Neuroinflammation Causes Alzheimer’s Disease; A New Focus for Breakthrough Therapies

Updated on March 30, 2023

The Alzheimer’s Treatment Landscape

There is incredible momentum in Alzheimer’s disease (AD) research creating promising treatment options for patients living with the disease. With new treatments coming to market, it is important for AD patients, caregivers and the healthcare community to understand the different therapeutic approaches to treating AD beyond targeting amyloid and tau. In addition, it is imperative for the healthcare and scientific community to accept the numerous failures of AD treatments over the past several decades in order to consider new methodologies. 

As the news of lecanemab’s accelerated FDA approval has settled, the scientific community has accepted the drug’s limited ability to slow cognitive decline. The consistently subpar results of anti-amyloid therapies such as lecanemab has forced a shift from the groupthink mentality around the “amyloid hypothesis,” to a focus on alternatives. High on everyone’s “alternative” list is neuroinflammation. 

Neuroinflammation is Driving AD

Neuroinflammation, or inflammation in the brain, is an important target for AD research. Of all the AD therapies, only neuroinflammation ties together every aspect of AD pathology. Neuroinflammation can cause neurodegeneration and synaptic dysfunction, the core pathologies of AD. Recent studies have shown that the vast majority of genetic changes associated with the disease are within the immune system of the brain. That is, Alzheimer’s disease is an immunologic disease, not a neurologic disease!

Chronic immune dysregulation, also referred to as chronic inflammation, is a low-grade inflammatory state that over time silently wreaks havoc in many ways. For patients with AD, the effects are most profound in the central nervous system. Chronic neuroinflammation is associated with progressive cognitive decline. The more neuroinflammation an AD patient has, the worse the cognitive decline. The immune system plays a critical role in AD progression – neuroinflammation an important target for AD therapy.

A Look Inside a Neuroinflammation Approach

While no FDA-approved AD treatments target neuroinflammation, there is promising news with XPro1595, a therapy being developed to treat AD by targeting activated immune cells in the brain to reduce neuroinflammation. Activated immune cells, microglia and astroglia cells, make up 50% of the cells in the brain. You can imagine when 50% of the cells of the brain get angry, bad things happen. In the case of AD, that bad thing is cognitive decline. 

Neuroinflammation is caused by inflammatory cytokines produced by the glial cells.  The most important neuroinflammatory cytokine is soluble Tumor Necrosis Factor (sTNF).  sTNF is the “master cytokine” that sits at the apex of the inflammation cascade.  Blocking sTNF stops neuroinflammation.  XPRO is a novel therapy that enters the brain and neutralizes sTNF to decrease the activation of glial cells and stem the ravages of neuroinflammation. 

Recently, a new pathology has become part of the Alzheimer’s disease complex. Myelin, the “insulation” on neurons, is a critical component for normal function of the brain.  Demyelination is recognized as a common feature in AD – the worse the cognitive decline, the worse the demyelination. The trifecta of pathology caused by neuroinflammation in AD and dysfunctional microglial cells is nerve cell death, synaptic impairment, and demyelination. By targeting the activated glial cells to fight neuroinflammation, XPro1595 decreases nerve cell death, improves synaptic function and promotes remyelination allowing repair and remodeling of the brain.  

Raising the Bar: Alzheimer’s Patients Deserve Better

Historically, eliminating amyloid plaques was the goal in the treatment of AD. We now know this is not enough. Looking to the future, patients deserve treatments that attack all the problems of AD – nerve cell death, synaptic dysfunction and demyelination. As an industry, we cannot define success as delaying disease progression by three to six months. Patients and their caregivers deserve a therapy that can stop the disease in its tracks. 

Targeting neuroinflammation in the brain to stimulate remodeling and repair of the brain is the key to improving cognitive function in AD. An effective therapy for AD will dramatically impact the quality of life for patients, their caregivers, and families. XPro1595 may be the disease modifying treatment needed to stop the progression of this devastating disease. And once we cross that threshold of a therapy that stops disease progression, we can focus on the ultimate goal: preventing AD before it robs anyone of their memories.

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RJ Tesi, M.D.

RJ Tesi, M.D., is the co-founder and CEO of INmune Bio (NASDAQ: INMB), a publicly traded, clinical-stage biotechnology company developing therapies that target the innate immune system to fight disease. INmune Bio has two product platforms that are both in clinical trials, the DN-TNF product platform, and the Natural Killer Cell Priming Platform which includes INKmune™.From November 2011 to May 2015, Dr. Tesi was CEO, President and Acting Chief Medical Officer of FPRT Bio Inc., a development-stage biotech company formed to develop XPro1595 for the treatment of neurodegenerative disease and other inflammatory diseases.