What Causes Alzheimer’s Disease: The Beta-Amyloid vs. Tau Debate

Scientist Explains with Dr. Wai Haung (Ho) Yu

September 1, 2022

What is Alzheimer’s disease?

Alzheimer’s disease (AD) was first discovered in the early 1900s by Alois Alzheimer. It is caused by the build-up of two proteins in the brain called 'plaques' and 'tangles'. Plaques are formed when a protein outside of a brain cell called beta-amyloid clumps together. Tangles are formed when a protein inside of a brain cell called tau twists together. The formation of these plaques and tangles interferes with the ability of brain cells to communicate with one another, and as a result, causes them to die over time.

Beta-amyloid vs. tau hypotheses

There has been a long standing debate on what is more important in AD: beta-amyloid (plaques) or tau (tangles). For many years, people have considered beta-amyloid to be the main cause of AD. We know that beta-amyloid can appear in the brain decades before tau. Additionally, gene mutations that cause early onset AD are linked to the production of beta-amyloid in the brain. However, over the course of two decades, clinical trials targeting beta-amyloid have been unsuccessful. These clinical trials have shown that clearing beta-amyloid from the brain does not necessarily cure AD, or slow down its progression. So we know that beta-amyloid cannot be the whole story.

Now let’s talk tau. While tau tangles develop after beta-amyloid plaques, these tangles correlate better with cognitive decline. For example, beta-amyloid can exist in the brain for years before any memory loss occurs. Additionally, tau tangles are seen not only in AD, but also in other neurodegenerative diseases like progressive supranuclear palsy (PSP) and Pick’s disease. Unfortunately, clinical trials targeting tau have also been largely unsuccessful.

Other explanations

The beta-amyloid and tau hypotheses have undoubtedly gained the most traction, but there are other factors to consider. For example, it is important to study and target neurodegeneration (loss of brain cells) itself, because once too many brain cells are lost, it’s a point of no return.

Neuroinflammation (inflammatory response in the brain) is also a factor, and understanding this process may reveal markers that are helpful for diagnosis. Studying population-wide genetics may also be helpful for diagnosis. This means taking thousands, or tens of thousands of people and looking at their genetic makeup to identify variances linked to AD. Lastly, targeting the processes by which beta-amyloid and tau become abnormal (i.e., the way the proteins fold) has strong potential, and has helped to reverse learning and memory deficits in animal models.