Swank Center for Memory Care and Geriatric Consultation, ChristianaCare
Learn how the immune system and inflammation play a role in the development of Alzheimer’s disease, and how targeting specific elements of the inflammatory process could be useful in treating or preventing this brain disorder.
Our understanding of diseases often follows a predictable journey. First, we begin to understand that a group of symptoms occur together. For example, we know that a sore throat can occur with cough and fever. Next, we learn to split hairs, separating disorders that appear similar but have different causes and courses. The sore throat with fever, cough, difficulty swallowing, and white spots on the tonsils is not like the one that doesn’t have these extra features. We often learn about the disease’s course before we know what causes the disease. In the case of the more severe sore throat, its potential for leaving serious heart damage was understood before its cause, strep infection, was made possible by advances in diagnostic techniques. Once a cause is known, researchers may be able to design a specific treatment, but not always. We know the antibiotics that are likely to defeat strep throat, but we still have no cure for the more common viral sore throat.
Where does our understanding of Alzheimer’s fit into this scheme? We recognize Alzheimer’s typical combination of symptoms: impaired episodic memory, changes in language or ability to recognize familiar things or perform familiar tasks, apathy or other changes in behavior, and increased dependence on others. We have learned, more or less, to differentiate Alzheimer’s clinically from other conditions that undermine cognitive functioning. We have imaging tools that identify associated brain changes such as atrophy, regional metabolic changes, and accumulation of amyloid plaques and damaged tau protein. However, the debate continues about the basic cause of Alzheimer’s. The swell of interest in inflammation is part of researchers’ efforts to understand better what allows, causes, or worsens Alzheimer’s.
The body’s immune system, which functions as a security guard by identifying and attacking potential sources of harm, is armed with a variety of protective weapons. Among the most important of these are the cells that roam through blood and tissues, disabling germs and eating their remains. In the bloodstream, these cells are called macrophages.
The related cells in the brain, a highly protected area with its own security system, are called microglia. Like macrophages, the microglia travel around in a resting state until “activated” by a possible danger. Activated microglia, like microscopic guard dogs, are intended to protect the brain but sometimes create havoc in the process. Microglia recognize the amyloid plaques of Alzheimer’s as unwanted and attack them as they would attack an infection.
Unlike an infection that can be defeated, however, the plaques remain a persistent irritant. In the smoldering battle between microglia and plaques, inflammatory chemicals called cytokines and damaging chemicals, such as peroxide, are released. Healthy brain cells can be caught in the friendly fire, and the collateral damage may include injury to healthy cells as well as stepped-up activity of the enzyme BACE1 (beta amyloid cleaving enzyme), which increases the production of toxic amyloid.
Research connecting inflammatory activity with the worsening of Alzheimer’s has come from several sources. Years ago, epidemiologic evidence (measuring the incidence of disease) linked anti-inflammatory drug use to reduced Alzheimer’s risk, although most (but not all) of the subsequent therapeutic trials failed to identify current anti-inflammatory medicines as a treatment or preventive medication for Alzheimer’s.
A current explanation of this therapeutic failure focuses on the different effects that anti-inflammatory treatment might have at different disease stages. They might be helpful as preventive agents but actually hurtful if used later in the course of Alzheimer’s, when their anti-inflammatory effects might interfere with the body’s self-protective response.
Animal studies have linked immune reactions to neurodegeneration and have even shown that virally induced inflammation of the brain leads to Alzheimer’s-like changes. In humans, severe head injury is known to be followed by brain inflammation, and this may explain why head trauma increases the risk for later Alzheimer’s. The complex chemistry of this process is being worked out in laboratories around the world.
Recent advances in neuroimaging allow us to label and view a mitochondrial protein, TSPO, which accumulates in the inflamed brain under conditions that activate microglia. Along with amyloid, this protein is increased in the brains of people with Alzheimer’s. The association of increased TSPO with decreased performance on the Mini-Mental State Examination, a test used to measure cognitive impairment, supports the idea that activation of microglia is bad for cognitive functioning. A current hypothesis is that inflammatory activity in the brain promotes Alzheimer’s by increasing the production of amyloid, killing healthy neurons, and ultimately reducing microglial cells’ ability to remove amyloid plaques.
If the connection between immune response and Alzheimer’s is one that contributes to disease, the next step will be to see whether this understanding leads to improved treatment. Among the lessons this theory holds for us are the following:
Explore a sample of the many research projects that BrightFocus funds regarding inflammation and Alzheimer's disease:
James Ellison, MD received his medical degree from UCSF in 1978 and trained in psychiatry at the Massachusetts General Hospital (1979-1982).
Donate to help end Alzheimer’s Disease
Receive Alzheimer’s research updates and inspiring stories
