Researchers from the Sloan Kettering Institute have uncovered what they say is the first direct evidence to show how a dysfunctional immune response can contribute to the pathology of Alzheimer’s disease. The study, published in the journal Nature, adds to a growing body of evidence highlighting the role of neuroinflammation in dementia and cognitive decline.
Early in 2019 an observational study was published that found a correlation between chronic inflammation in middle-age and cognitive decline in one’s senior years. The study was not the first to suggest a relationship between inflammation and dementia. In fact, a compelling body of evidence is growing to support a hypothesis arguing the neurodegeneration seen in diseases such as Alzheimer’s may be underpinned by dysfunctional inflammatory processes.
“We’ve known that the immune system plays a role in Alzheimer’s disease – for example, it helps to clean up beta-amyloid plaques in the brain,” says Yueming Li, an author on the new study. “But this is the first direct evidence that immune response contributes to the production of beta-amyloid plaques – the defining feature of Alzheimer’s disease.”
The neurodegeneration associated with Alzheimer’s disease is still primarily thought to be the result of toxic accumulations of amyloid beta proteins. This new study has, for the first time, demonstrated how these amyloid beta aggregations, called plaques, may be fundamentally driven by an immune system protein.
The researchers focused on a molecule called interferon-induced transmembrane protein 3 (IFITM3), an immune response protein known to restrict viral infections. IFITM3 was found to enhance the activity of an enzyme called gamma-secretase, which has previously been seen to play a major role in triggering the development of amyloid beta plaques.
Levels of IFITM3 are known to increase with age, and higher than average IFITM3 levels have been seen in some patients suffering late-onset Alzheimer’s disease.
In mouse models of Alzheimer’s the researchers discovered that when they knocked out IFITM3 production in the animals, gamma-secretase activity subsequently dropped, which ultimately led to reduced accumulation of amyloid beta plaques. The study claims this is the first direct mechanistic link between a neuroinflammatory process and the development of amyloid beta plaques.
The study raises a number of questions highlighting the deeply complex nature of Alzheimer’s disease. For example, IFITM3 is produced by the immune system in response to viral infections, so it is reasonable to hypothesize viral infections possibly increase one’s risk of developing Alzheimer’s. Some scientists have recently rekindled an old hypothesis suggesting the herpes virus plays a significant role in the onset of Alzheimer’s.
Another question the research raises is whether IFITM3-triggered neurodegeneration is a specific sub-type of Alzheimer’s disease. The protein was not seen in heightened levels in all Alzheimer’s patients studied, adding weight to the belief Alzheimer’s may not be a single disease, but in fact it could be a number of relatively different diseases. The new study suggests increased IFITM3 levels could be a way of identifying a specific sub-type of the disease.
“… identification of subpopulations of individuals with Alzheimer’s disease will aid in studying the underlying mechanisms and developing precision medicine treatments,” the researchers conclude in the study.
The study was published in the journal Nature.