World Alzheimer’s Day: After 25 Years of Amyloid Hypothesis Research, Where Are We Now?

World Alzheimer’s Day: After 25 Years of Amyloid Hypothesis Research, Where Are We Now?

Twenty-five years have passed since researchers launched the idea that Alzheimer’s is a direct result of clumps of amyloid-beta littering the brain. The amyloid hypothesis of Alzheimer’s disease, as it is called, quickly raised hopes among researchers and patients alike that the dreaded disease would soon be under our control. But a cure seems as distant today as it did then.

So what have researchers concluded over the last 25 years, and why is the progress here so slow when other research fields are advancing by leaps and bounds?

The complex reality of simplicity

The amyloid hypothesis of Alzheimer’s disease was simple. An imbalance in the production or removal of amyloid-beta was said to cause an accumulation and clumping of the peptide in the brain, which was toxic in itself and, in turn, set off a cascade of events leading to neurodegeneration and loss of brain tissue.

So if patients dying of Alzheimer’s disease have brains full of a protein that kills their nerve cells, the problem should be easily solved by removing the protein, researchers believed.

The idea born in the early 1990s was that if researchers learned the molecular secrets of the protein — asking questions like ‘what makes it aggregate,’ or ‘in what way does it kill neurons’ — it would just be a matter of time before a treatment, or even cure, could be developed. Unfortunately, the simple idea turned out to be a lot more complex than scientists imagined.

Studies of protein aggregation are arduous and slow tasks. The problem with protein aggregation is that, in contrast to studies of other cellular processes or structures, evolution has worked to reduce protein aggregation, rather than to optimize it. This biological fact makes it particularly difficult to study such processes in a dish.

Protein aggregation is nearly always studied in artificial solutions. However, when a biological entity, such as a protein, is placed in an artificial environment, the circumstances surrounding each experiment influence the results, leading to study findings that — more often than not — contradict each other.

Protein aggregation processes also depend on too many cellular players to make studies in cell models straightforward, and although several new methods have been developed in recent years, the field remains shrouded in uncertainties.

So, what about mice? Surely the most common species in studies of Alzheimer’s disease may tell researchers something.

Numerous mouse models of Alzheimer’s disease do exist, and  genetically engineered mice, particularly, have helped researchers to understand the disease.

Nevertheless, although mice show some of the behavioral symptoms of Alzheimer’s and do lose nerve cell connections, the similarity has proven to be elusive. Studies point out that none of the mouse models fully captures all aspects of human cognitive deterioration. And none show progressive irreversible neurodegeneration, as it is seen in humans.

Evidence seen in different lights 

Although the amyloid hypothesis has dominated the Alzheimer’s research field for 25 years now, the slow progress in proving it right and, particularly, the failures of the numerous clinical trials have led many researchers to question the theory’s validity.

What real evidence is there supporting the idea that the amyloid protein is the disease villain? Are sceptics viewing this evidence through a different lens?

A large part of the research supporting the amyloid-beta hypothesis stem from studies of the inherited, early onset versions of the disease. Amyloid-beta is produced when a protein known as the amyloid precursor protein, or APP, is cleaved into smaller pieces. This chopping is done by several enzymes and gives rise to a number of different protein parts, or peptides as they are called by scientists.

Mutations in the amyloid-beta region of the APP gene are known to cause early onset Alzheimer’s. A family of factors involved in the cleavage process, presenilins, are also linked to early onset inherited Alzheimer’s, and the discovery of an amyloid-lowering APP mutation is considered to be major evidence in support of the hypothesis. People with this gene variant are protected from Alzheimer’s.

But, according to critics, this mechanism may not be representative for all early onset cases, let alone for late onset Alzheimer’s. Genetic studies of sporadic, late onset Alzheimer’s disease find no direct links to the APP gene or the enzymes cleaving the protein.

The most well-known risk gene is, instead, APOE4, and it has, indeed, been linked to the presence of amyloid deposits in the brain. The problem is that imaging studies trying to link the risk gene to signs of neurodegeneration and brain tissue loss tend to not agree — some find that APOE4 associates with neurodegeneration, while others don’t. By all means, researchers agree that the effects of the gene on the brain are subtle.

Another crucial component supporting the amyloid hypothesis is that the APP gene sits on the very chromosome that is duplicated in Down’s syndrome. People with Down’s, therefore, have an increased production of amyloid-beta, and all have heavy amyloid plaque deposits in their brain. Most also develop Alzheimer’s disease.

Again, other researchers point out that although amyloid plaques are present in virtually all people with Down’s, not all develop Alzheimer’s. In fact, the same is true for all people. Amyloid plaques can be found in about 25–30 percent of cognitively normal people, and evidence from clinical trials shows that the removal of plaque does not necessarily improve cognition.

Drug development lessons learned

It has likely escaped no one that decades of research into the amyloid hypothesis has not led to one single drug based on the theory, despite hundreds of clinical trials. Researchers tend to explain this extremely high failure rate in different ways.

Early on, scientists believed that removing plaque from the brains of patients would reverse the disease, just as it did in mice. When this failed, the idea was born that amyloid needs to be targeted before extensive deposits exist. And so, clinical trials moved from trying to reverse established Alzheimer’s to focusing on individuals at risk for Alzheimer’s disease and those with mild cognitive decline.

According to others, failure can instead be explained by factors such as inadequate drug potency and dosing, and unacknowledged processing of an experimental drug in the body.

Moving away from plaque

One of the biggest amendments to the amyloid theory in later years is the belief that it is not the presence of insoluble plaque that trigger the progressive neurodegeneration, but rather small soluble amyloid-beta aggregates, known as oligomers. Numerous studies have shown that the oligomeric form of amyloid-beta is much more toxic to the brain than plaque.

Many reviews looking at the failure of clinical trials also point out that none of the drugs currently in clinical trials target the oligomers.

A fact that often fails to get mentioned in the debates of amyloid-beta-harnessing drugs is that researchers have not been able to prove that amyloid-beta oligomers really exist in living beings. Such protein formations may instead be triggered by the method used to find them.

Is there a path beyond amyloid-beta?

Today, voices are increasingly being raised that the amyloid hypothesis is too simple.

In an article that stirred the research field last year, Karl Herrup with the Hong Kong University of Science and Technology argued that there is very little evidence supporting a simple linear model, where amyloid-beta is both necessary and sufficient to cause Alzheimer’s.

Herrup by no means denies that the amyloid protein is likely a key player in the development of Alzheimer’s disease. But in his view, it alone cannot explain the disease’s complexity.

Some worry that devotion to the theory may have caused researchers to view all findings through an amyloid lens, blinding them to alternative explanations.

“A hypothesis that remains unproven yet catches the collective imagination can become, with the passage of time, so seductive that it dominates peer review opinion and arrests the development of alternative ideas,” Gary Morris wrote in his 2014 review, “Inconsistencies and Controversies Surrounding the Amyloid Hypothesis of Alzheimer’s Disease.”

But if the amyloid hypothesis is unable to explain why and how Alzheimer’s develops, are there any alternative theories? The truth is, there are plenty, and according to researchers such as Herrup, they are likely all equally valid.

Studies highlighting the role of tau, brain inflammation, faulty cellular processes, metal ion imbalance, oxidative damage, and problems with cells’ energy-producing mitochondria may all have a tale to tell. Considering the apparent complexity of human Alzheimer’s disease, keeping an open mind to all these possibilities is likely the best way forward for Alzheimer’s research — a notion favored by even the most devoted supporters of the amyloid hypothesis.


  1. Alzheimer's researcher says:

    It has actually been 32 years since George Glenner first proposed the amyloid hypothesis of Alzheimer’s disease. It was reiterated in light of the gene mutations later on (25 years ago).

  2. Lane Simonian says:

    This is one of the best articles that I have read on amyloid and Alzheimer’s disease in several years. In my twelve years of studying Alzheimer’s disease as a non-scientist (although with some background in biology), I have come to the conclusion that oxidative stress is the true cause of Alzheimer’s disease. The following chart and quote help lay out the case.

    “Malinow’s team found that when mice are missing the PKC alpha gene, neurons functioned normally, even when amyloid beta was present. Then, when they restored PKC alpha, amyloid beta once again impaired neuronal function. In other words, amyloid beta doesn’t inhibit brain function unless PKC alpha is active.”

    I am a visual person, so it might help for some readers to print out the chart to follow the rest.

    Protein kinase C leads to the secretion of the amyloid precursor proteins, caspase 3 leads to the first cut in the amyloid precursor protein (the beta secretase cut), intracellular calcium release leads to the second cut in amyloid (the gamma secretase cut which leads to amyloid oligomers) and to hyperphosphorylated tau, and peroxynitrite mediated nitration of amyloid oligomers leads to amyloid plaques and to nitrated tau proteins. The amyloid precursor protein and amyloid oligomers further activate protein kinase C via increasing g protein signalling. However, many other factors increase this signalling including the ApoE4 gene, psychological stress, various environmental toxins (such as various pesticides, air pollutants, and industrial solvents), and moderate to heavy smoking. Mice don’t replicate the degree of oxidative damage found in humans with Alzheimer’s disease, they simply replicate the oxidative damage produced by the amyloid precursor protein and amyloid oligomers (and perhaps by stress).

    The key pathway in Alzheimer’s disease is protein kinase C activation, NMDA receptor activation, and peroxynitrite and caspase 3 formation. Nitro-oxidative stress produced by peroxynitrite inhibits the synthesis and release of neurotransmitters involved in short-term memory, sleep, mood, social recognition, and alertness, inhibits neurotransmissions, limits the flow of blood and inhibits the transport of glucose in the brain which can lead to delusions, at high levels (due to psychological stress) peroxynitrite contributes to agitation, aggression, and hallucinations, prevents the regeneration of neurons in the hippocampus, and in conjunction with caspase 3 causes the death of neurons.

    Peroxynitrite exhausts the brain own master antioxidant–glutathione. To treat the disease, external antioxidants must be used. The most effective of these are eugenol found in various essential oils via aromatherapy (Jimbo, et al. 2009) and syringic acid and ferulic acid in panax ginseng (Heo, et al. 2011 and 2012).

    Removing amyloid oligomers does very little to treat Alzheimer’s disease because it removes only one source of oxidative stress (and removing amyloid plaques probably does even less). To treat the disease, one needs to scavenge peroxynitrite and reverse part of the nitro-oxidative damage that it has done to the brain.

  3. Dante Marciani says:

    Excellent analysis of the amyloid-beta hypothesis status. In fact, plaque seems to a protective mechanism, while there is increasing evidence that the smaller soluble amyloid oligomers are highly neurotoxic. Yet, with the exception of aducanumab, none of the drugs tested target those oligomeric forms, which may explain the consistent clinical failures. An interesting observation is that amyloid may not be the single causal agent, indeed, new findings indicate that amyloid may the triggering agent, but that it has many partners in crime, like tau, neuroinflammation and others; hence, a multi-prong approach may be therapeutically much more effective. As the article concludes, considering the complexities of this disease, keeping an open mind is the best approach to study and solve the problem.

    • Tim Bossie says:

      Thank you for the very thought out and detailed response to this post. We are glad that you liked it and are appreciative of your insight. Thanks!

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