to open this file; it contains a Powerpoint template for an AOP diagram and instructions for editing and saving the diagram. Be sure to save the diagram as jpeg, jpg, gif, png, or bmp format. Once the diagram is edited to its final state, upload the image file as described above. More help


List the name and affiliation information of the individual(s)/organisation(s) that created/developed the AOP. In the context of the OECD AOP Development Workplan, this would typically be the individuals and organisation that submitted an AOP development proposal to the EAGMST. Significant contributors to the AOP should also be listed. A corresponding author with contact information may be provided here. This author does not need an account on the AOP-KB and can be distinct from the point of contact below. The list of authors will be included in any snapshot made from an AOP. More help

Erwin L Roggen, CEO ToxGenSolutions BV

Maria Tsamou, Senior Scientist, ToxGenSolutions BV

Point of Contact

Indicate the point of contact for the AOP-KB entry itself. This person is responsible for managing the AOP entry in the AOP-KB and controls write access to the page by defining the contributors as described below. Clicking on the name will allow any wiki user to correspond with the point of contact via the email address associated with their user profile in the AOP-KB. This person can be the same as the corresponding author listed in the authors section but isn’t required to be. In cases where the individuals are different, the corresponding author would be the appropriate person to contact for scientific issues whereas the point of contact would be the appropriate person to contact about technical issues with the AOP-KB entry itself. Corresponding authors and the point of contact are encouraged to monitor comments on their AOPs and develop or coordinate responses as appropriate.  More help
Brendan Ferreri-Hanberry   (email point of contact)


List user names of all  authors contributing to or revising pages in the AOP-KB that are linked to the AOP description. This information is mainly used to control write access to the AOP page and is controlled by the Point of Contact.  More help
  • Erwin L Roggen
  • Brendan Ferreri-Hanberry


The status section is used to provide AOP-KB users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. “Author Status” is an author defined field that is designated by selecting one of several options from a drop-down menu (Table 3). The “Author Status” field should be changed by the point of contact, as appropriate, as AOP development proceeds. See page 22 of the User Handbook for definitions of selection options. More help
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite
This AOP was last modified on May 08, 2022 11:33
The date the AOP was last modified is automatically tracked by the AOP-KB. The date modified field can be used to evaluate how actively the page is under development and how recently the version within the AOP-Wiki has been updated compared to any snapshots that were generated. More help

Revision dates for related pages

Page Revision Date/Time
Mitochondrial dysfunction November 02, 2020 07:11
Oxidative Stress March 03, 2022 11:52
Memory Loss October 26, 2021 03:35
Impaired axonial transport January 29, 2019 10:07
Decrease of neuronal network function May 28, 2018 11:36
Neuroinflammation February 23, 2021 04:56
Accumulation, Cytosolic toxic Tau oligomers October 26, 2021 06:53
Hyperphosphorylation of Tau October 26, 2021 06:57
Dysfunctional Autophagy October 26, 2021 06:59
Synaptic dysfunction October 26, 2021 06:58
Mitochondrial dysfunction leads to Oxidative Stress October 26, 2021 03:50
Oxidative Stress leads to p-Tau October 26, 2021 07:08
Dysfunctional autophagy leads to Accumulation, Toxic Tau oligomers October 26, 2021 07:03
Accumulation, Toxic Tau oligomers leads to Impaired axonial transport October 26, 2021 07:04
Impaired axonial transport leads to Dysfunctional synapses October 26, 2021 07:11
Dysfunctional synapses leads to Neuronal network function, Decreased October 26, 2021 07:06
Accumulation, Toxic Tau oligomers leads to Neuroinflammation October 26, 2021 07:12
Neuroinflammation leads to Neuronal network function, Decreased October 26, 2021 03:50
Neuronal network function, Decreased leads to Memory Loss October 26, 2021 04:51


In the abstract section, authors should provide a concise and informative summation of the AOP under development that can stand-alone from the AOP page. Abstracts should typically be 200-400 words in length (similar to an abstract for a journal article). Suggested content for the abstract includes the following: The background/purpose for initiation of the AOP’s development (if there was a specific intent) A brief description of the MIE, AO, and/or major KEs that define the pathway A short summation of the overall WoE supporting the AOP and identification of major knowledge gaps (if any) If a brief statement about how the AOP may be applied (optional). The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance More help

The worldwide prevalence of sporadic (late-onset) Alzheimer’s disease (sAD) is dramatically increasing. Aging and genetics are important risk factors, but systemic and environmental factors contribute to this risk in a still poorly understood way. Within the frame of BioMed21, the Adverse Outcome Pathway (AOP) concept for toxicology was recommended as a tool for enhancing human disease research and accelerating translation of data into human applications. Its potential to capture biological knowledge and to increase mechanistic understanding about human diseases has been substantiated since. In pursuit of the tau-cascade hypothesis, a tau-driven AOP blueprint toward the adverse outcome of memory loss is proposed. Sequences of key events and plausible key event relationships, triggered by the bidirectional relationship between brain cholesterol and glucose dysmetabolism, and contributing to memory loss are captured. To portray how environmental factors may contribute to sAD progression, information on chemicals and drugs, that experimentally or epidemiologically associate with the risk of AD and mechanistically link to sAD progression, are mapped on this AOP. The evidence suggests that chemicals may accelerate disease progression by plugging into sAD relevant processes. The proposed AOP is a simplified framework of key events and plausible key event relationships representing one specific aspect of sAD pathology, and an attempt to portray chemical interference. Other sAD-related AOPs (e.g., A-beta-driven AOP) and a better understanding of the impact of aging and genetic polymorphism are needed to further expand our mechanistic understanding of early AD pathology and the potential impact of environmental and systemic risk factors.

Background (optional)

This optional subsection should be used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development. The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. Examples of potential uses of the optional background section are listed on pages 24-25 of the User Handbook. More help

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help


Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a stressor and the biological system) of an AOP. More help
Key Events (KE)
This table summarises all of the KEs of the AOP. This table is populated in the AOP-Wiki as KEs are added to the AOP. Each table entry acts as a link to the individual KE description page.  More help
Adverse Outcomes (AO)
An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP.  More help
Sequence Type Event ID Title Short name
1 KE 1816 Mitochondrial dysfunction Mitochondrial dysfunction
2 KE 1392 Oxidative Stress Oxidative Stress
3 KE 1943 Hyperphosphorylation of Tau p-Tau
4 KE 1945 Dysfunctional Autophagy Dysfunctional autophagy
5 KE 1942 Accumulation, Cytosolic toxic Tau oligomers Accumulation, Toxic Tau oligomers
6 KE 1944 Synaptic dysfunction Dysfunctional synapses
7 KE 1582 Impaired axonial transport Impaired axonial transport
8 KE 188 Neuroinflammation Neuroinflammation
9 KE 386 Decrease of neuronal network function Neuronal network function, Decreased
10 AO 1941 Memory Loss Memory Loss

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarises all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP. Each table entry acts as a link to the individual KER description page.To add a key event relationship click on either Add relationship: events adjacent in sequence or Add relationship: events non-adjacent in sequence.For example, if the intended sequence of KEs for the AOP is [KE1 > KE2 > KE3 > KE4]; relationships between KE1 and KE2; KE2 and KE3; and KE3 and KE4 would be defined using the add relationship: events adjacent in sequence button.  Relationships between KE1 and KE3; KE2 and KE4; or KE1 and KE4, for example, should be created using the add relationship: events non-adjacent button. This helps to both organize the table with regard to which KERs define the main sequence of KEs and those that provide additional supporting evidence and aids computational analysis of AOP networks, where non-adjacent KERs can result in artifacts (see Villeneuve et al. 2018; DOI: 10.1002/etc.4124).After clicking either option, the user will be brought to a new page entitled ‘Add Relationship to AOP.’ To create a new relationship, select an upstream event and a downstream event from the drop down menus. The KER will automatically be designated as either adjacent or non-adjacent depending on the button selected. The fields “Evidence” and “Quantitative understanding” can be selected from the drop-down options at the time of creation of the relationship, or can be added later. See the Users Handbook, page 52 (Assess Evidence Supporting All KERs for guiding questions, etc.).  Click ‘Create [adjacent/non-adjacent] relationship.’  The new relationship should be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. To edit a key event relationship, click ‘Edit’ next to the name of the relationship you wish to edit. The user will be directed to an Editing Relationship page where they can edit the Evidence, and Quantitative Understanding fields using the drop down menus. Once finished editing, click ‘Update [adjacent/non-adjacent] relationship’ to update these fields and return to the AOP page.To remove a key event relationship to an AOP page, under Summary of the AOP, next to “Relationships Between Two Key Events (Including MIEs and AOs)” click ‘Remove’ The relationship should no longer be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. More help

Network View

The AOP-Wiki automatically generates a network view of the AOP. This network graphic is based on the information provided in the MIE, KEs, AO, KERs and WoE summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help


The stressor field is a structured data field that can be used to annotate an AOP with standardised terms identifying stressors known to trigger the MIE/AOP. Most often these are chemical names selected from established chemical ontologies. However, depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). It can also include non-chemical stressors such as genetic or environmental factors. Although AOPs themselves are not chemical or stressor-specific, linking to stressor terms known to be relevant to different AOPs can aid users in searching for AOPs that may be relevant to a given stressor. More help

Life Stage Applicability

Identify the life stage for which the KE is known to be applicable. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
mouse Mus musculus High NCBI

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
Sex Evidence
Mixed High

Overall Assessment of the AOP

This section addresses the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and WoE for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). The goal of the overall assessment is to provide a high level synthesis and overview of the relative confidence in the AOP and where the significant gaps or weaknesses are (if they exist). Users or readers can drill down into the finer details captured in the KE and KER descriptions, and/or associated summary tables, as appropriate to their needs.Assessment of the AOP is organised into a number of steps. Guidance on pages 59-62 of the User Handbook is available to facilitate assignment of categories of high, moderate, or low confidence for each consideration. While it is not necessary to repeat lengthy text that appears elsewhere in the AOP description (or related KE and KER descriptions), a brief explanation or rationale for the selection of high, moderate, or low confidence should be made. More help

Domain of Applicability

The relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context are defined in this section. Biological domain of applicability is informed by the “Description” and “Biological Domain of Applicability” sections of each KE and KER description (see sections 2G and 3E for details). In essence the taxa/life-stage/sex applicability is defined based on the groups of organisms for which the measurements represented by the KEs can feasibly be measured and the functional and regulatory relationships represented by the KERs are operative.The relevant biological domain of applicability of the AOP as a whole will nearly always be defined based on the most narrowly restricted of its KEs and KERs. For example, if most of the KEs apply to either sex, but one is relevant to females only, the biological domain of applicability of the AOP as a whole would be limited to females. While much of the detail defining the domain of applicability may be found in the individual KE and KER descriptions, the rationale for defining the relevant biological domain of applicability of the overall AOP should be briefly summarised on the AOP page. More help

Homo sapiens

Essentiality of the Key Events

An important aspect of assessing an AOP is evaluating the essentiality of its KEs. The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence.The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs.When assembling the support for essentiality of the KEs, authors should organise relevant data in a tabular format. The objective is to summarise briefly the nature and numbers of investigations in which the essentiality of KEs has been experimentally explored either directly or indirectly. See pages 50-51 in the User Handbook for further definitions and clarifications.  More help

Evidence Assessment

The biological plausibility, empirical support, and quantitative understanding from each KER in an AOP are assessed together.  Biological plausibility of each of the KERs in the AOP is the most influential consideration in assessing WoE or degree of confidence in an overall hypothesised AOP for potential regulatory application (Meek et al., 2014; 2014a). Empirical support entails consideration of experimental data in terms of the associations between KEs – namely dose-response concordance and temporal relationships between and across multiple KEs. It is examined most often in studies of dose-response/incidence and temporal relationships for stressors that impact the pathway. While less influential than biological plausibility of the KERs and essentiality of the KEs, empirical support can increase confidence in the relationships included in an AOP. For clarification on how to rate the given empirical support for a KER, as well as examples, see pages 53- 55 of the User Handbook.  More help

KER4: Mitochondrial dysfunction (KE1) - Oxidative stress (KE2)

The biological plausibility: Pathological ROS levels result in oxidation and loss of function of proteins, lipids, and nucleic acids. The resulting oxidative stress directly, or via mitochondrial dysfunction, results in less mitochondrial biomass, intracellular ATP and respiratory complexes, elevated concentration of intracellular Ca2+ and activated Ca2+-dependent calpains, cellular dysfunction and eventually cell death [70, 136-138].

The empirical support: Oxidative imbalance is predominant in AD pathogenesis [139, 140]. Accumulated 8-oxoguanine (8-oxoG), oxidized guanine, a marker for nuclear and mitochondrial DNA damage, has been found in postmortem AD hippocampus [141, 142]. Enhanced lipid peroxidation, oxidized protein and nucleic acids, and a significant decrease in antioxidant enzyme activity are reported in AD [131, 136, 143]. Proteomic analysis shows a 2-fold increase in mitochondrial protein nitration and oxidation in subjects with MCI when compared to healthy subjects, but not in AD subjects, suggesting that mitochondrial dysfunction occurs during early development of disease [144]. Several studies report that neuronal stress increases cytosolic Ca2+-activated calpain expression leading to neuropathological diseases, such as AD [145-147].

Overall assessment: Data suggest that GSH depletion and mitochondrial dysfunction are plausible causes for excessive ROS levels, but lack quantitative data about threshold, magnitude, and duration. KER4 describes the link between the upstream event ‘mitochondrial dysfunction’ and the downstream event ‘oxidative stress’. Both events are considered adjacent, despite the evidence for this relation is classified as moderate due to some  inconsistencies.

KER5: Oxidative Stress (KE2) - p-tau (KE3)

The biological plausibility: The evidence suggest that ROS induced oxidative stress promotes pathological tau modifications and disruption of the mechanisms involved in proper mitochondrialfunctionality [139, 150-152]. Hyperphosphorylation of tau disrupts its affinity for microtubules, increases its resistance to degradation, and induces conformational changes promoting aggregation [49]. Hence, a proper regulation between tau protein phosphorylation and dephosphorylation of the many phosphorylation sites of tau is detrimental for a healthy neuronal cell physiology [153-155]. Under excessive oxidative stress Ca2+-dependent calpains activate cyclin-dependent kinase 5 (Cdk5) and GSK3β, both involved in tau hyperphosphorylation and shown to be important for proper neural development, synaptic signaling, learning and memory [155, 156]. Cdk5 and GSK3β interact with the truncated regulatory unit of p35 (p25), also a product of calpain activation [157]. Cdk5/p25 and GSK3β/p25 mediated tau phosphorylation decreases the affinity of tau for microtubules, disrupts the cytoskeleton and causes apoptosis [158, 159]. The GSK3β/p25 complex inhibits PP2A phosphorylation through increased inhibitory Tyr307 phosphorylation and decreases expression of PP2A [160]. The data suggest a GSK3β-Cdk5-PP2A synergy in tauopathy, which is characterized by decreased affinity of tau for microtubules, abnormal hyperphosphorylation, aggregation and eventually synaptic dysfunction [161-164]. 

The empirical support: Mitochondrial dysfunction (KE1) and/or oxidative stress (KE2) activate the calpain signaling pathway, a process that precedes p-tau formation during the early stages of AD development [165]. Available evidence suggests that oxidative stress through tau hyperphosphorylation contributes to tau pathology and AD [166]. Calpain mediated activation of the tau kinases Cdk5 and GSK3β correlates with the degree of pathology (Braak stage II-III) and precedes tau phosphorylation and synaptic loss [165]. Proteomic analysis suggests that loss of function of neuronal peptidyl prolyl cis-trans isomerase 1 (Pin1) by oxidative damage, and its downregulation in AD hippocampus, are linked to tau phosphorylation and AD neurofibrillary pathology [167]. The observation that human truncated tau protein expression leads to accumulation of ROS and cortical neuron death in rats, suggests that tau modification may also precede oxidative stress [168].

Overall assessment: Data support that excessive ROS levels are a plausible cause for tau pathology, and that both events are adjacent. Even though it technologically is possible to measure ROS levels in vitro, it was not possible to find threshold and magnitude values, nor duration of exposure, that are  required to result in a persistent adverse impact on p-tau levels.

KER7: Dysfunctional autophagy (KE4) - cytosolic toxic tau (KE5)

The biological plausibility: Progressive dysfunction of neuronal autophagic capacity contributes to the formation of an initiating substrate complex needed for the initial seeding (or nucleation) of tau (and Aβ) aggregation. As a result, cytosolic tau oligomers are formed, followed by UPS-mediated autocatalytic propagation of tau aggregation [33]. At synaptic sites, accumulated tau oligomers are correlated with accumulated ubiquitinated proteins, proteasomes and related chaperones [200]. 

The empirical support: Cytosolic toxic tau oligomers are observed at very early stages of the AD [173], with human AD brain containing more tau oligomers than control samples [201]. Inhibition of autophagy in a neuroblastoma cell model of tauopathy results in elevated levels of soluble and insoluble forms of tau [199]. Observations of internalized tau aggregates colocalizing with lysosomal markers suggest a plausible role of autophagy in tau degradation or lack thereof when dysfunctional. Supporting evidence is provided by a study showing that intracellular tau seed-induced aggregate formation is inhibited by activation of autophagy with rapamycin [202]. 

Overall assessment: It is plausible that a decreasing capacity to exhibit effective autophagy (KE4), in an environment of elevated p-tau (KE3), plays an important role in the accumulation of cytosolic pathologic tau variants (KE5). While the data indicate that defective autophagy, elevated p-tau and cytosolic tau levels are adjacent, there were no quantitative data found concerning threshold, magnitude or duration required to observe an adverse effect driving the development of memory loss.

KER8: Cytosolic toxic tau (KE5) - dysfunctional axonal transport (KE6), KER9: dysfunctional axonal transport (KE6) - dysfunctional synapses (KE7), KER10: dysfunctional synapses (KE7) - neuronal dysfunction (KE9)

The biological plausibility: Tau protein drives cognitive impairment by the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor pathways [203]. In the neuronal dendrites, p-tau targets Fyn kinase, a substrate for the NMDA receptor at postsynaptic compartments [204, 205]. This results in delocalization of tau from axon to synapses and somatodendritic compartments, which causes NFT formation and eventually synaptic dysfunction [153, 171]. Soluble tau oligomers exert more acute toxicity than the insoluble ones [206]. Especially dimers are effectively self-associating into large oligomeric tau nuclei of aggregation. These pathological tau aggregates are cytosolic, but also appear in the extracellular space, and correlate with synaptic dysfunction, neuronal toxicity, and degeneration [206, 207]. In human induced pluripotent stem cells (iPSC)-derived neurons, induction of tau oligomers, but not monomers, drives pathological p-tau aggregation and causes neurite retraction, synaptic loss, neurotransmitters imbalance and neuronal cell death [202]. In mice, subcortical injection of oligomers reduces the expression of synaptic vesicle-associated proteins leading to synaptic dysfunction. Pathogenic tau oligomers also negatively affect mitochondria, suggesting an amplifying circle of toxic Ca2+-mediated events linking KE3 and KE5, and leading to mitochondrial dysfunction and synaptic loss [208, 209]. Tau-induced mitochondrial dysfunction (KE1) is characterized by a decrease in mitochondrial complex I levels, activation of caspase-9 and the apoptotic mitochondrial pathway [208]. Toxic Tau35 may be implicated in intraneuronal insulin accumulation and impaired insulin signaling through interactions with phosphatase and tensin homolog protein (PTEN), which inhibits dephosphorylation of PIP3 to PIP2 [210, 211].

The empirical support: Synaptic loss is associated with early cognitive decline in the neocortex and limbic system, with reductions in synaptic density at preclinical and terminal stage in AD pathology of 25% and 55%, respectively [212, 213]. The levels of markers for presynaptic terminals, synaptic vesicle and synaptic protein are reduced in early stage of AD [214]. Along the same line, a tau transgenic mouse was found to exhibit a decreased expression of synaptic proteins, such as synaptophysin, synapsin, synaptojanin, and synaptobrevin [203]. An acute exposure to extracellular human tau oligomers caused memory impairment in mice [215] probably through inhibition of IRS1 and PTEN activities and subsequent insulin resistance. Abnormal inhibitory serine phosphorylation of IRS1 by INSR has been linked to brain insulin resistance in tauopathy, including AD pathology [211].

Overall assessment: The evidence supports enhanced cytosolic toxic tau levels (KE5) being adjacent to dysfunctional axonal transport (KE6) which results subsequently in synaptic (KE7) and neural (KE9) dysfunction. Thresholds values, degree, and duration of dysfunction of these KEs required to drive this series KEs towards memory loss are not known.

KER11: Toxic tau oligomers (KE5) - Neuroinflammation (KE8), KER12: Neuroinflammation (KE8) - Neuronal dysfunction (KE9)

The biological plausibility: Small soluble tau oligomers cause inflammatory signalling in the brain by activating microglia. These inflammatory responses are mediated by activated inflammasome and promote proinflammatory interleukin 1β (IL-1β) release, which is controlled by activation of caspase-1[217]. Activation of microglia and astroglia, and subsequent release of proinflammatory cytokines occur in the brain of humans and mice exposed to p-tau [218, 219]. Colocalization of activated microglia and astroglia, and proinflammatory cytokines with tau oligomers has been observed in mouse brain, suggesting that tau oligomers play a role in neuroinflammation and in accelerating neuronal dysfunction and neurodegeneration [220]. Tau oligomer levels correlate with High Mobility Group Box 1 (HMGB1) levels, an important pro-inflammatory marker in the brain [220], with recruitment of brain T-cells being linked to tau pathology and neuroinflammatory processes [221, 222].

The empirical support: Neuroinflammatory response in AD brain is driven by potent inflammatory mediators [223] and free radicals [224]. In a cross-sectional study of elderly adults with normal cognition and impaired cognition, six CSF neuroinflammatory markers (interleukin 15 (IL-15), monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor receptor 1 (VEGFR-1), soluble intercellular adhesion molecule-1 (sICAM1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and vascular endothelial growth factor-D (VEGF-D)) correlated with tau levels in CSF, while none correlated with Aβ levels in CSF [225]. 

Overall assessment: There is strong evidence that processes resulting in increased cytosolic toxic tau levels (KE5) are adjacent to neuroinflammation (KE8), a condition that is widely accepted to play an important role in memory loss (AO) and neurodegeneration. The levels of cytotoxic tau, nor the duration of exposure, required to obtain a detectable inflammatory response sufficient to drive neuronal dysfunction are not known.

KER13: Neuronal dysfunction (KE9) - Memory loss (AO)

Neuronal dysfunction is one of the most well-characterized hallmarks in AD pathogenesis. Particularly, loss of memory at early stage of the disease is associated with neuronal dysfunction in the upper layer of entorhinal cortex, an early affected brain region in preclinical state of the disease [226]. Synaptic dysfunction results in cognitive impairment and neuronal cell death [202, 227, 228]. Brain insulin signaling impairment decreases AKT signaling, which is crucial for cell survival and function [229] and negatively affects synaptic plasticity and memory [230, 231]. A toxic relationship exists between soluble tau oligomers and neuroinflammation, which cause eventually neuronal damage, activating inflammatory mediators and free radicals [220, 223, 224]. In AD mouse models, chronic neuronal tumor necrosis factor α (TNF-α) expression correlates with neuronal death [232]. Significant loss in neuronal density occurs in the hippocampus and cerebral cortex of AD patients [233-235], and is AD-stage dependent [236].

Overall assessment: Despite the lack of data on quantity and temporality data, the evidence supports neuronal dysfunction (KE9) to be adjacent to memory loss (AO).

Quantitative Understanding

Some proof of concept examples to address the WoE considerations for AOPs quantitatively have recently been developed, based on the rank ordering of the relevant Bradford Hill considerations (i.e., biological plausibility, essentiality and empirical support) (Becker et al., 2017; Becker et al, 2015; Collier et al., 2016). Suggested quantitation of the various elements is expert derived, without collective consideration currently of appropriate reporting templates or formal expert engagement. Though not essential, developers may wish to assign comparative quantitative values to the extent of the supporting data based on the three critical Bradford Hill considerations for AOPs, as a basis to contribute to collective experience.Specific attention is also given to how precisely and accurately one can potentially predict an impact on KEdownstream based on some measurement of KEupstream. This is captured in the form of quantitative understanding calls for each KER. See pages 55-56 of the User Handbook for a review of quantitative understanding for KER's. More help

Considerations for Potential Applications of the AOP (optional)

At their discretion, the developer may include in this section discussion of the potential applications of an AOP to support regulatory decision-making. This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. While it is challenging to foresee all potential regulatory application of AOPs and any application will ultimately lie within the purview of regulatory agencies, potential applications may be apparent as the AOP is being developed, particularly if it was initiated with a particular application in mind. This optional section is intended to provide the developer with an opportunity to suggest potential regulatory applications and describe his or her rationale.To edit the “Considerations for Potential Applications of the AOP” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Considerations for Potential Applications of the AOP” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page or 'Update and continue' to continue editing AOP text sections.  The new text should appear under the “Considerations for Potential Applications of the AOP” section on the AOP page. More help

As the proposed AOP captures the defects that can occur before the manifestation of the disease, these depicted sequences of events, which can eventually lead to the targeted AO, may be helpful in defining the early stage(s) of AD development. The application of the AOP conceptual framework may help identify new biomarkers for early diagnosis, new druggable targets and develop novel therapies; however, it should be considered that this area of study is still in its infancy, and no diagnostic tests or therapeutic approaches suitable for AD have been derived from AOPs thus far.


List the bibliographic references to original papers, books or other documents used to support the AOP. More help