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AOP: 429


A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the 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
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The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help
Handbook Version v2.0

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool


The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Erwin L Roggen, CEO ToxGenSolutions BV

Maria Tsamou, Senior Scientist, ToxGenSolutions BV

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Brendan Ferreri-Hanberry   (email point of contact)


Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Erwin L Roggen
  • Brendan Ferreri-Hanberry


This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help

OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
This AOP was last modified on May 26, 2024 20:39

Revision dates for related pages

Page Revision Date/Time
Mitochondrial dysfunction EMPTY April 17, 2024 08:25
Oxidative Stress March 08, 2024 12:28
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 July 15, 2022 09:54
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 January 04, 2023 18:47
Mitochondrial dysfunction EMPTY 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


A concise and informative summation of the AOP under development that can stand-alone from the AOP page. 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.

AOP Development Strategy


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. More help


Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). 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 prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
KE 1816 Mitochondrial dysfunction EMPTY Mitochondrial dysfunction EMPTY
KE 1392 Oxidative Stress Oxidative Stress
KE 1943 Hyperphosphorylation of Tau p-Tau
KE 1945 Dysfunctional Autophagy Dysfunctional autophagy
KE 1942 Accumulation, Cytosolic toxic Tau oligomers Accumulation, Toxic Tau oligomers
KE 1944 Synaptic dysfunction Dysfunctional synapses
KE 1582 Impaired axonial transport Impaired axonial transport
KE 188 Neuroinflammation Neuroinflammation
KE 386 Decrease of neuronal network function Neuronal network function, Decreased
AO 1941 Memory Loss Memory Loss

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes 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. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (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

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP 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. More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
mouse Mus musculus High NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Mixed High

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Homo sapiens

Essentiality of the Key Events

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. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. 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).

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Considerations for Potential Applications of the AOP (optional)

Addressess 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. 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 of the literature that was cited for this AOP. More help