The Amyloid Cascade Hypothesis and Alzheimer's Disease

Last updated: July 2022

John Hardy and Gerald Higgins published their amyloid cascade hypothesis in 1992. Amyloid is a protein that normally is not found in our bodies. But it is found in the brains of people with Alzheimer's disease.

Because of this, Hardy and Higgins hypothesized, proposed and tried to test the idea, that amyloid must cause Alzheimer's.

Since then, there has been much more research into Alzheimer's. Now there is a debate about whether the amyloid cascade hypothesis is correct.1,2

How amyloid works in Alzheimer's

The brain shrinks a little as we age, but it is not normal to lose neurons (brain cells) in large numbers.

In people with Alzheimer's disease, though, many brain cells stop working or die. This occurs when amyloid clumps together and forms plaques. These plaques collect between neurons, which impairs their function. Amyloid can form plaques when what is called the amyloid precursor protein breaks down.3

Later, another protein called tau starts forming tangles. These tangles bind to the internal structure of neurons, blocking their ability to communicate with each other. Tangles form in specific parts of the brain that are responsible for memory. A build-up of amyloid causes tau to rapidly spread in the brain.3

In support of the hypothesis

Scientists have studied the brains and genes of people with Alzheimer's disease. For some people, Alzheimer's disease runs in the family.

These people carry a genetic mutation (change) to the amyloid precursor protein. The mutation causes their bodies to make amyloid. This same genetic mutation occurs in some people with Down syndrome who develop early-onset dementia.1,2

There is another clue that supports the hypothesis. Some people have another genetic mutation – called the Icelandic mutation – that affects the amyloid precursor protein. People with the Icelandic mutation produce much less amyloid. In turn, they are much less likely to develop Alzheimer's.2

Based on early clues like these, scientists developed various drugs to attack the amyloid protein.1

The case against the hypothesis

As doctors continued to study Alzheimer's disease, they found additional evidence. This evidence suggested that the amyloid cascade hypothesis was wrong, or only partially right.

For example, many studies found that people can have amyloid plaques but have no signs of problems with their memory or thinking.1

Drugs were developed that targeted amyloid. However, while the drugs cleared the plaques memory decline continued. This made doctors think that the amyloid cascade hypothesis had faults.1

Other studies looked at how the amyloid and tau proteins work together in mice. These studies called into question the idea that amyloid causes plaques first and tau tangles later. Now, doctors believe that Alzheimer's develops as the result of several complex processes in the body.4

Where we are today

Currently, most doctors believe that a combination of factors influences whether a person develops Alzheimer's disease. These factors include:5

  1. Genetics
  2. Lifestyle
  3. Environment

Future Alzheimer's treatment research

After years of Alzheimer's research, doctors agree that amyloid plays a role in the development of Alzheimer's disease. But there is much debate about this. Doctors believe there are probably other factors we do not yet understand that play a role too.5

Today's research focuses on multiple treatments for Alzheimer's. Current treatments focus on improving symptoms and stopping the progression of Alzheimer's. Eventually, Alzheimer's may be treated with a combination of drugs, much like cancer and HIV/AIDS.5

Currently, scientists are studying:5

  • Monoclonal antibodies that prevent amyloid from clumping into plaques or removing the plaques
  • A cancer drug that may turn off a protein, which has reversed memory loss in mice
  • Drugs that reduce the amount of amyloid made in the brain
  • Drugs and vaccines that prevent tau from forming tangles
  • An immune system drug that may protect the brain from harmful proteins
  • How insulin and other hormones affect the brain and its ability to work
  • How heart and blood vessel health is tied to dementia

The amyloid cascade hypothesis gave doctors an early guess at the cause of Alzheimer's. And the hypothesis shaped research for many years. However, like all hypotheses, it needs revisions. Now doctors are pursuing a more complex understanding of Alzheimer's. They want to know what it will take to control or stop the disease.

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