A Preventive Window In Post-TBI Care and Subsequent Alzheimer Pathology

A substantial body of evidence links traumatic brain injury (TBI) to elevated Alzheimer disease risk, yet the molecular pathway connecting an acute head injury to chronic neurodegenerative pathology is not completely understood. New preclinical data implicate soluble tumor necrosis factor (TNF) signaling through its receptor TNFR1 as a driver of this progression, demonstrating that TBI produces a measurable rise in BACE1, amyloid beta 42, and the apoptotic marker caspase-3 within a defined post-injury window.^1,2 Using a 3xTg-AD mouse model designed to isolate injury-induced pathology from age-related disease onset, investigators found that selective inhibition of soluble TNF with XPro1595—administered shortly after injury—blocked this cascade and prevented associated deficits in learning, memory, and pain sensitivity. Notably, cognitive and nociceptive outcomes tracked together across treatment groups, suggesting a shared inflammatory mechanism may underlie symptoms often managed separately in clinical practice. In this discussion, Kirsty J. Dixon, PhD, describes the collaborative origins of this research, the biological rationale connecting TBI to Alzheimer pathology, and the translational potential of intervening on soluble TNF in the acute aftermath of injury.

Psychiatric Times: What is XPro1595, and what was it investigated for in your recent paper?

Kirsty J. Dixon, PhD: XPro1595 is a selective inhibitor of soluble TNF, the pro-inflammatory form of tumor necrosis factor, that does not inhibit membrane-bound form and its protective receptor, TNFR2. That selectivity is the key difference from other available anti-TNF drugs, which block the whole pathway. It is a dominant-negative version of TNF: it binds native soluble TNF so the protein can no longer signal through its receptor TNFR1. It crosses the blood-brain barrier and is administered subcutaneously.

Here, we investigated it in an animal model of traumatic brain injury as a driver of amyloid beta—a key pathological marker in Alzheimer disease. TBI is a well-established risk factor for Alzheimer disease, but there has been a gap in the biology that connects them. The question we asked was direct: if we neutralize soluble TNF right after an injury, can we stop the inflammatory cascade that carries a head injury toward later Alzheimer pathology? In this model, we could.

PT: What background did this study build off of?

Dixon: This study came out of 2 lines of work coming together. On my side, we had already shown that selectively inhibiting soluble TNF with XPro1595, given shortly after a traumatic brain injury, had reduced gliosis, protected hippocampal neurons and their connections, and improved cognition, depressive-like behavior, and pain (measured as dermal hypersensitivity) in mice. That told us soluble TNF is a real driver of the damage that follows an injury, and that this molecule can change the outcome.

The Alzheimer research side came through Elliott Mufson, PhD, a neuropathologist at Barrow Neurological Institute and my collaborator on this work. Mufson and I first worked together on the Department of Defense/VA’s Chronic Effects of Neurotrauma Consortium, which tracks the long-term consequences of brain injury. TBI is a well-established risk factor for Alzheimer disease, and the 2 share a great deal of pathology, but the mechanism connecting them was never well defined. Mufson brought the Alzheimer neuropathology; I brought the injury models. The question we set out to answer was specific: is the soluble TNF signal switched on by a head injury part of what accelerates Alzheimer-type pathology in the memory circuit, and can blocking it early interrupt that process?

To test this, we took the intervention that worked in our TBI studies into an Alzheimer-prone mouse, the 3xTg-AD model. We gave the mice brain injuries (similar to that which happens in humans) before these develop pathology endogenously (naturally on their own) and asked whether blocking soluble TNF right after the injury would keep the injury from switching on the amyloid machinery. Ultimately, it did.

PT: Which findings do you see as most relevant for practicing psychiatric clinicians?

Dixon: First, that brain injury creates a window during which you can act. A single moderate TBI produced a temporary but clear rise in BACE1 and Aβ42, along with deficits in learning, memory, and pain sensitivity. Treating the inflammation right after the injury, rather than treating the amyloid, prevented all of the subsequent pathophysiology. That tells us that post-injury inflammation is a driver, not just a marker.Second, cognition and pain moved together. The animal groups with memory deficits were the same ones with heightened pain sensitivity, and both resolved with treatment. In patients recovering from a head injury, cognitive complaints, mood, and chronic pain often occur together. This points to a shared inflammatory mechanism beneath symptoms that are usually managed one at a time.

PT: What is the established connection of TBI and Alzheimer pathology?

Dixon: We have known for decades that a serious head injury raises the risk of Alzheimer disease. What we have not understood is the biological connection, and this study speaks to one part of it. When the brain is injured, the immune response releases soluble TNF, which signals through the TNFR1 receptor. In our data, that signal drove up BACE1, the enzyme that cleaves amyloid precursor protein into Aβ42, the neurotoxic fragment that seeds amyloid plaques. TNFR1 and Aβ42 tracked BACE1 on the same timeline, and so did caspase-3, a marker of cell death.

Amyloid is only part of the picture. Alzheimer disease is defined by both amyloid plaques and neurofibrillary tangles of tau, and the literature ties head injury to both, with chronic neuroinflammation underneath. Soluble TNF sits at the apex of these threads, and all of them converge on the same memory circuit that becomes impaired in patients with Alzheimer disease. What our study adds is a clean demonstration of one of them, the amyloid arm, and that blocking soluble TNF early shuts it down, along with the any cognitive impairments.

PT: How would XPro1595 as a post-TBI treatment option fulfill unmet needs in TBI and Alzheimer's disease treatment?

Dixon: The need is real. There is no approved treatment that lowers the long-term dementia risk after a serious head injury. Care is supportive. So it is notable that one biologic, starting acutely after the TBI, prevented the whole picture: the amyloid response, the cell-death signal, the cognitive deficits, and pain. That is the profile you want in a preventive treatment—block the harmful signal early, and leave the healthy biology intact. It points to a different approach, treating the window right after injury to change the trajectory before pathology sets in. It does not compete with the amyloid-clearing antibodies used later in established disease. It works earlier, and further upstream.

PT: What are the next steps in evaluating this drug for post-TBI use?

Dixon: There are always more questions to be asked, such as the underlying mechanisms of action (direct or indirect effect of treatment on brain cells), and questions like these give rise to identifying whether delayed treatments would work equally as well as treatments administered acutely following the injury—an important factor to consider given the frequency with which TBIs occur in the general community, and the ease (or lack thereof) of accessing immediate treatment options. Clinically, data generated in these studies support transition to human clinical trials of patients with TBI.

Dr Dixon is associate professor of surgery and director of the Neurotrauma Repair Laboratory at the Virginia Commonwealth University School of Medicine.

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.