Could NLRP3 be the missing link between amyloid pathology and tau-mediated neurodegeneration? Dr Gennaro Pagano explains how insights from the GRADUATE trial is informing the next generation of Alzheimer’s disease therapies and advancing our understanding of neuroinflammation.
touchNEUROLOGY coverage of AAIC 2026
Late-breaking reverse translational analyses from the Phase III GRADUATE programme presented at the Alzheimer’s Association International Conference (AAIC) 2026 have provided new insights into the role of the NLRP3 inflammasome in Alzheimer’s disease. In this interview, we speak with Dr Gennaro Pagano (Roche/Genentech, Basel, Switzerland) who discusses how these findings strengthen the evidence for NLRP3 as a promising therapeutic target linking amyloid pathology, neuroinflammation and downstream tau pathology.
Dr Pagano explains how analyses of cerebrospinal fluid biomarkers from more than 500 participants in the GRADUATE trials demonstrated that higher baseline NLRP3 activity was associated with faster cognitive decline, before describing how complementary preclinical studies showed that NLRP3 inhibition could reduce amyloid-driven tau phosphorylation. He also explores the implications of these findings for future Alzheimer’s disease therapies, including the potential of NLRP3 inhibitors in combination with amyloid-lowering treatments, the importance of reverse translational research in guiding drug development and the need for greater collaboration across academia, industry and charities to accelerate progress towards more effective therapies.
Questions
- What role does the NLRP3 inflammasome play in Alzheimer’s disease progression, and why has it emerged as a promising therapeutic target? (00:15)
- Could you summarize the key findings from the reverse translational analyses of the GRADUATE phase 3 trials, and what new insights do they provide into the role of NLRP3 in Alzheimer’s disease? (01:05)
- How have these findings changed our understanding of the relationship between amyloid pathology and neuroinflammation, and what do they suggest about the biological mechanisms driving disease progression? (02:42)
- Looking ahead, how could these data influence the development of future Alzheimer’s disease therapies, and what role do you see for NLRP3-targeted approaches, either alone or in combination with anti-amyloid treatments? (03:47)
- What are the next steps? (04:58)
- What do you envisage in the future directions of Alzheimer’s disease research? (06:05)
- What did you find were the most important therapeutic and treatment updates presented at AAIC 2026? (07:10)
Associated abstract
The role of NLRP3 in Alzheimer’s disease: reverse translational data from GRADUATE ph3 trials which took place at Tuesday 14 July, AAIC, London UK (Perspectives Session: Neuroimmune Targets for Neurodegenerative Diseases) 14:00-15:30 BST
Disclosures: Gennaro Pagano has received honoraria/honorarium from F.Hoffmann-La Roche Ltd, and has major stock/is a shareholder in F.Hoffmann-La Roche Ltd.
This content has been developed independently by Touch Medical Media for touchNEUROLOGY. It is not affiliated with the Alzheimer’s Association International Conference (AAIC). Unapproved products or unapproved uses of approved products may be discussed by the faculty; these situations may reflect the approval status in one or more jurisdictions. No endorsement of unapproved products or unapproved uses is either made or implied by mention of these products or uses by Touch Medical Media or any sponsor. Views expressed are the speaker’s own and do not necessarily reflect the views of Touch Medical Media.
Transcript
Hi, I’m Dr Gennaro Pagano, and I work at Roche/Genentech in Basel.
Q. What role does the NLRP3 inflammasome play in Alzheimer’s disease progression, and why has it emerged as a promising therapeutic target?
NLRP3 represents one of the promising microglial targets in Alzheimer’s disease. We demonstrated in the GRADUATE Phase III trial that the pathway is activated in the brain by measuring cerebrospinal fluid (CSF) from patients with Alzheimer’s disease. We then went back preclinically to evaluate whether NLRP3 could be activated by amyloid plaques. We discovered that amyloid fibrils, particularly in preclinical models, are associated with increased NLRP3 activation and downstream effects on tau.
By giving an NLRP3 inhibitor, we could reduce this effect, with downstream effects on tau. This is our hypothesis regarding the mechanism of action of these potential drugs.
Q. Could you summarize the key findings from the reverse translational analyses of the GRADUATE phase 3 trials, and what new insights do they provide into the role of NLRP3 in Alzheimer’s disease?
Since many years, people have been talking about NLRP3 as a promising target. The beauty of large Phase III trials that allow us to evaluate these hypotheses in humans is that having a hypothesis is one thing, but having data is another. I had the opportunity, with my team, to reanalyse the CSF data from these large Phase II and Phase III studies, with 520 people recruited to the CSF substudy. We measured NLRP3-related biomarkers and correlated them with different biomarkers in the CSF at baseline. But we also evaluated something more interesting: whether the baseline values were predictive of progression over time.
What we found was that participants in GRADUATE who had higher levels of NLRP3 were the ones who progressed faster in terms of cognitive decline. But this is only one step in neurodegeneration. So, what we did was go back to preclinical models and test how an inhibitor could work. We linked amyloid plaques to tau phosphorylation. In our human model system in vitro, an NLRP3 inhibitor was able to reduce the downstream effect of amyloid plaque and amyloid fibril activation on tau.
Q. How have these findings changed our understanding of the relationship between amyloid pathology and neuroinflammation, and what do they suggest about the biological mechanisms driving disease progression?
Alzheimer’s disease progression is complex. There are several targets, and thinking that with one single molecule or one single target you can stop the disease is probably overly optimistic. What we learned from these experiments and studies is that we need to consider different targets, and NLRP3 may play a crucial role in the link between amyloid and tau.
We know that tau itself is more closely associated with cognitive impairment. People who develop amyloid plaques can take many years to develop dementia. But once they start developing tau or large amounts of tau, they develop the symptoms that bring them to the clinic, where we try to treat them. So, by learning about the link between NLRP3 and tau, we could potentially slow or eventually stop the progression of Alzheimer’s disease.
Q. Looking ahead, how could these data influence the development of future Alzheimer’s disease therapies, and what role do you see for NLRP3-targeted approaches, either alone or in combination with anti-amyloid treatments?
We are scratching the surface of what is beneficial for patients with Alzheimer’s disease. We need to stop the disease, and to do that, we need multiple targets and multiple drugs that act on the same pathway or, even better, on multiple pathways.
At the moment, we have several amyloid-lowering therapies, and they might also indirectly reduce NLRP3 activation by removing the plaques. But it is possible that, once the plaques are removed, the microglial cells that have been activated remain overactivated over time, especially in the advanced stages of the disease. So, by giving an NLRP3 inhibitor, we can switch off this excessive activation of the pathway and potentially have a powerful synergistic combination with current amyloid-lowering drugs.
Again, it is difficult to say today what the best way to position this drug is, because data from Phase II studies will be necessary. Different companies, groups and academic groups are working on these targets. Once we have human data, we will be able to say where the best positioning for this type of approach might be.
Q. What are the next steps?
I think we need to keep learning from our clinical trials, go back preclinically with the key learnings, not base everything on hypotheses, but test those hypotheses and be ready to pivot if we find different data.
Again, the hypothesis is the starting point. The data is what drives us. What I have demonstrated with my Phase III results, I would like to test again in other trials, because this is only the beginning and not the end of hypothesis generation. We need to test the hypothesis in another trial and in another preclinical model. If it is confirmed, then we can start pursuing it over other hypotheses.
Again, it is a difficult task because all of these experiments are extremely expensive. We cannot do too many at the same time, but it is very important to get the most out of them and not simply say, “The trial is negative, now we stop.” We need to learn from our mistakes. The only thing we can do is continue developing drugs for patients with Alzheimer’s disease.
Q. What do you envisage in the future directions of Alzheimer’s disease research?
I would like to add that people living with Alzheimer’s disease are in extreme need. We have a complex disorder to stop, and we need to keep evaluating the biology without any prespecified hypotheses, but by looking at the data.
There are several Phase II and Phase III trials that will read out in the coming years, so we need to be ready as scientists, industry and charities – all the groups working in this field – to work together in a more precompetitive approach. We should try to agree on the rules of the game, such as imaging biomarkers and blood biomarkers, and try to agree on what the minimum package necessary is when we have a validated target.
This might change completely because most of the targets today are not validated. We have many targets, not just one. So, if we are able to agree on what the minimum package is for a validated target, then many groups can invest heavily and perhaps we will have one, two or more drugs.
Q. What did you find were the most important therapeutic and treatment updates presented at AAIC 2026?
This question is difficult to answer because today is only Day 2 and there will be Day 3 tomorrow. So, we also need to see what happens tomorrow. But there are many different approaches that have been presented for the first time.
I’m extremely excited that people are presenting the data publicly, with all the detail that is necessary for the field. We have new data on amyloid lowering, tau lowering and inflammatory pathways.
I was in one of the sessions today where some of the work we just discussed was presented, but there were also other companies presenting data from other targets in the neuroimmune space. So, it is an extremely vibrant and exciting time.
AAIC gives us a platform where different stakeholders can talk and explain their different points of view. I think it is exciting to be part of an ecosystem like that, because people share their ideas simply by moving, thinking and asking questions.
I learned a lot today from the questions I received during my session, and I think many others have benefited from the other sessions too.
Interviewer/Editor: Katey Gabrysch
Cite: GRADUATE: Targeting the NLRP3 inflammasome in Alzheimer’s disease. touchNEUROLOGY. xx
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