Amyloid Beta Plaques, Pathogens, and Alzheimer’s Disease

Photo via Pexels by Andrea Piacquadio

Amyloid beta plaques are associated with Alzheimer’s disease, but they also occur in people who do not develop dementia. What causes the plaques, and what is the difference between people with plaques who develop dementia and those who do not? The answers to these questions are still unclear, but infectious disease may play a role.

Where amyloid beta protein is found

Amyloid beta plaques are made up of amyloid beta protein and other materials that build up outside of brain cells. The resulting substance isn’t fully understood, but what is known is that it damages adjoining nerve cells. The plaques are mainly confined to the brain but can occasionally be found in the spinal column.

Some conditions, like tuberculosis and Hodgkin’s lymphoma, cause a buildup of amyloid beta inside cells throughout the body.

The history of the amyloid beta plaque and dementia connection

1892 –   Paul Oscar Blocq and Gheorghe Marinescu first described amyloid beta plaques.

They worked at a teaching hospital associated with the Sorbonne, Pitié-Salpêtrière University Hospital. Founded in 1656, this hospital’s main focus was serving the poor, with a special interest in better understanding mental disorders. Blocq and Marinescu together and individually made several discoveries by investigating the brains of individuals with these disorders who had died.

1906 –   Alois Alzheimer reported discovering the plaques along with neurofibrillary tangles in the brain of a woman he had treated for progressive dementia for 5 years.

Alzheimer later described another case of what seemed to be the same disease. When the patient passed away and further research was conducted, neurofibrillary tangles were found. Was Alzheimer wrong about the similarity of the two cases?

When Alzheimer died in 1915, few people had paid attention to his finding except for Emil Kraepelin, who named the condition “Alzheimer’s disease” in his textbook on psychiatric disorders. Almost no one else used the term “Alzheimer’s disease” again for more than 50 years.

1995 – Pathology slides from two Alzheimer’s patients were reevaluated with new techniques.

The evaluation concluded the two patients were at different stages of the same progressive disease. Perhaps Alzheimer had seen what at the time he could not entirely scientifically prove.

Alzheimer’s work set the stage for more research on amyloid plaques. One particularly interesting topic is support for the correlation between the plaques and dementia. Many people with amyloid beta plaques never develop dementia and some Alzheimer’s disease patients may never develop plaques. While people with Alzheimer’s disease at 50 and do not have a genetic risk are 86% likely to have amyloid beta plaques, people with Alzheimer’s disease at 90 are only 68% likely to have amyloid beta plaques. How can further research be conducted to clarify the issue?

Amyloid beta plaques occur in all kinds of animals, but the way they entangle with nerve cells and their association with dementia are unique to humans. This hinders advancement in dementia research using animal models. Now, researchers use transgenic animals that have genes added that cause them to develop disease models like humans.

The pathogen hypothesis

Scientists debate the causes and development of amyloid plaques. Some researchers believe that pathogens play a role in the development amyloid plaques, but not dementia. Within this theory, there are three hypotheses:

Hypothesis #1: Pathogens, not amyloid plaques, cause dementia. This is an alternative to the amyloid plaque hypothesis. Infections that may play a role include three Herpes viruses, Chlamydia pneumoniae, Borrelia burgdorferi (the cause of Lyme disease), and Porphyromonas gingivalis. Entrepreneur Leslie Norins put up a prize of $1 million dollars to anyone who could prove that Alzheimer’s disease was caused by a pathogen, as discussed in a Nature article in 2020.

The idea behind the pathogen hypothesis was that amyloid plaques were an incidental finding and that actually an infection caused the disease. This theory would contextualize why some people who have plaques don’t get dementia. Studies either follow people with these infections and inspect participants’ brains, or they inspect the brains of people who die from Alzheimer’s. These pathogens support a direct relationship between infection and disease. In this case, prevention would mean avoiding the infection.

Hypothesis #2: Infection triggers a host response that builds the amyloid plaques, leading to disease. Recent genetic research and research on how amyloid beta is part of the immune response supports this theory. Researchers continue to ponder whether those with genetic predispositions to a pathogenic response of plaques could receive preventative treatment.

Hypothesis #3: Amyloid plaques and pathogens combine to create a uniquely damaging immunological response. This hypothesis was not directly discussed in the Nature article, but it recently received support in a study in transgenic mice looking at Lupus, an autoimmune condition. Lupus carries an increased risk of all kinds of dementia, including Alzheimer’s disease.

Researchers studied biofilms created by gut infections in the mice. These biofilms included another kind of amyloid protein, Amyloid curi. And when amyloid curi and pathogen DNA are bonded together, the transgenic mice are much more likely to develop the auto antibodies (antibodies against self) that are characteristic of Lupus.

If pathogens do play a role, does it really matter? Some researchers believe that looking at infections is the wrong direction. Age remains the biggest risk factor for Alzheimer’s. All people have increased inflammation as they age and more dysfunctional immune responses. Some researchers question the relevance of studying infectious diseases and amyloid plaques. At the same time, not a lot is known about how a subclinical infection relates to this inevitable part of aging.

Lyme disease has been associated with Alzheimer’s disease. Find out more about Galaxy Diagnostics’ Lyme Borrelia Nanotrap Antigen Test.

Conclusion

As closely as Alzheimer’s disease has been studied, much about this diagnosis remains a mystery. The relevance of new discoveries, such as pathogens embedded in amyloid plaques, remains an open question. Part of the reason for this is that Alzheimer’s disease is unique to our species and difficult to study in animal models. Ultimately, what people want to know is what lifestyle and medical interventions can prevent Alzheimer’s disease, and right now that information remains elusive.

References

Walker, L. C. (2020). Aβ plaques. Free Neuropathology, 1. https://doi.org/10.17879/freeneuropathology-2020-3025 https://www.uni-muenster.de/Ejournals/index.php/fnp/article/view/3025

Hippius, H. (2003). The discovery of Alzheimer’s disease. Dialogues in Clinical Neuroscience, 5(1), 101-108. https://doi.org/10.31887/DCNS.2003.5.1/hhippius  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181715/

Abbott, A. (2020, November 4). Are infections seeding some cases of Alzheimer’s disease? Nature. https://www.nature.com/articles/d41586-020-03084-9

Gregory, A. (2021, September 9). Transport noise linked to increased risk of dementia, study finds. The Guardian. https://www.theguardian.com/society/2021/sep/09/transport-noise-linked-to-increased-risk-of-dementia-study-finds

Temple University. (2015, July 7). Research team finds bacterial biofilms may play a role in lupus, MS, other auto-immune diseases [Press release]. https://www.technologynetworks.com/neuroscience/news/research-team-finds-bacterial-biofilms-may-play-role-lupus-ms-other-auto-immune-283383

Hanover, L. (2021, March 17). Dementia tied to most common form of lupus, study finds. AJMC. https://www.ajmc.com/view/dementia-tied-to-most-common-form-of-lupus-study-finds

Gómez-Isla, T., & Frosch, M. P. (2022). Lesions without symptoms: understanding resilience to Alzheimer disease neuropathological changes. Nature Reviews. Neurology. Online ahead of print. https://doi.org/10.1038/s41582-022-00642-9 https://pubmed.ncbi.nlm.nih.gov/35332316/

National Institute on Aging. (2021, July 8). Alzheimer’s disease fact sheet. https://www.nia.nih.gov/health/alzheimers-disease-fact-sheet

Ossenkoppele, R. et al. (2015). Prevalence of amyloid PET positivity in dementia syndromes. JAMA, 313(19), 1939-1949. https://doi.org/10.1001/jama.2015.4669 https://www.ncbinlm.nih.gov/pmc/articles/PMC4517678/

Itzhaki, R. F. (2016). Microbes and Alzheimer’s disease. Journal of Alzheimer’s Disease, 51(4), 979-984. 10.3233/JAD-160152