AD

Overall			No human genetic link to AD NLRP3 is not differentially expressed in AD brain but several genes near NLRP3 (GSDMD, IL18 and PYCARD) are up-regulated in parahippocampal gyrus of AD and increased with AD-related pathology burden. NLRP3-pathway is up-regulated in immune-activated patient group
			mRNA			Protein
Region	Cohort		Altered? (baseline, T0)	∝ each other	∝ with Baseline severity/progression?	Altered?	∝ with Baseline severity/progression?	∝ other
Brain	MSBB bulk ((N=~300 for RNA-seq))		-BA10:, prefrontal -cortex -BA22: posterior superior temporal gyrus -BA36: perirhinal cortex (para-hippocampal region) -BA44: frontal cortex -Only GSDMD is significantly increased in parahippocampal gyrus of AD(1.3X)(MCI 에선 =)  - NLRP3, ASC, Casp-1, IL1B, il18 등 모두 =	NLRP3 ∝ ASC (coffecient 0.35) NLRP3 ∝ IL18 (coffecient 0.5) Nlrp3 가 다른 것들과는 안 correlation.	[parahippocampal gyrus(ba36)] (GSDMD & IL18) ∝ (CERAD & BRAAK) (둘다 medium degree 로) • ASC & CERAD (medium degree)   Nlrp3, casp1, il1b, IL18 모두 no correlation	Parahippocampal gyrus (TMT labeling) AD=106, HC=22, MCI=18) [AD & MCI 모두에서] ASC: = CASP1: = IL18: = GSDMD: = NLRP3, & IL1B were not available.	-CERAD: (ASC, CASP1, IL18 GSDMD) correlation X -Braak: (ASC, GSDMD) correlation O (casp1, il18, MIF) correlation X, -CDR: (ASC, IL18) correlation O, (casp1, gsdmd) correlation X NLRP3, & IL1B were not available.
	ROSMAP bulk: DLPFC		(N=627) NLRP3, ASC, Casp-1, IL1B, il18, GSDSD, 등 모두 =		NLRP3, ASC, Casp-1, IL1B, il18, GSDSD, 등 모두 no correlation with CERAD or BRAAK - (의외) NLRP3 and HMGB1 positively ∝ MMSE - (기대) GSDMD negatively ∝ MMSE. - (ASC, CASP1, IL1B, IL18 모두 no correlation with MMSE) NLRP3, IL18, ASC GSDMD 가 일부 Brain region 에서만 ∝ CDR-SB -ASC, IL1B 는 어떤 지역에서도 No correlation with CDR-SB	(N=395), Between AD, asymAD, HC,: ASC, CASP1, HMGB1, MIF, and GSDMD were not different. • NLRP3, IL1B and IL18 were not available.	(N=395): (ASC, CASP1 HMGB1, MIF, GSDMD) 모두 no correlation with CERAD or BRAAK • (NLRP3, IL1B, IL18 were not available)
	ROSMAP scRNAseq		DLPFC(microglial) N=48) [{Mathys, 2019 #2093} NLRP3, ASC, Casp-1, IL1B, il18,, 등 모두 = (GSDSD 는 안 봄)
ROSMAP, Emory, Mount Sinai		{Johnson, 2021 #2048} Nearly half of the protein co-expression modules cohorts and brain regions, highlighting the proteopathic nature of AD. For example, there were also 18 protein network modules that were not preserved in the RNA network including the AD-associated modules M7 MAPK/metabolism, M24 ubiquitination, M29 glycosylation/ER and M42 matrisome. ... significant proportion of biological changes relevant to AD pathophysiology are occurring through mechanisms that are not reflected through changes in protein abundance or co-expression. The ultimate biological effectors of AD genetic and environmental risk are often the proteins and the metabolic pathways they regulate.
CSF		Sz: 2019-2020 for AD with the MSD panels. This is essentially a replica of what Zemin has proposed with the PrecisionMed samples. The AD ... "longitudinal", 2 visits over 6-12 months → IL-1b: BLQ in AD & HC → IL18: not available
Blood

Molecular subtypes AD

	A	B1	B2	C1	C2	AD?
predominant	tau	tau	Tau	Aβ	Aβ
Immune-related pathways			Immune-related pathways	↑↑ Immune-related pathways	Immune-related pathways
↑	Jonghun: NLRP3 (Limitation is that there is no biomarker for discriminating the subgroups. Also even though the NLRP3 pathway is up-regulated in C1 group, it is not specifically higher than the other immune pathways such as 'inflammatory response' (slide #12 heatmap)
synaptic markers				APOE4
	Jonghun: Regarding the C3AR1, the Complement pathway is up regulated even before sub-clustering
↓	Immune-related pathways NLRP3	glutaminergic, GABAergic and dendritic synaptic pathway

Competitor

Drug / Vendor	Compound description	Trial details	Notes
(Genali)			BM: PLASMA il-18, csf MCP-1 (=CCL2), CSF NFL (but data: D305N mouse shows elevation of these, no data of drug effect)
Inzomelid / Inflazome / Roche	A similar compound to MCC950	N=80, P1, NCT04015076, SAD & MAD, completed, HV & CAPS patients, Healthy adults received single or multiple ascending doses or placebo. CAPS patients received drug per an open-label protocol 2ndary endpoints: Pharmacodynamic activity [Time Frame: Day 1-5 for SAD and Day 1-9 for MAD] | NLRP3 Inhibition in whole blood	- Reduction in CAPS symptom scores [Time Frame: Days 1-15] Reduction in Physician CAPS scores based on questionnaire In a March 26, 2020, press release, Inflazome announced a linear relationship between blood levels of drug and correlation with NLRP3 levels, but no data were provided. The press release stated that the drug was well-tolerable, and claimed that one CAPS patient showed rapid improvement after taking inzomelid, on unspecified clinical parameters. Ph 1b for PD withdrawn "strategic decision by sponsor"; Ph 2b for CAPS terminated
Dapansutrile / Olatec	(indeterminate)
Neumora	Neumora Therapeutics gets 2.1M pounds from Parkinson's UK to perform safety and efficacy experiments with their NLRP3i
Novartis	IFM 2427/DFV890; peripheral	Compound A: in clinic, osteoarthritis Compund B: neurodegeneration NCT04868968 - Phase 1: completed - Phase 2: COVID-19 pneumonia (no reduction in severity of disease compared with standard of care - CRP levels were reduced). - Phase 2: FCAS - Phase 2: Knee osteoarthritis - No brain penetrant compound entering the clinic yet	Note: Canakinumab: ➤ Novartis is currently running a Ph2 clinical trial for mild cognitive impairment with their Canakinumab (anti-IL-1b antibody). It will read on Feb 2026. classic.clinicaltrials.gov/ct2/show/record/NCT04795466
Ventyx	VTX2735, peripheral	Ventyx has moved into p2 with their peripheral compound VTX-2735 for "proof of mechanism" trial for CAPS, This trial enrolled 7 patients with familial cold autoinflammatory syndrome (FCAS), the most common form of CAPS. Treatment with VTX2735 demonstrated clinically meaningful improvements in disease activity, including an 85% mean reduction in the Key Symptom Score during Treatment Period 1. Reductions in inflammatory biomarkers were also observed, consistent with improvements in disease activity. VTX2735 was well-tolerated, and all drug-related adverse events were graded mild. We believe these data establish compelling clinical proof of concept for our peripheral NLRP3 inhibitor VTX2735. We plan to evaluate VTX2735 in cardiovascular diseases with an initial focus on the secondary prevention of major adverse cardiovascular events (MACE) and recurrent pericarditis.

Uncertain Spans

location	transcription	uncertainty
Brain MSBB / mRNA cells	the mRNA coffecient token reads as a typo for coefficient; preserved verbatim.	source typography preserved.
ROSMAP bulk DLPFC / mRNA cell	reads GSDSD (instead of GSDMD) in NLRP3, ASC, Casp-1, IL1B, il18, GSDSD, 등 모두 =; preserved verbatim.	low confidence on whether GSDSD is a typo for GSDMD or a different gene.
Molecular subtypes AD / column placement	the column boundaries for B1 / B2 / C1 / C2 are partly inferred from the visible cell text and may not exactly match the source layout.	low confidence on column-by-subtype placement.
Competitor / Inzomelid / Roche listing	the right header column reads Inzomelid / Inflazome / Roche; the precise vendor sequence (Roche acquisition timing of Inflazome) is preserved verbatim.	low confidence on whether Roche is a separate row or part of the Inflazome row.