Rethinking Alzheimer's Disease

By Ari Magill MD

Alzheimer’s disease looms as a great specter on the elderly, robbing them of fundamental qualities we associate with the human condition. The ailment was first described by Bavarian-born German psychiatrist and neuropathologist, Aloysius “Alois” Alzheimer, in the early 1900s. Because of how the name of the disease sounds and because it is associated with advancing age, the malady has been colloquially referred to as “old timers’ disease.” While not inevitable with aging, Alzheimer’s disease is an epidemic ever increasing in size and scope with the aging of the population. The disease delivers a powerful blow to the economy in terms of lost wealth and productivity, not to mention stinging social consequences, including loss of intangibles such as well-being, creativity, and personhood.

Research and treatment strategies thus far have focused on directly attacking the neuropathology, as originally described by Dr. Alzheimer, with the bulk of the energy and resources focusing on abnormal “promiscuous” buildup of a protein called beta-amyloid leading to the formation of neurotoxic plaques. Beta-amyloid plaques are thought to instigate the malfunction and death of neurons by triggering neurons to accrue tangles of another protein known as tau within the interior of the cell. Dysfunction of blood flow and inflammation within the brain also play key roles, but the exact way they enter into the disease process equation is difficult to tease out. This war-on-amyloid approach has not been successful up to now in terms of translating bench research into effective disease-modifying therapy for human beings.

Two lines of research stand out in this author’s opinion for boldness and thinking outside the box. They represent a fresh way of looking at the disease, and it starts with a basic question as most brilliant ideas do. The question is: “what is the normal function of beta-amyloid in human beings?” This question has long plagued researchers and the question was largely swept under the rug, with the idea that beta-amyloid must represent some form of molecular garbage.

In the past decade, there have been studies showing beta amyloid has blood-vessel promoting (angiogenic) properties. Having more blood vessels seems like a good thing for the brain on initial inspection, but the excessive branching and buildup of cerebral microvessels induced by amyloid are dysfunctional and result in impaired cerebral blood flow that blocks removal of toxic amyloid. In this light, Alzheimer’s disease can be viewed as a disease of abnormal microvascular proliferation, similar to diabetic retinal disease, but involving the substance of the brain instead of the retina. The end result of this hyper-vascularity is build-up of beta-amyloid “gunk” in the brain with beta-amyloid buildup preventing its own removal. Another negative consequence of deranged angiogenesis is a breakdown of the blood-brain barrier, the semi-permeable wall that stands between potential pathogens and toxins in the blood and the fluid between cells within the brain, called the interstitial fluid. Breakdown of the blood brain barrier has been shown to precede well-recognized Alzheimer’s pathology, including the buildup of amyloid plaques.

Beta-amyloid might promote branching and aberrant growth of microvessels, but is that its primary function? A novel idea by a group of researchers at Harvard led by Kumar et al. is opening up a whole new way of thinking about beta amyloid, one in which beta-amyloid acts as an antibiotic generated by cells within our own brains to fight infection.

This concept was hinted at by prior studies linking Alzheimer’s risk and Alzheimer’s pathology to herpes simplex virus I, the same virus that causes cold sores. The implication was that Alzheimer’s disease might develop from reactivated herpes virus infection, a concept that has not been well received in the medical science community. There was some suggested evidence on a cellular and tissue level to legitimize the idea. Although not rigorously studied, microbes, including bacteria, fungi, and viruses, appear to be more frequently found in the brains of the elderly, and with even greater regularity within brains afflicted by Alzheimer’s disease. Also, herpes simplex virus I can trigger a well-characterized brain infection, called HSV encephalitis, with a predilection for similar areas of the brain to those affected in Alzheimer’s disease, including the hippocampal nuclei that serve as memory centers in the brain.

The new research from Harvard shows that beta-amyloid protein binds to sugar molecules located on the cell walls of microbial pathogens. The protein is composed of tentacle-like structures that clump bacteria together and ensnare them like insects in a spider’s web. Specifically the Harvard researchers exposed the brains of experimental mice genetically engineered to express Alzheimer’s-like pathology to Salmonella Typhimurium. Exposure to the bacterium stimulated the generation and expansion of beta amyloid plaques overnight around areas of bacterial inoculation, where the bacterium served as a focal point and nidus for surrounding protein scaffold.

The role of aging in the disease process of Alzheimer’s disease comes into play given that there is a natural breakdown of the blood-brain barrier with advancing age. This allows more microbial pathogens and pathogenic proteins access to the brain that would stimulate beta-amyloid production. Combined with the angiogenic properties of beta amyloid, we can see how a self-perpetuating chain reaction would ensue since beta amyloid buildup further erodes the blood brain barrier and hinders its own clearance. There are plans to compare the brains of patients with Alzheimer’s to control brains looking to find genetic evidence of pathogenic species in Alzheimer’s-infected brains not found in control brains using next-generation gene sequencing technology. In addition, amyloid plaques themselves will be evaluated for the presence of microbial pathogens.

The ultimate goal of course is effective treatments for this devastating illness. Antimicrobial agents including antibiotics as well as agents that remove pathogens, such as drugs that bolster the immune system, might fit the bill by limiting the stimulus for beta-amyloid production. Another avenue would be anti-antigenic chemotherapeutic agents to enhance the integrity of the blood brain barrier.

About the author:
Ari Magill, M.D. earned his BS in Zoology from University of Texas in Austin, TX, graduated with an MD from UT Southwest Medical School in Dallas, TX. Dr. Magill completed Neurology residency at the University of Arizona in Tucson, AZ, completed Movement Disorder Neurology Fellowship at University of Colorado Anschutz Medical Center in Aurora, CO. Dr. Magill will be starting work in private practice as a neurohospitalist at NW Hospital in Tucson, AZ.
Dr. Magill is an avid science fiction reader and enjoys writing.
Dr. Magill is currently developing interactive case scenarios for a CD to accompany a textbook for advanced EMTs for Williamstown Communications, a medical education company.