The Amyloid Cascade Hypothesis of Alzheimer's Disease

Some researchers believe that the amyloid cascade hypothesis best explains the cause of Alzheimer's disease.

While many questions are still unanswered, the amyloid cascade hypothesis proposes that excessive accumulation of a peptide called amyloid-beta is the key event in Alzheimer's disease: This accumulation sets off a series of events that results in the death of brain cells, and eventually, Alzheimer's disease.

Doctor viewing patient's brain scan on digital tablet in laboratory
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What Is Amyloid-Beta?

Amyloid-beta, also called beta-amyloid, is formed from a large protein called amyloid precursor protein (APP). Researchers don't exactly know the function of APP yet, but it may impact the activity of brain cells.

Special enzymes (called secretase) cut this protein at specific sites, and one of the products of this "cleavage" is the amyloid-beta peptide.

These amyloid-beta peptides clump together into what's called oligomers, and according to the amyloid cascade hypothesis, it is these oligomers that are toxic to brain cells, causing the very early cognitive problems in Alzheimer's disease.

Later, these oligomers form the plaques that are characteristic of Alzheimer's disease, but it is the oligomers—as opposed to the plaques—that are the actual toxic agents.

Synapse Destruction

In fact, research published in the journal Science in 2013 found amyloid-beta begins destroying synapses before it clumps into plaques that lead to nerve cell death.

Using genetically engineered mice, investigators identified a new protein, called PirB in mice and LilrB2 in humans, attracts amyloid-beta clusters and sets off a cascade of biochemical activities that result in the destruction of synapses.

The mice without PirB were resistant to memory breakdown and synapse loss associated with Alzheimer’s disease.

Actin and Cofilin

In addition, the research pinpointed another enzyme, cofilin, and its interaction with the protein actin may be the key to understanding memory decline in Alzheimer's disease.

Actin is a building-block protein essential to maintaining the synaptic structure. Cofilin breaks down actin. 

When amyloid-beta binds with PirB, cofilin activity revs up, resulting in the destruction of actin and the deterioration of synapses leading to memory loss.

Drug Targets

The amyloid-beta hypothesis has been instrumental in the development of drugs to prevent and treat Alzheimer's disease. However, to date, pharmaceutical companies have not had much success with it.


In 2016, Eli Lilly ceased trials of its Alzheimer's drug solanezumab after patients taking it demonstrated no signs of improvement compared to those taking a placebo.

The drug, designed to reduce the build-up of amyloid plaques on the brain, was studied in 2,129 patients diagnosed with mild dementia due to Alzheimer's participated in the multi-national EXPEDITION3 trial.

While research suggests solanezumab was effective in breaking down amyloid-beta plaques, the drug did not have an impact on cognitive functioning.


In 2017, Merck ceased trials of it's Alzheimer's drug verubecestat, a beta-amyloid precursor protein-cleaving enzyme 1 (BACE) inhibitor.

In a study of 1,958 patients with a clinical diagnosis of mild-to-moderate Alzheimer's disease, the drug was found to reduce levels of beta-amyloid in cerebral-spinal fluid but did not impact memory or cognitive function.

The trial was halted early due to lack of efficacy and adverse events, including rash, falls and injuries, sleep disturbance, suicidal ideation, weight loss, and hair-color change.

Alternate Theories

While several lines of evidence that support the amyloid cascade hypothesis, there are also a number of challenges to it. For one thing, the amyloid-beta that accumulates in plaques occurs in normal aging as well as Alzheimer's disease.

For another, deposits of another protein called tau form tangles that correlate better with cognitive problems in Alzheimer's disease than do plaques.

Finally, there are other alternative theories, such as the mitochondrial cascade hypothesis, that have been proposed as explanations of what causes Alzheimer's disease.

3 Sources
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  1. Kim T, Vidal GS, Djurisic M, et al. Human LilrB2 is a β-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer's model. Science. 2013;341(6152):1399-1404. doi:10.1126/science.1242077

  2. Honig LS, Vellas B, Woodward M, et al. Trial of Solanezumab for Mild Dementia Due to Alzheimer's Disease. N Engl J Med. 2018;378(4):321-330. doi:10.1056/NEJMoa1705971

  3. Egan MF, Kost J, Tariot PN, et al. Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer's Disease. N Engl J Med. 2018;378(18):1691-1703. doi:10.1056/NEJMoa1706441

Additional Reading

By Andrew Rosenzweig, MD
Andrew Rosenzweig, MD, MPH, is an Alzheimer's disease expert and the chief clinical officer for MedOptions.