TABLE 2.

Outcome-direction matrix after TLR4 inhibition, antagonism, genetic suppression, or pathway validation in AD-related models.

No.	Study/approach/evidence role	Inflammatory or microglial outcome	Amyloid-related outcome	Neuronal/synaptic/trophic outcome	Functional/behavioral outcome	Conservative overall interpretation
1	Song et al., 2011; TLR4 loss-of-function; core in vivo paradox	Decreased selected microglial/cytokine readouts.	Increased later Aβ deposition, fibrillar Aβ, and soluble Aβ42.	Not reported.	Worsened Morris water maze acquisition; probe trial not clearly changed.	Inflammation improved while amyloid burden and acquisition learning worsened.
2	Wu et al., 2015; CLI-095/PDTC; supportive neuronal mechanism	Decreased LPS-induced neuronal TNF-α and IL-1β; microglia not assessed.	CLI-095/PDTC reversed LPS-induced ADAM10 downregulation, BACE-1/PS-1 upregulation, β-APP increase, and Aβ1–42 secretion in neurons; no plaque-burden or Aβ-clearance data.	Not reported.	Not reported.	Supports a neuronal TLR4/NF-κB–APP-processing link only; no in vivo amyloid-clearance or therapeutic-efficacy inference.
3	Balducci et al., 2017; Cyp/KO; core acute in vivo function	Decreased acute AβO-induced glial activation and IL-1β-associated inflammation.	Not reported for plaque burden or Aβ clearance.	Not reported.	Improved AβO-induced novel object recognition memory-establishment impairment.	Benefit applies to acute AβO-driven inflammatory memory impairment, not chronic amyloid handling.
4	Cui et al., 2020; TAK-242; core pharmacological in vivo	Decreased microglial activation, M1 markers, and MyD88/NF-κB/NLRP3 signaling; increased M2/phagocytic markers.	Decreased Aβ plaque load; BV2 bead phagocytosis increased, but direct Aβ phagocytosis was not specifically quantified.	Reduced Bax/DNA fragmentation and conditioned-medium-induced neuronal apoptosis.	Improved Morris water maze performance.	Beneficial cross-layer pattern in APP/PS1 mice.
5	Liu et al., 2020; CLI-095; supportive microglial mechanism	Decreased Aβ1–42-induced NLRP3/ASC/caspase-1/IL-1β and inflammatory mediators.	Not reported.	Reduced microglia-conditioned-medium neurotoxicity toward HT-22 cells.	Not reported.	Supports cellular TLR4/NLRP3-mediated microglial neurotoxicity pathway.
6	Hughes et al., 2020; RSLA/TAK-242/KO; supportive ex vivo mechanism-function	Decreased TLR4/MyD88-dependent cytokine responses; antagonists blocked glial TNF-α in culture.	Not reported.	Mixed: RSLA rescued Aβ-induced LTP impairment, whereas TAK-242 did not; antagonists reduced co-culture cell death.	No animal behavior; LTP was used as an ex vivo functional readout.	Shows synaptic/cell-death effects are compound- and compartment-dependent.
7	Chen et al., 2021; TAK-242 validation; oxysophoridine primary	TAK-242-sensitive reduction in TLR4/MyD88/NF-κB, cytokines, and oxidative stress in BV2 cells.	Not reported.	BV2 viability/oxidative stress assessed; neuronal pathology not reported.	Not reported.	Pathway-validation evidence only; not direct TLR4-inhibitor efficacy.
8	Balu et al., 2023; IAXO-101; core context-dependent in vivo	Decreased most clearly in female E4FAD; limited or absent in male E4FAD and female E3FAD contexts.	Mixed: prevention showed memory benefit without Aβ reduction and increased cortical Thio-S; reversal reduced histological Aβ/fibrillar amyloid.	Not reported.	Improved Morris water maze probe memory in female E4FAD only.	Benefit depends on sex, APOE genotype, and treatment window.
9	Dou et al., 2024; TLR4 knockdown/overexpression; supportive genetic cell mode	TLR4 knockdown decreased BV2 cytokines, NLRP3/caspase-1, Bax, and apoptosis; overexpression showed the opposite pattern.	Not reported for Aβ clearance, plaque burden, or APP processing.	Reduced BV2 tau-related proteins after knockdown; not neuronal tau pathology.	Not reported.	Supports TLR4-dependent BV2 inflammatory, apoptotic, and tau-related cellular changes only.
10	Zhu et al., 2024; TLR4 siRNA/CLI-095/NSC23766; core pathway evidence	Decreased TLR4/Rac1/NLRP3 activation and inflammatory mediator expression in cells and mice.	Reduced hippocampal Aβ deposition was reported after Rac1 inhibition; CLI-095-related Aβ lowering should not be overgeneralized.	Not reported for neuronal loss, synaptic proteins, BDNF, or tau.	Improved Morris water maze performance after CLI-095 or NSC23766.	Supports a targetable Aβ–TLR4–Rac1–NLRP3 inflammatory axis; behavioral improvement was observed after CLI-095 or NSC23766, whereas amyloid-deposition reduction should be attributed mainly to Rac1 inhibition.
11	Ahangaran et al., 2026; TAK-242 ± JQ1; core discordant in vivo	Decreased CD86/CD163-based microglial polarization index; canonical TLR4 downstream signaling was not reported.	Not reported.	JQ1 improved mature BDNF-related measures; TAK-242 alone did not consistently rescue BDNF readouts.	Mixed/adverse: JQ1 improved memory outcomes, whereas TAK-242 alone failed to rescue Morris water maze performance and co-treatment attenuated JQ1-related spatial and aversive memory benefits.	Selected microglial improvement after TAK-242 did not guarantee neurotrophic or spatial cognitive rescue; TLR4 inhibition attenuated JQ1-related memory facilitation.

Outcome directions should be interpreted together with evidence directness and intervention category in Table 1. “Mixed” indicates inconsistent directions across models, interventions, or endpoints; “not reported” indicates no direct assessment. Pharmacological inhibition or antagonism, genetic loss-of-function or knockout, gene-silencing approaches, pathway-validation strategies, and combination/co-intervention designs were not treated as biologically interchangeable. For Zhu et al. (2024) amyloid-deposition findings should be attributed to the specific Rac1-inhibition experiment rather than generalized to all TLR4-targeting approaches. For Ahangaran et al. (2026) TAK-242 should not be described as consistently behaviorally beneficial.