My Alzheimer's Journey

Part 118 - Alzheimer's and Genetics Study

Does Alzheimer’s Start In The Body Instead Of The Brain? A New Study Says YES.

By Greg Rowland

A common definition of Alzheimer's disease is a biological process that begins with the buildup of proteins in the form of amyloid plaques and neurofibrillary tangles in the brain. This definition assumes the Amyloid Cascade Hypothesis is correct.

In 1991, Sir John Hardy and Gerald Higgins published an article in Science titled, “Alzheimer’s Disease: The Amyloid Cascade Hypothesis”. Based on years of research, the hypothesis states the deposition of the amyloid-β peptide in the brain is a central event in Alzheimer's disease pathology.

This hypothesis drove all Alzheimer’s research for more than twenty years.

In 2020, a new study made allegations that some evidence used to create the Amyloid Cascade Hypothesis were fraudulent. Thus, a controversy was born among leading researchers, neurologists, and pharmaceutical companies. Many people believe that amyloid plaques may be a result of Alzheimer’s disease, not the cause.

Meet Cesar Cunha

With a background in Biochemistry and Neuroscience, Cesar Cunha has always wanted to pursue research in Alzheimer's disease. His interest in human genetics led him to accepting a prestigious PhD fellowship from the Novo Nordisk Foundation.

The Novo Nordisk Foundation Center for Basic Metabolic Research (located at the University of Copenhagen in Denmark) focuses primarily on obesity and type 2 diabetes research, with a big emphasis in human genetics. This emphasis on human genetics opened the door for Cunha to perform Alzheimer's research in an environment that was not constrained by the Amyloid Cascade Hypothesis.

Cunha led a team of researchers to explore an idea that the initiation of Alzheimer's disease is not in the brain. Their comprehensive study resulted in a determination that the initiation of Alzheimer’s disease starts in immune cells outside the brain.

It seems counterintuitive that the risk of Alzheimer’s disease initiates somewhere different from where the pathology occurs. According to Cunha, this phenomenon is not very common. But it does happen. He said another example of the phenomenon is obesity. The genetic risk of obesity disease is concentrated in the brain, yet, the pathology is obviously the accumulation of fat tissue.

Cunha and his team mapped the entire genetic architecture of Alzheimer's disease across the whole body. This complex and challenging process required using genetic data from previous studies involving more than 85,000 people with Alzheimer’s and around 485,000 people without it.

The researchers analyzed gene activity across roughly five million single cells, covering forty body regions and the entire brain. The goal of the analysis was to learn where in the body are the genes associated with Alzheimer’s risk active. They focused on around one thousand genes that contain variants known to raise Alzheimer’s risk.

The study found that peripheral cell types are the primary targets of Alzheimer's genetic risk. Peripheral cells circulate in the bloodstream for immune defense. They also found Alzheimer’s genetic risk in certain organs, including the lungs and the digestive system. The only cell type in the brain that was actually significant in their analysis was microglia (immune effector cells.) The researchers found no other cell type in the brain enriched for Alzheimer's genetic risk.

Even the regions of the brain that specifically accumulate amyloid and tau were not enriched for Alzheimer's genetic risk.

Mounting evidence from previous studies suggests that viral infections may contribute to the onset and progression of neurodegenerative diseases, including Alzheimer’s disease. This further supports the findings of the University of Copenhagen team, since they found an association between the peripheral immune genetic signature of Alzheimer's disease and the immune cells of the lungs, digestive system, and other organs. In other words, a viral infection in your lungs may trigger a process that results in Alzheimer’s disease many years later.

This study strengthens the long held belief that genetics are the mechanisms that increase the risk of Alzheimer’s. It also signals (with strong evidence) that these Alzheimer’s risk genetics are acting primarily outside the brain, more specifically in immune cells.

Cunha said the next step is clinical valuation of their findings and eventual translation to patient stratification. That will not happen quickly. As in all large scientific discoveries, money is the driving force.

Hopefully, this study will open the minds of people who have held firm to the Amyloid Cascade Hypothesis. There is now data indicating that Alzheimer’s disease begins in the body’s immune system; likely, years before symptoms of Alzheimer’s disease appear.

Genetic testing and disease prevention have just become even more important.

A preprint of the study is published in MedRxiv.