TABLE 3.

Evidence-level synthesis of inflammatory, amyloid-related, and functional outcome patterns after TLR4 inhibition, antagonism, genetic suppression, or pathway validation in AD-related models.

No.	Study	Layer 1: TLR4/inflammatory or microglial signaling	Layer 2: amyloid-related, neuronal, synaptic, or trophic evidence	Layer 3: functional/behavioral evidence	Contribution to inflammatory–amyloid–functional dissociation	Interpretation for Figure 2/hypothesis-generating synthesis
1	Song et al., 2011	TLR4 mutation reduced microglial activation and selected cytokine/chemokine responses.	Increased later Aβ deposition, fibrillar Aβ, and soluble Aβ42.	Impaired Morris water maze acquisition; probe trial not clearly worsened.	Strong paradox evidence: target-proximal inflammatory attenuation coincided with downstream amyloid worsening.	Protective/clearance-side branch: TLR4-dependent microglial activation may support Aβ handling in some stages.
2	Wu et al., 2015	CLI-095/PDTC reduced neuronal inflammatory signaling; microglia not assessed.	CLI-095/PDTC reversed LPS-induced ADAM10 downregulation, BACE-1/PS-1 upregulation, β-APP increase, and Aβ1–42 secretion in primary hippocampal neurons; no plaque or clearance evidence.	Not assessed.	Supportive neuronal mechanism only.	Mechanistic branch: neuronal TLR4/NF-κB activation may promote amyloidogenic APP processing and Aβ1–42 secretion, but this does not establish in vivo amyloid-clearance or therapeutic efficacy.
3	Balducci et al., 2017	TLR4 blockade/knockout reduced AβO-induced glial activation and IL-1β-associated inflammation.	Chronic amyloid handling, neuronal loss, synaptic proteins, and BDNF were not assessed.	Prevented AβO-induced novel object recognition memory-establishment impairment.	Beneficial-inhibition evidence in acute soluble AβO context.	Beneficial branch: TLR4 suppression may help when soluble AβO acutely drives inflammatory memory impairment.
4	Cui et al., 2020	TAK-242 reduced M1 markers and MyD88/NF-κB/NLRP3 signaling and increased M2/phagocytic markers.	Reduced Aβ plaques and neuronal apoptosis-related readouts; direct Aβ phagocytosis was not specifically quantified.	Improved Morris water maze performance.	Higher-directness beneficial cross-layer evidence.	Beneficial branch: inhibition helps when maladaptive TLR4/MyD88/NF-κB/NLRP3 signaling dominates.
5	Liu et al., 2020	CLI-095 attenuated Aβ-induced NLRP3/ASC/caspase-1/IL-1β signaling.	Reduced microglia-conditioned-medium neurotoxicity; no Aβ plaque, APP-processing, synaptic, or BDNF data.	Not assessed.	Supportive microglial mechanism only.	Mechanistic arrow: Aβ→ TLR4 → NLRP3/caspase-1/IL-1β→ microglia-mediated neuronal injury.
6	Hughes et al., 2020	Aβ42 oligomers induced TLR4/MyD88 cytokine responses; antagonists blocked glial TNF-α in culture.	RSLA rescued LTP impairment but TAK-242 did not; antagonists reduced co-culture cell death.	No animal behavior; LTP served as an ex vivo functional readout.	Mechanistic-functional evidence showing compound/compartment dissociation.	Links soluble Aβ aggregates, TLR4 inflammation, synaptic plasticity failure, and neuron–glia toxicity.
7	Chen et al., 2021	TAK-242 reduced Aβ-induced TLR4/MyD88/NF-κB and inflammatory–oxidative readouts in BV2 cells.	BV2 viability/oxidative stress assessed; Aβ plaque, clearance, APP processing, neuronal pathology, and BDNF were not assessed.	Not assessed.	Pathway-validation evidence only; oxysophoridine was the primary compound.	Cellular pathway branch: Aβ activates microglial TLR4/MyD88/NF-κB signaling.
8	Balu et al., 2023	IAXO-101 reduced microglial reactivity most clearly in female E4FAD mice.	Mixed amyloid effects by prevention/reversal paradigm.	Improved Morris water maze probe memory in female E4FAD only.	Strong context-dependent evidence; effects varied by sex, APOE genotype, and timing.	Precision-context layer: TLR4 antagonism may benefit selected APOE4 inflammatory contexts, not universally.
9	Dou et al., 2024	TLR4 knockdown reduced BV2 cytokines, NLRP3/caspase-1, Bax, and apoptosis; overexpression showed the opposite direction.	Reduced BV2 tau-related protein changes; no Aβ clearance, plaque, APP processing, or in vivo pathology.	Not assessed.	Supportive genetic cell-model evidence only.	Cellular branch: Aβ1–42 activates TLR4-dependent microglial inflammatory and apoptotic signaling.
10	Zhu et al., 2024	TLR4 knockdown/CLI-095 reduced TLR4/Rac1/NLRP3 activation and inflammatory mediators.	NSC23766 reduced hippocampal Aβ deposition; CLI-095-related Aβ lowering should not be overgeneralized.	CLI-095 and NSC23766 improved Morris water maze performance.	Higher-directness in vivo pathway evidence, but not definitive evidence that direct TLR4 inhibition itself reduces amyloid deposition.	Mechanistic axis: Aβ→ TLR4 → Rac1 → NLRP3 → inflammatory cytokines → cognitive impairment; amyloid-deposition improvement should be attributed conservatively to Rac1 inhibition.
11	Ahangaran et al., 2026	TAK-242 reduced CD86/CD163 index; canonical TLR4 downstream signaling was not quantified.	JQ1 improved BDNF measures; TAK-242 alone did not consistently improve BDNF; Aβ plaque/clearance was not assessed.	JQ1 improved spatial-memory and BDNF-related outcomes, whereas TAK-242 alone did not rescue spatial memory and co-treatment attenuated JQ1-related spatial and aversive memory benefits.	Discordant evidence: selected microglial improvement after TAK-242 did not proportionally translate downstream.	Paradox/dissociation branch: receptor-level TLR4 inhibition may not guarantee neurotrophic or spatial-memory benefit and may interfere with JQ1-related memory facilitation.

The three layers represent inflammatory/microglial signaling, amyloid-related or neurocellular outcomes, and functional/behavioral outcomes. Cross-layer interpretation was based mainly on higher-directness in vivo evidence. Cellular, ex vivo, and pathway-validation studies were used only to support mechanistic plausibility. The revised interpretation prevents over-attribution of Rac1-inhibition effects to direct TLR4 inhibition and avoids overstating TAK-242 as behaviorally beneficial in Ahangaran et al. (2026).