Why are scientists redefining Alzheimer's disease?

Alzheimer's disease is a progressive neurodegenerative disorder, thought to be caused by buildup of proteins in the brain. But there is increasing evidence that different biological processes are at the heart of the disease, providing scientists with a different approach to possible therapies.

In a plenary session delivered at the Alzheimer's Association International Conference (AAIC) 2017, held in London, United Kingdom, Julie Williams, Ph.D. - a professor in the Division of Psychological Medicine and Clinical Neurosciences at Cardiff University in the U.K. - challenged the traditional views of Alzheimer's disease by saying that "immunity is playing a significant role" in the disease.

Alzheimer's disease is the sixth leading cause of death in the United States, affecting more than 5 million adults in the country.

The traditional view is that proteins accumulate in the brains of patients, leading to neuronal death. The culprits are the amyloid beta peptide and the tau protein.

How are scientists challenging the traditional view that abnormal protein buildup in the brain is to blame for the neurodegeneration seen in Alzheimer's disease?

Joint efforts to identify new genetic variants

Until 2009, only four genes were known to be associated with Alzheimer's disease. Mutations in three of these - APP, presenilin 1, and presenilin 2 - cause the inherited form of Alzheimer's. This typically develops early in life, between the ages of 30 and 50. It is also known as early-onset Alzheimer's disease.

Less than 1 percent of Alzheimer's disease patients have this inherited form of the condition, in which an overproduction or abnormal folding of amyloid beta in the brain can be observed.

The majority of patients have the sporadic form of Alzheimer's. Despite the fact that mutations in the apolipoprotein E gene (APOE) were known to be involved in susceptibility and earlier age of onset, only a subset of patients have the variant associated with the disease.

Predicting an individual's risk of developing the disease with accuracy is, therefore, a challenge. For many years, there was a serious lack of progress in research looking to establish the underlying causes of susceptibility.

Today, we know that sporadic Alzheimer's disease has a large genetic component, with its heritability being in the range of 58 to 79 percent. This means that other genetic variants must be involved.

Identifying individuals at risk

In a study published in the journal Neurobiology of Aging in 2017, Prof. William's team used their knowledge of susceptibility genes to test how accurately they could predict an individual's risk of Alzheimer's disease.

Using data from 17,000 Alzheimer's patients and 37,000 controls, and looking at 87,583 mutations, they were able to identify the condition with an accuracy of 74.5 percent.

Prof. Williams explained that they were "now able to predict quite a lot of the risk of AD [Alzheimer's disease] and it's better than looking at APOE."

So might the amyloid buildup seen in Alzheimer's patients be less of a problem with excess production and more to do with other processes?

Prof. Williams challenged the audience to imagine a scenario wherein there was no historic knowledge of the genes implicated in amyloid processing being involved in Alzheimer's disease. "Alzheimer's disease is more of an autoinflammatory disease, than anything else," Prof. Williams said.

"What we are seeing with immunity is happening quite early in the disease and maybe a primary event that is happening alongside amyloid [accumulation]," she added. "What we need to do is to understand mechanisms."

The team's latest discovery was published this week in Nature Genetics, and it supports this theory.

This study, performed by the IGAP group, identified two new genetic variants that confer Alzheimer's disease risk. The genes - phospholipase C gamma and B-3-domain-containing transcription factor ABI3 - are highly expressed in microglial cells in the brain, which are part of the immune system.

Prof. Williams told the audience that scientists around the world are now studying genetic models to better understand how the immune system is involved in the neurodegeneration seen in Alzheimer's.

What is really important is how researchers are putting this new knowledge and redefinition of the condition to use.

The above are excerpts taken from a story published in MNT Weekly story By Yella Hewings-Martin, PhD, Published Thursday 20 July 2017. It is an important and for the full story please go here