Alzheimer’s Mysterious Origins May Be Driven by “Exhausted” Immune Cells, Study Reveals

Scientists could be one step closer to understanding the complex nature of Alzheimer's disease thanks to a new study from New York City's Rockefeller University.

Increased Risk for Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative disease characterized by neuronal loss, progressive synaptic dysfunction, and cognitive decline. It is the most common type of dementia and involves regions of the brain that control thought, language, and memory.

In 2020, about 5.8 million Americans were living with Alzheimer's disease, according to the U.S. Centers for Disease Control and Prevention. It is even projected to triple to 14 million by 2060.

Even with the advancements in medicine, scientists still do not yet fully understand the cause of this disease. It is believed that this condition is brought about by an abnormal buildup of proteins in and around the brain cells. However, the exact factors that trigger this process remain unclear. Experts assume that particular genetic variants can increase a person's likelihood of developing Alzheimer's disease.

Upon closer examination, it was found that a variant of the gene APOE appears in 40 - 60% of patients diagnosed with Alzheimer's. This gene, which exists in three forms, produces proteins carrying cholesterol and fats through the bloodstream. APOE4 is the gene variant most commonly associated with Alzheimer's and is found in around 20 - 30% of the US population.

Unraveling the Mystery

In a recent study, the Rockefeller team revealed that the risk associated with this genetic variant may originate from its ability to wear out the brain's immune system. The paper discusses their findings: "An exhausted-like microglial population accumulates in aged and APOE4 genotype Alzheimer's brains."

The human brain contains two major types of cells - neurons and glia. The neurons serve as the wires of the brain, which transmit chemical signals throughout the brain and the body. On the other hand, the glia are like cellular electricians that protect and maintain neurons. Among the glial cells are the microglia, also known as the specialized immune cells of the brain.

The immune cells play a vital role in cleaning up any molecular debris in our brain, protecting us from abnormal protein buildups that can lead to Alzheimer's disease. But over time, the immune cells can get exhausted, worn out, and less efficient at cleaning up this malicious debris.

The research team discovered that the brains of older mice and those with the APOE4 variant possess these fatigued immune cells. According to Rockefeller Leon Hess professor Sohail Tavazoie, a similar phenomenon was discovered in human data sets. These exhausted cells have been immersed in this inflammatory environment for years until they reach the time when they can no longer cope with their surroundings. The scientists assume that if these cells can be reverted to a healthy state, they could probably prevent the development of Alzheimer's disease.

In this study, the researchers demonstrated that aducanumab, a recently approved drug against Alzheimer's, can improve the symptoms by rehabilitating the damaged immune cells. Interestingly, the mice with the APOE4 variant improved their conditions after taking the drug, unlike those with other forms of APOE.

This could be the first hint that aducanumab works differently with various genotypes, something that clinicians should look into. The team's discovery not only shines light on the mysterious mechanisms that underpin the disease but also provides useful insights for the development of treatments in the future.