Is Alzheimer’s an Autoimmune Disease? Researchers Weigh In

  • Research in Brief
Published on:
Illustration of amyloid beta protein assembling around brain cells
A recent paper by Dr. Weaver and his collaborators highlights findings from various studies evaluating what makes amyloid beta proteins (pictured) assemble in high densities around brain cells.

What: A team of researchers has conceptualized Alzheimer’s disease (AD) as an autoimmune disease and identified the body’s natural regulators of this autoimmunity. Designing drugs to imitate these innate regulators is the next step and could provide a novel therapeutic approach for Alzheimer’s disease.

Where: Meier-Stephenson FS, Meier-Stephenson VC, Carter MD, et al. Alzheimer’s Disease as an Autoimmune Disorder of Innate Immunity Endogenously Modulated by Tryptophan Metabolites. Alzheimer’s Dement. 2022 

BrightFocus Connection: Lead author Don Weaver, MD, PhD, of the Krembil Brain Institute, University Health Network, Toronto (and formerly of Dalhousie University, Halifax, Nova Scotia, Canada), and coauthor Ottavio Arancio, MD, PhD, of the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at Columbia University Medical Center, New York City (along with Edwin De Pauw, PhD, of the Université de Liège in Belgium) received a $1M grant from the BrightFocus Alzheimer’s Disease Research program to study protein misfolding in Alzheimer’s disease and explore the possibility of a single, unified treatment approach.

Why It’s Important:
Alzheimer’s disease results from a build-up of toxic proteins in and around brain cells. Characteristically, as part of the disease process, these proteins have been molecularly modified from their original functional states. When high numbers of one such protein—amyloid beta (Aβ)—gather, they form plaques around brain cells. Pinpointing why Aβ accumulates and starts to aggregate into plaques will help scientists develop treatments to interrupt that process. 

A recent paper by Dr. Weaver and his collaborators highlights findings from various studies evaluating what makes Aβ proteins assemble in high densities around brain cells. The scientists designed and synthesized 471 new chemical entities to represent the various things that might stimulate Aβ build-up, such as infection, trauma, and air pollution. 

In response to some stimuli, the researchers noticed, Aβ is released as an early innate immune system response that triggers a misdirected attack on neurons. Aβ responds to bacteria and neurons in much the same way, breaking them down to “protect” the body. After this misdirected attack, degenerating neurons release substances that elicit further Aβ release. The result is a chronic, self-perpetuating autoimmune cycle, destroying neurons over time. 

After confirming these immunological actions of Aβ, the team looked for naturally occurring brain regulators of innate immunity that could be leveraged to potentially modulate Aβ response to harmful stimuli. The scientists screened 1,137 small molecules often found in the brain, including tryptophan—an amino acid that produces and maintains the body's proteins. The team identified tryptophan metabolism as a naturally occurring, already-present regulator of brain autoimmunity that could interrupt Aβ’s harmful attacks on neurons.

The understanding gained from these studies demonstrate how the body may possibly ward off Aβ’s problematic autoimmune response and may be useful in guiding development of new therapies. For example, targeting tryptophan metabolism with small molecule drugs could greatly diminish the disease’s impact on people who are at risk for Alzheimer’s or in its early stages.

Most important though is that this work highlights the intersection between two pathological processes contributing to AD that are often investigated as independent disease mechanisms – immune disruption and protein misprocessing. Based on these findings, Alzheimer's can be characterized as an autoimmune disease with interdependent immune-protein interactions that exacerbate disease pathogenesis. This leads to a whole new way of thinking about the disease and opens up new avenues for study and treatment.

Dr. Weaver was recently recognized with a 2022 Oskar Fischer Prize for his unconventional hypothesis and success at building evidence that Alzheimer’s may be rooted in an autoimmune response. The endowed awards, given by the University of Texas at San Antonio, recognize innovative ideas in Alzheimer’s research that look beyond prevailing theories.