The Amyloid Cascade Hypothesis

Paul Seidler, PhD

Research scientist at UCLA in the Molecular Biology Institute

  • Expert Advice
Published on:
Medical illustration of amyloid plaques accumulating outside of a brain cell (neuron).
Image courtesy of the National Institute on Aging/National Institutes of Health

Learn how neuroscientists are exploring a protein, amyloid beta, that is associated with the development of Alzheimer’s disease.

We’ve all been there. You have a problem, but you’ve also got a solution in mind.  Or so you thought; instead you discover your solution was not the remedy you expected.  For neuroscientists, this familiar conundrum is embodied in attempts to better understand and treat Alzheimer’s disease. What we know is that dense deposits of two proteins, amyloid beta and tau, overtake the brains of people with Alzheimer’s disease, and the brain suffers atrophy, neuronal cell death and damaged blood vessels, which deprives the brain of oxygen and nutrients and causes toxins to accumulate.

The Case for Amyloid Beta

Scientists are working feverishly to discover the cause of Alzheimer’s disease because they believe that if they develop drugs to target the cause, Alzheimer’s disease could be treated and even prevented. If you journey back to your middle school science fair days, you’ll likely recall the first step of the scientific method is to develop a testable hypothesis.  For neuroscientists, this is the “amyloid cascade hypothesis.” The hypothesis was borne from compelling observations such as the apparent link of early disease onset with genetic factors that increased amyloid beta deposition, and scientific data showing that synthetic deposits of amyloid beta kill lab-grown cells in petri dishes.

Armed with this knowledge, scientists proposed that amyloid beta deposits drive all other changes in the brain that are associated with Alzheimer’s disease (tangled deposits of tau, blood vessel deterioration, neuronal cell death and brain atrophy). Thus amyloid beta deposits were the clear drug target.

The Amyloid Cascade Hypothesis Hits a Snag

Or so scientists thought. The hypothesis hit a snag when amyloid beta therapeutics that were tested in the clinic successfully cleared amyloid beta deposits, but without halting cognitive decline. It is worth noting that in a subset of patients, the progressive cognitive decline was at least slowed!

The lack of clear cognitive benefit from amyloid beta therapy spawned revisions to the amyloid cascade hypothesis, and even new hypothesizes about what drives Alzheimer’s disease. Critics of the hypothesis cited failed clinical trials and other supporting data (such as the discovery that some individuals can actually remain cognitively normal in spite of harboring amyloid beta deposits) to suggest that amyloid beta may not be the driver of disease that people thought, but rather is a calculated biological response to some other mysterious pathogen.  In this view, amyloid beta deposits would represent residual scars (like a scab that seals a cut). Proponents of the amyloid cascade hypothesis suggested that amyloid beta therapy was simply administered too late in the disease progression.

Valid arguments can be made for both perspectives, and as explained below, it is even possible that the truth is somewhere in between.  

Supporting the case to try treating patients earlier with amyloid beta therapies:

  • Brain cells are lost as Alzheimer’s disease progresses, and these cells do not regenerate. Thus it may not be reasonable to expect complete recovery if cognition fades beyond a certain point.

  • Amyloid beta deposits are not working in isolation and therefore we shouldn’t be surprised that it may not be enough to merely clear amyloid beta deposits from the brain, especially if we don’t begin treatment earlier. It is likely and even predicted that co-therapies need to be developed to treat each of the disease markers as they appear: (a) amyloid beta deposits; (b) tau tangles; and possibly even (c) deterioration of blood vessels (although it is still not known if the latter is a cause or effect of protein deposits).

By now you may be wondering why not simply treat people with amyloid beta therapies earlier to see if this prevents AD. One reason is we don’t have reliable biomarkers to predict who will develop AD. Thus, most doctors wait until there is mild cognitive impairment to begin therapeutic treatments. And since we now know that tau tangles correlate better than amyloid beta deposits with cognitive loss, once dementia symptoms are apparent, co-therapy could be a necessity.

Is Amyloid Beta Both Good and Bad?

What if amyloid beta is a misunderstood do-gooder that responds to some unknown injury in the brain? Would this suggest amyloid deposits are produced by the brain in an attempt to encapsulate or neutralize a pathogen? If so, could there be instances when amyloid beta deposits are good, and yet others when they are bad? If we look to the field of cancer, it is clear that the context of the protein is what dictates whether it is good, or harmful.  We know there are crucially important proteins in the body that become dysregulated, and that associated hyperactivity triggers cascades that promote tumor growth. By extension, it is possible that amyloid beta deposits are good at some regulated level, and that Alzheimer’s disease manifests from an uncontrolled slew of amyloid deposition that is yet another example of dysregulation in disease biology. One way scientists think this might work is through the tendency of amyloid deposits to over-activate the brain’s immune cells, which inadvertently distribute tangled tau throughout the brain.

A final point to consider is the lens we use to view amyloid deposits. We must acknowledge the possibility that not all amyloid beta deposits are equal, and that some could have a beneficial role, while others are pathological. In the case of tangled tau deposits, it is known that subtle differences at the microscopic level manifest from radically different atomic arrangements of the tangles in different tau-driven neurodegenerative diseases. It is possible that different forms of amyloid beta similarly exhibit microscopic variations that explain the otherwise confounding appearance of these deposits in both Alzheimer’s disease and cognitively resilient individuals.

Progress is Coming Fast

Like most hypothesizes the amyloid cascade hypothesis required revision, and we are witnessing the scientific process as it unfolds. The simplicity of the original hypothesis paved the way for scrutinizing experiments, which have led to revised hypothesizes with added complexity. The jury is still out as to whether aspects of the original hypothesis are correct, and more importantly, whether revelations from it will lead to a treatment for Alzheimer’s disease.  But progress is coming fast, and the turning point will be sudden when scientists discover the formula of the disease, and the corresponding antidote.

About the author

Headshot of Paul Seidler, PhD

Paul Seidler, PhD

Research scientist at UCLA in the Molecular Biology Institute

Paul Seidler, PhD, is a research scientist at UCLA in the Molecular Biology Institute, working as a senior-level postdoctoral fellow in the laboratory of Dr. David Eisenberg, a leader in structural biology of amyloid-related diseases.

Stay in touch

Receive Alzheimer's Disease research updates and inspiring stories

Donate to Alzheimer’s Disease Research

Your gift can help lead to treatments and a cure to end Alzheimer’s. Fund the latest, promising research and help provide valuable information to families living with this disease.

I would like to donate