For quite some time, the focus of the cause of Alzheimer’s disease was on beta-amyloid, a protein that accumulates in the brains of individuals with the disease and which appears to cause at least some of the damage that results in memory and cognition issues. There are other candidates, and research appears to be heating up on the role of inflammation—perhaps triggered by beta-amyloid—in Alzheimer’s.
But before beta-amyloid was implicated in 1984, many researchers believed that an infectious agent was involved in the disease and research continues in this area.
On July 16, the Alzheimer’s Association International Conference (AAIC) 2019 hosted a panel titled, “Is There a Causative Role for Infectious Organisms in Alzheimer’s Disease?”
Panelists included Ben Readhead, assistant professor, ASU-Banner Neurodegenerative Disease Research Center; Ruth Frances Itzhaki, Emeritus Professor, Faculty of Biology Medicine and Health, University of Manchester; Robert D. Moir, assistant professor in Neurology, Genetics and Aging Research Unit, McCance Center for Brain, Health MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School; Todd Golde, director, Evelyn F. and William L. McKnight Brain Institute and director of 1Florida Alzheimer’s Disease Research Center; and Michael T. Heneka, professor of Clinical Neuroscience, Department of Neurodegenerative Disease and Geriatric Psychiatry/Neurology at University of Bonn Medical Center and the German Center for Neurodegenerative Disease (DZNE).
Robert Moir took time to speak with BioSpace ahead of the panel to discuss the subject of infectious agents and the role they may play in Alzheimer’s disease.
“In 1984, Abeta was identified as the protein generating amyloid in the Alzheimer’s disease brain,” Moir said,” the hallmark pathology. It was assumed at the time Abeta was only found in AD brain and the protein’s propensity to form amyloid was intrinsically abnormal. As an abnormal catabolic byproduct of disease, it was assumed the protein has no function. This had a big impact on the idea of infection as an AD etiological factor—essentially sidelined it.”
He went on to say that the amyloid model essentially presented three obstacles to an infection etiology for the disease. One, Moir said, “Who needs infection when it can be explained by an abnormal activity of Abeta?”
Second, there was no clear mechanism for how an infectious agent would drive amyloidosis and other pathologies. And third, no single pathogen has been identified that is present in the majority or overwhelming number of Alzheimer’s cases.
“For any particular pathogen,” Moir said, “uninfected AD patients can be identified with extensive beta-amyloid deposition. These long-standing concerns have stymied the serious consideration of infection as an etiological factor for AD.”
In 1990, however, researchers found that the pathway that creates beta-amyloid is a common one, not an abnormal pathway, and that it is involved in generating hundreds of important proteins. This undercut the rationale for a functionless beta-amyloid, and in fact, research found that the same beta-amyloid found in human brains was found in more than half of all vertebrates, and that in humans the genetic sequence is remarkably well conserved, being more than 400 million years old.
“Such remarkable evolutionary conservation suggests an important function and a protein highly optimized for its role,” Moir said. “Ten years ago, we identified beta-amyloid as an antimicrobial peptide whose job was to protect the brain against fungi, bacteria and viral infections. Moreover, it does it by trapping microbes in amyloid.”
This presents three strong theories. First, amyloid accumulation is a response to invading pathogens. Second, microbes directly “seed” the deposition of beta-amyloid. And third, bacterial, fungal and viral pathogens can “seed” amyloid in multiple different types of neuroinfection, which accelerates the accumulation of beta-amyloid.
“There have been multiple fungal, bacterial, and viral neuroinfections linked to Alzheimer’s,” Moir said. “The most studies (and arguably strongest data) is for herpes simplex 1. However, data showing microbes in Alzheimer’s brain raise the question of if the infection came before AD or after—pathogens making their way into and across a weakened blood-brain barrier. This remains to be resolved. However, the finding that microbes can seed amyloid suggest infection will accelerate the disease in either case.”
In terms of the current focus of the biopharma industry, Moir says that many are looking at anti-inflammatories as an approach to treatment and prevention, “and all but one has abandoned anti-Abeta drugs. Anti-infectives face the same problem as anti-Abeta drugs—it will need to be a prodromal administration and at present, there is no reliable way to identify people in the early stages of pre-dementia Alzheimer’s disease. It is early days for the anti-inflammatories, but stage III clinical trials are underway.”