Preventing Alzheimer Disease After Brain Injury: Targeting TNF With XPro1595

Traumatic brain injury (TBI) is a known environmental risk factors for development of Alzheimer disease, though the biological mechanism linking the conditions is incompletely understood. A newly published preclinical study offers evidence that soluble tumor necrosis factor (TNF), the disease-driving form of this inflammatory cytokine, is related to head injury and the amyloid pathology, neuronal loss, and functional deficits characteristic of Alzheimer disease.^1,2 In a 3xTg-AD mouse model, selective neutralization of soluble TNF with the investigational agent XPro1595 prevented the injury-induced rise in neurotoxic amyloid beta and preserved learning, memory, and pain-related outcomes following TBI. Because XPro1595 has an established human safety and pharmacokinetic profile and is in active clinical development for Alzheimer disease, these findings raise the possibility of an upstream, inflammation-targeted intervention for a large and currently unserved population at elevated dementia risk. Psychiatric Times spoke with CJ Barnum, PhD, on the neuroinflammatory link between TBI and Alzheimer pathology, the selectivity of XPro1595 for soluble TNF, and the implications of these findings for clinical translation.

Psychiatric Times: How are TBI and Alzheimer pathology connected?

CJ Barnum, PhD: The risk for Alzheimer disease following a TBI is well established. What has been less clear is what exactly connects the 2. Increasingly, the evidence points to neuroinflammation, and this study adds to it. A head injury sets off a neuroinflammatory response in the brain, one that can persist well after the injury itself, and that same response drives the production of the plaques, tangles, and neuronal cell death that define Alzheimer disease in predisposed individuals. The data now suggests that you can mitigate that risk by effectively addressing the neuroinflammation following a TBI. Quiet the inflammation, and you act on the disease at its source rather than its end products.

PT: We know TNF is related to inflammation and dementias, but how does XPro1595 work to neutralize soluble TNF specifically?

Barnum: TNF comes in 2 forms, and they have opposite jobs. Soluble TNF drives the chronic inflammation behind neurodegeneration. Membrane-bound TNF does the useful work. It helps the brain's immune cells, the glia, support neurons in nearly every way, much like how a parent support an infant.

The problem with the TNF inhibitors used today, the ones familiar from rheumatoid arthritis and similar conditions, is that they block both forms at once. These therapies shut down the harmful soluble TNF but also switches off the supportive membrane-bound form, which can severely impair the homeostatic function of these cells. We have seen what that can cost. When multiple sclerosis patients were treated with a non-selective TNF blocker, their disease got worse, not better. In the brain, the goal has to be to calm the harmful inflammation without shutting down the glia's normal job.

XPro1595 is built to do exactly that—it is selective. It looks like soluble TNF itself, so it pairs with the real thing and locks it into a complex that can no longer signal, while leaving the membrane-bound form untouched. You take out the harmful signal and leave the protective one working. That tips the balance back toward the supportive side. A short video explanation can be found here.

PT: What aspects of this investigation are most useful for practicing psychiatric clinicians?

Barnum: The most important finding is that we can alter Alzheimer-type pathology by going after inflammation instead of amyloid. When the soluble TNF signal was neutralized, the amyloid response, neuronal cell death, and behavioral deficits were all prevented. For a field that has spent 20 years focused almost entirely on amyloid, these are compelling data that point to a different approach.

Second, the behavior aligns with what clinicians see in patients: worsened memory, more pain. Both moved with the inflammation, and both were prevented by treatment. That points to a single inflammatory root under symptoms psychiatry usually treats separately. Given how much interest there is now in neuroinflammation across mood, cognition, and pain, that connection is worth pursuing.

PT: Are these findings in mice encouraging for human translation in this indication?

Barnum: Yes, and more than a typical mouse study would justify. XPro1595 is not a research compound anymore. It is already being used with patients, with a known safety and tolerability profile. The doses that worked in these mice scale to doses we have already given patients and the drug does cross the blood-brain barrier in humans.

Most mouse findings die on the way to the clinic for predictable reasons: unknown safety, no brain exposure, a target that does not behave the same way in humans. None of those apply here. The biology is right, the target is human, and the drug is already in the clinic. Efficacy still has to be proven in patients. But this is about as de-risked as preclinical data gets, and it is worth moving on.

PT: How would XPro1595 as a post-TBI treatment option fulfill unmet needs in the Alzheimer disease space?

Barnum: This population is large, and no one is serving it. Millions of individuals carry higher Alzheimer disease risk because of a prior head injury: athletes, veterans, individuals who have been in serious accidents. There is nothing on the market aimed at that risk. The approved Alzheimer drugs are anti-amyloid antibodies. They act late, on plaque that is already there, and they do nothing about the inflammation driving the disease or the injury that started it.

XPro1595 works at the other end of the problem. It shuts off the inflammatory signal that produces amyloid and kills neurons in the first place. That upstream position is where you want to be if the goal is to prevent or slow the disease rather than clean up after it. And this is not hypothetical. XPro1595 is already in clinical development in Alzheimer disease, so the premise is being tested in patients now. The TBI work extends the same logic to an earlier starting point—the window right after the injury.

It is also worth noting that the benefit here does not depend entirely on the connection to Alzheimer disease. TBI is a large unmet need in its own right, with no approved therapy that changes its course, and in this study, treatment prevented the cognitive and pain deficits that followed the injury. For clinicians managing patients after a head injury, that is a nearer-term reason to care, whatever the long-term dementia risk turns out to be.

Dr Barnum is vice president of neuroscience at INmune Bio.

References

1. INmune Bio’s XPro1595 prevents brain-injury-induced Alzheimer’s pathology, memory loss, and pain in new peer-reviewed preclinical study. Press release. July 15, 2026. Accessed July 24, 2026. https://www.biospace.com/press-releases/inmune-bios-xpro1595-prevents-brain-injury-induced-alzheimers-pathology-memory-loss-and-pain-in-new-peer-reviewed-preclinical-study

2. Poffenberger CN, Taylor MM, Larson K, et al. Inhibition of soluble TNF mitigates traumatic brain injury as a risk factor for the development of amyloidogenic proteins and functional deficits in 3xTg-AD mice. J Neurotrauma. 2026.