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Inflamyloid: What Is It and Why Is It Important in Alzheimer's Disease?

 Inflamyloid: What Is It and Why Is It Important in Alzheimer's Disease? content piece image
AstraZeneca's Damian Crowther gave a webinar on the imflamyloid October 24 on Technology Networks. Credit: AstraZeneca
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Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Classically, the “amyloid” hypothesis, which ties the disease’s spread to that of amyloid protein, is thought to underlie AD’s pathology. After years of mixed to negative results in clinical trials, new research is underway to investigate what role the brain’s own immune system plays in amyloid-driven disease; an “infla-myloid” hypothesis.

In a new Technology Networks webinar,  Damian Crowther, Director of Neuroscience R&D at AstraZeneca’s IMED Biotech Unit, outlines the theoretical role of the inflamyloid and suggests how we can use immune targets to tackle AD. 

Given the devastating impact of AD on patients and wider society, it is no surprise that much time and effort has been expended in the pursuit of a therapy for the disease. Despite this investment, there have been repeated high-profile clinical trial failures in AD research (and rare success stories), such as:

  • Semegacestat – A gamma-secretase inhibitor, part of the secretase inhibitor class of drugs that aims to “stop the tap” of amyloid being produced in the brain. In a phase III trial, Semagacestat produced nasty side effects including skin tumors and actually resulted in worse cognitive outcomes. 

  • Avagacestat – Also a gamma-secretase inhibitor, avagacestat was designed to avoid side effects related to notch-pathway inhibition. Nonetheless, some side-effects persisted, and produced the same negative effects on cognitive performance as semegacestat. 

  • Verebecestat – This beta-secretase inhibitor, tested in a huge trial with 650 patients-per-arm, was shown to be ineffective in disappointing results published earlier this year. 

  • Aducanumab – Taking a different approach from the failing secretase inhibitor-class drugs above, aducanumab is an anti-amyloid beta antibody, which aims to mop up amyloid beta plaques and oligomers. Whilst a similar drug, solanezumab, was found to be ineffective, aducanumab, which targets amyloid plaques, proved effective at slowing cognitive decline in early trial results published in 2016. 

Crowther concludes in his webinar that we have largely exhausted the obvious targets proposed by the amyloid hypothesis, and that the net must be cast wider to find effective therapies.

Looking back at genomic studies that have sought to identify risk factors for AD, Crowther notes that mutations in TREM2, a scavenger protein, present on microglial immune cells throughout the brain, confer a four-fold increase in risk of sporadic AD, (albeit only in 1 in 3000 people). These mutations disrupt TREM2’s scavenging function. One of the mutations, R47H, causes increased apoptosis of myeloid cells. Furthermore, mutations which knock out TREM2 have been shown to inhibit the ability of microglia to target amyloid plaques in mouse models of AD.

From a therapeutic angle, agonistic antibodies that promote TREM2 favor the survival and migration of immune cells in mutant mice and in wild type mice. This evidence is part of a wider body of genome-wide association studies which provide evidence linking genes in the innate immune system to the risk of AD. In his webinar, Crowther points to a “hub” of potential immune targets for AD; TREM2, TLR4, and CD33, that could provide a starting point for new therapies.

This inflamyloid approach, rather than demeriting the amyloid hypothesis, simply provides another way of targeting the processes in the brain that lead to amyloid pathology; instead of attempting to restrain amyloid through secretase inhibition,  Crowther's conclusion is that we should look to improving the ability of our own immune system to restrain plaques and their spread, alongside further development of anti-amyloid antibodies.

Altogether, inflamyloid research suggests an avenue of research that is sufficiently bold and innovative to overcome an intractable disease.

Watch Damian Crowther’s webinar here