The Evolving Approach of Targeting Neuroinflammation in Alzheimer's Disease
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Dementias and related diseases of cognitive decline pose an enormous and growing burden on our societies and health economies. According to a 2020 global burden of disease study, there is a large and increasing burden of non-communicable neurological disorders in the United States, with up to a five-fold variation in the burden of and trends in particular neurological disorders across the country. The increase is largely driven by the neurodegenerative disease, Alzheimer’s disease (AD), and by an aging population in general.
Not surprisingly, the development of strategies to curb this frightening surge is a high priority for life science research today, but the field has failed in identifying candidates to stop the progression of AD. For decades, research on AD has focused on pathomechanisms linked to two of the major pathological hallmarks of extracellular deposition of beta-amyloid peptides and intra-neuronal formation of neurofibrils. More than 200 clinical trials have resulted in one approval (Aduhelm) with safety concerns and a marginal slowing of decline. These results demand a different, more promising approach.
The most promising approach is to change the behavior of our own immune system.
The immune system and inflammation
The body’s innate immune system serves similar to a defensive security system by recognizing and defending against invading pathogens that could cause infection and disease. Among the wide variety of cells, tissues, proteins and organs involved in this process, microglia, a cell that acts as the first and main form of active immune defense in the central nervous system (CNS), serves in the most critical role of orchestrating brain inflammation. In response to infection, microglia orchestrate a multi-factorial attack that includes inflammatory chemicals such as cytokines and chemokines, reactive oxygen species, and even leverages the neurotoxic properties of glutamate to dispatch the pathogen. Although these chemicals are released in order to combat harmful pathogens, they have equally detrimental effects on the body including brain cells. These detrimental effects on the body are best depicted by chronic neuroinflammation.
There is increasing evidence that chronic neuroinflammation adversely impacts every biological mechanism implicated in AD. Acceptance of this was largely influenced by advanced genetic studies that found greater than 60% of the genes that portend high risk for AD are genes that govern some aspect of immune function. Amyloid itself has been suggested to be an immune molecule after data emerged showing amyloid was an extremely potent antimicrobial. Such broad effects illustrate the significance of the immune system to CNS function and disease and resulted in widespread support and commitment to develop therapies that target the immune system. However, targeting neuroinflammation to treat AD is not as simple as just stopping chronic neuroinflammation caused by microglial activation. The approach must allow microglial cells to perform their critical supportive functions involved in the care and maintenance of neurons. This is not trivial. Immunosuppressive therapies have been shown to exacerbate neurologic disease prompting a black box warning. In other words, how you target the immune system is as important as what you target in the immune system. It must be anti-inflammatory but not glial-suppressive.
A precise approach to targeting neuroinflammation has been hampered by the lack of the right drug until recently.
A promising shift in approach
While drug development failures have been gut wrenching for individuals with AD and their family members, disproving current approaches may paradoxically be positive for the industry as scientists and companies are being forced to step back, evaluate the data, and commit to innovative new programs and therapies. This is illustrated in recent developments of AD research shifting from amyloid plaque and tau protein to biomarkers that target neuroinflammation. The reasons include failures in amyloid and tau therapeutics and new findings that are helping to uncover the breadth of pathology in the onset and progression of this neurodegenerative condition.
The notion that AD is caused by chronic inflammation is supported by genome-wide association data in humans and abundant animal data. That makes targeting inflammation in and around nerve cells in the brain one of several promising strategies for treating it. A recent study by researchers from the University of Pittsburgh School of Medicine found that neuroinflammation is the key driver of the spread of pathologically misfolded proteins in the brain and causes cognitive impairment in patients with AD.
Precision medicine in AD
There is one thing all scientists agree on: there is no single cause of AD and successfully treating AD will require treatment combinations that will be as different as the number of people with AD. Yet, we still treat it as one size fits all. Cancer therapies have made incredible breakthroughs by using biomarkers to inform treatment. Biomarkers help us align our treatment with the patients’ pathology allowing clinical teams to identify and treat only those most likely to respond to treatment. The idea is simple, if you are targeting inflammation, the patient should have inflammation. Of course, this applies to treatments beyond inflammation, and we need to strive to identify the right patients for a given treatment. Research continues to support our belief that a neuroinflammatory treatment will be part of any combination strategy.
Targeting neuroinflammation via the innate immune system is a promising avenue that can provide us hope in AD treatment.