Can Breaking down Brain Plaques Prevent Alzheimer’s?

Check out this answer from Consensus:

While breaking down brain plaques shows promise in preclinical studies, the translation to human treatment remains complex. Immunization and natural compounds like Uncaria tomentosa have demonstrated potential in reducing plaque load. However, the long-term clinical benefits, such as improved survival and cognitive function, are still uncertain. Further research is needed to fully understand the role of plaque reduction in preventing or treating Alzheimer’s disease.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss. One of the hallmark features of AD is the accumulation of amyloid-beta (Aβ) plaques in the brain. Recent research has focused on whether breaking down these plaques can prevent or reverse the symptoms of Alzheimer’s. This article explores various studies that investigate the potential of plaque reduction as a therapeutic strategy for AD.

Immunization Approaches

Immunization with Aβ

A study published in Nature demonstrated that immunization with Aβ in genetically engineered mice could reverse or prevent plaque formation and neural damage. This finding raises the possibility of immunizing humans to prevent or reverse Alzheimer’s disease. However, it remains uncertain whether plaque formation directly causes Alzheimer’s symptoms1.

Long-term Effects of Aβ42 Immunization

A follow-up study of a phase I trial assessed the long-term effects of immunization with full-length amyloid-beta peptide (Aβ42). The study found that immunization could clear amyloid plaques from the brain. However, despite the clearance of plaques, there was no evidence of improved survival or delay in the progression to severe dementia among the immunized patients4.

Natural Compounds

Uncaria tomentosa (Cat’s Claw)

Research has identified a specific plant extract, Uncaria tomentosa (cat’s claw), as a potent inhibitor and reducer of both Aβ plaques and tau protein tangles. The study showed that the plant extract could prevent the formation and aggregation of Aβ fibrils and tau tangles, as well as disaggregate preformed fibrils. This natural compound demonstrated significant potential in reducing brain plaque load and improving memory in transgenic mice2.

Antibody Therapies

Plaque-Specific Antibody

A study developed a plaque-specific antibody targeting a modified Aβ peptide (Aβ(p3-42)). This antibody showed robust clearance of pre-existing plaques without causing microhemorrhage. In contrast, a comparator antibody that targeted both soluble and insoluble Aβ lacked efficacy in lowering existing plaques and had a significant risk of microhemorrhage. These findings suggest that antibody specificity for deposited plaques is crucial for effective plaque removal3.

 

---

Can breaking down brain plaques prevent Alzheimer’s?

Rebecca M Nisbet has answered Unlikely

An expert from Queensland Brain Institute in Alzheimer’s Disease

Amyloid plaques are one of the defining pathologies of Alzheimer’s disease. They are formed by the gradual build-up of a toxic protein called amyloid-beta in brain and are observed later in the disease progression. Therefore, if amyloid plaques are detected in the brain of an individual presenting with dementia then they likely already have Alzheimer’s disease and breaking up the plaques will not prevent them from getting it. Studies in animals have shown that effectively breaking up the amyloid plaques and removing the toxic amyloid-beta from the brain will, however, reduce the disease progression and improve memory (A study from our group demonstrated this using non-invasive scanning ultrasound: Leinenga, G. and Götz, J., Science Translational Medicine , 2015). Unfortunately, the restoration of memory has not been replicated in human clinical trials yet, despite the successful clearance of amyloid-plaques. However, this may be due to other factors, such as the design of the trials, rather than the treatments themselves.  In summary, breaking up amyloid plaques will not prevent Alzheimer’s disease but may slow down its progression. 

 

Can breaking down brain plaques prevent Alzheimer’s?

James Cory-Wright has answered Uncertain

An expert from Royal Berkshire Hospital NHS Foundation Trust in Medicine

Brain plaques are a hallmark of Alzheimer’s disease (AD) and the degree of brain plaque correlates with the severity of the disease. However, it is thought that the plaques are an end product of the brain damaging process, and not the cause. 

A recent drug trial demonstrated that a monoclonal antibody drug called Lecanemab was able to break down amyloid plaques in patients with established mild Alzheimer’s disease and this slowed progression of the disease. 

This is the first trial of a plaque targeting monoclonal antibody (MAB) to show a positive outcome. There are several proposed reasons for why this particular trial was successful whereas other similar trials were not. In this trial only people with mild AD were included. It is thought that plaque clearing MABs will not work in patients with more severe disease as extensive and irreversible damage has already taken place. Another reason is that the MAB used in this trial targeted the toxic intermediates as opposed to the plaques themselves, whereas other MABs have targeted the latter. Finally, this trial reduced amyloid levels more effectively and quicker than other trials.

However, this trial does raise some questions. Although amyloid plaque was reduced to a very low level the symptomatic effects were very small during this 18-month trial. This mismatch highlights our lack of understanding of the pathogenesis behind AD. Perhaps there are other processes in AD that are more important than amyloid plaque formation, alternatively, there may be a time-delay for cognitive changes to be seen. 

It is yet to be determined whether giving this MAB to people without established brain plaques could prevent Alzheimer’s disease and, like all drugs, this may come with some risks. 

In summary, as breaking down plaques in individuals with mild AD results in some modest delay in memory decline and symptoms, it may well be the case that breaking down plaques in individuals without AD may prevent it altogether – however more research is needed to demonstrate this.

 

Can breaking down brain plaques prevent Alzheimer’s?

Martin Hallbeck has answered Unlikely

An expert from Linköping University in Alzheimer’s Disease, Neurodegenerative Disease, Parkinson’s Disease

Baser on current literature plaques does not seem to drive disease. In addition several drug trials aimed at clearing plaques have failed. That said, AB lowering drugs could be beneficial, especially if targeting the soluble aggregates.

 

Can breaking down brain plaques prevent Alzheimer’s?

George Perry has answered Unlikely

An expert from University of Texas at San Antonio in Neurodegenerative Disease, Alzheimer’s Disease, Parkinson’s Disease, Metabolomics

From what we now know—-NO—plaque removal does not benefit patients.

 

Can breaking down brain plaques prevent Alzheimer’s?

Louise C Serpell has answered Unlikely

An expert from University of Sussex in Alzheimer’s Disease

I believe this is unlikely and that in order to target amyloid plaques in AD, it would be necessary to prevent assembly of beta amyloid in the first place. The causes of AD are still not well understood, but there is good evidence that Amyloid beta (Abeta) (which forms plaques) plays an important role in the cause of disease. Some drugs do aim to break up plaques but it remains unclear whether these plaques are actually causing disease or whether some earlier structure of Abeta is more disease-causing. Oligomers are also formed by Abeta. These structures may be precursors to plaques and thought to be more “toxic”. One concern with “breaking up plaques” would be that it would generate more oligomers, thus leading to a worse outcome and exacerbation of disease.

Often, amyloid plaques are found in individuals who already have symptoms, so there is no way to reverse these symptoms even if you were able to dissolve the plaques.

In summary, we still don’t know, but the best strategy will be to try to prevent Alzheimer’s disease at very early stages. Therefore, early diagnosis is really important and we need more research into the causes and methods for early diagnosis.

 

Can breaking down brain plaques prevent Alzheimer’s?

Tim Wilkinson has answered Unlikely

An expert from Edinburgh University in Neurology, Alzheimer’s Disease, Cognitive Science, Epidemiology

So far, no method of breaking down/removing amyloid plaques has been shown to prevent symptomatic Alzheimer’s disease in humans.

We now think that the plaques and tangles in Alzheimer’s disease are present many years (even decades) before a patient develops cognitive symptoms (see references below for this). This is important, because it might explain why we haven’t yet found a treatment that works in preventing Alzheimer’s disease – maybe, if we wait until someone has symptoms (e.g. memory loss), it is too late for any treatment to work. With this in mind, researchers are trying to find ways of identifying people who are at risk of developing symptoms due to Alzheimer’s disease in the future – it is possible that if we were to try these interventions in these people, they may help to prevent or delay the onset of symptoms. This is just a theory though. It is very difficult to do in practice.

To summarise: as things stand, no intervention has been shown to prevent or delay the onset of Alzheimer’s disease in humans.

References:

Bateman RJ, Xiong C, Benzinger TLS, Fagan AM, Goate A, Fox NC, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med. 2012;367: 795–804

Mortimer JA, Borenstein AR, Gosche KM, Snowdon DA. Very Early Detection of Alzheimer Neuropathology and the Role of Brain Reserve in Modifying Its Clinical Expression. J Geriatr Psychiatry Neurol. 2005;18: 218–223.

 

Can breaking down brain plaques prevent Alzheimer’s?

Donald R Royall has answered Unlikely

An expert from University of Texas Health Science Center at San Antonio in Psychiatry, Internal Medicine

In my opinion this is unlikely. However, you get the answer to the question you ask. Neuritic plaques (NP) are one of the two lesions Alzheimer described. The other is the neurofibrillary tangle (NFT). Both are present in Alzheimer’s Disease (AD). “Breaking down” NP could not then prevent AD. You already have it.

Regardless, not all persons with these lesions are demented. We can imagine preclinical stages of AD. Some persons have NFT only. Most of those are not demented. Even some with both lesions are not demented. NP are made of beta amyloid. Amyloid appears to be deposited before dementia’s onset. So, breaking down NP might prevent dementia, and some clinical trials are trying to do just that.

However, the answer to the question “can breaking down plaques prevent dementia?” hinges on amyloid’s association with dementia. The news here is not so good. NP are weakly associated with cognitive performance, and may have no association independently of NFT, which are more strongly related. Moreover, not all cognitive impairments are dementing and it is not clear that NP are associated with dementia’s essential features. Furthermore, amyloid deposition occurs before dementia’s onset and does not develop further as dementia progresses. NP may even restrict the development of NFT. So why get rid of them?

On the other hand, animal models of AD have been engineered that accumulate excessive levels of beta amyloid and NP. Medications that prevent or reverse beta amyloid deposition can prevent or reverse cognitive impairment in those animals. However, none have been successful in humans, and many have tried.

Another problem is that there are many risk factors for dementia and they don’t all work through NP. Several may be present in the same patient. Depression, for example, appears to double the risk of AD. It does not do this by increasing NP and NFT. Even if NP are related to dementia, an intervention on them alone may neither prevent it nor reverse it in the presence of other risks, beginning with NFT.

For all these reasons, I think it is unlikely that an anti-amyloid intervention will prevent or reverse dementia, aside from the exceptional case of certain rare genetic disorders, which, like the engineered animal models, result in excessive amyloid accumulations in the absence of other dementia risks.

 

Can breaking down brain plaques prevent Alzheimer’s?

Michael G Agadjanyan has answered Unlikely

An expert from The Institute for Molecular Medicine in Immunology

Inhibition of amyloid beta oligomerization and plaque formation in healthy people likely will prevent/delay the disease, while braking down plaques unlikely will work in AD patients. Thus, protective measure (including preventive vaccination) will likely prevent/delay AD, while amyloid beta therapeutic measure unlikely will be effective.

 

Can breaking down brain plaques prevent Alzheimer’s?

J Sanchez-Ramos has answered Unlikely

An expert from University of South Florida in Neurology

Simply lowering the amyloid burden of brain in patients with AD by passive or active immunization against beta-amyloid is not sufficient to stop or prevent the disease. It will require prevention of the development and accumulation intracellular neuro-fibrially tangles, the other very important component in the neuro-pathogenesis of the disease.

 

Can breaking down brain plaques prevent Alzheimer’s?

Helmut M Hügel has answered Likely

An expert from RMIT in Mental Health

You are what and the amount you eat. The ideal dietary food would contain precursor molecules, that can be metabolised into brain permeable conjugates and interact with amyloid proteins to impede or prevent the formation of amyloid oligomers and fibrils. The consumption of fruits and beverages high in polyphenol content is associated with higher gut microbe diversity and better health. The closest current solution appears to come from dietary patterns. A higher adherence to a Mediterranean diet and a high intake of fruit is associated with less accumulation of Aβ and less cerebral AD pathology accumulation over time. This highlights the paramount importance of lifespan healthy diets and lifestyles, early disease intervention with amyloid inhibitors, and the need for sensitive disease biomarkers. There is no simple answer to preventing AD. Dementia dehumanises, ageing is a driver of AD risk. However, education and its consequences can help to delay, defeat and reverse neurodegeneration. 

 

Can breaking down brain plaques prevent Alzheimer’s?

Thomas van Groen has answered Unlikely

An expert from University of Alabama at Birmingham in Alzheimer’s Disease

Plaques do not seem to do any significant harm as such, and breaking them up might cause problems by creating toxic fragments

 

Can breaking down brain plaques prevent Alzheimer’s?

Larry Baum has answered Unlikely

An expert from University of Hong Kong in Alzheimer’s Disease, Genetics, Neuroscience

I’m not aware that this has been tried yet. But a vaccine that breaks down brain plaques was tested in people who already have Alzheimer’s, and it didn’t reverse or slow the progression of dementia. But what would happen if this were tried before people develop dementia? We don’t know yet, but I’d guess that dismantling plaques would not prevent dementia. Aβ is the molecule that aggregates together to form plaques, and I’d guess that reducing Aβ at an earlier stage, per

 

haps before it forms plaques or before it’s created, would prevent dementia. I think so because people get Alzheimer’s at a young age if they have a mutation that leads them to produce a high level of Aβ.

Antibodies that remove Aβ, the molecule that aggregates together to form plaques, and drugs to inhibit production of Aβ, can reduce the formation of plaques. They were tested in Alzheimer’s and didn’t reverse or slow the worsening of dementia. Thus, does Aβ have nothing to do with causing Alzheimer’s? People get Alzheimer’s at a young age if they have a mutation that leads them to produce a high level of Aβ. Therefore it seems likely that Aβ does lead to Alzheimer’s, but that once it forms plaques, removing plaques doesn’t reverse dementia.

Now Aβ-reducing treatments are being tested in people without dementia but who are genetically prone to develop Alzheimer’s. We’ll know in a few years whether they work to prevent dementia.

 

Can breaking down brain plaques prevent Alzheimer’s?

Christopher A Mitchell has answered Unlikely

An expert from Ulster University in Neurodegenerative Disease, Cardiovascular Disease, Immunopathology, Histopathology, Osteology

Dr Royall sums up the clinical evidence nicely, underlining the fact that we don’t really know if plaques are the result of AD progression, are actually causal or are a combination of both. There is a lot of debate among scientists about this. Certainly, in mouse models there is reasonable evidence to support the hypothesis that preventing plaques forming or breaking them down can prevent AD (at least in the mouse). But as we are aware, what happens in a mouse does not necessarily translate into successful therapy for humans.

However, there is good news. There is good epidemiological evidence that maintaining a healthy diet (i.e. specifically not being type 2 diabetic), exercising, perhaps even learning a second language (?) decreases your risk of AD and may help to slow progression of this cruellest of diseases.

 

Can breaking down brain plaques prevent Alzheimer’s?

Menno P Witter has answered Extremely Unlikely

An expert from Norwegian University of Science and Technology in Neuroscience, Neurodegenerative Disease

The evidence gathered so far indicates that amyloid plaques do not drive the disease, but result from an underlying process that causes neuronal death alongside formation of such amyloid plaques. The strongest evidence for this is that the number of amyloid plaques a person has tells us little about that person’s cognitive status. In other words, you may have quite a lot of plaques in your brain and remain in good mental health. However, it is important to underline that plaques are nevertheless a pathological entity and, if we imagine there was no other underlying process driving the disease, there would likely still be a limit to how many plaques a person could develop while staying healthy. This is because plaques very likely contribute to the disease by impairing the capacity for efficient signaling between brain cells. In addition, densely formed plaques, which is one of several types, are known to induce a strong local inflammatory response, and this is likely to damage nearby neurons. Nevertheless, it appears the brain is able to compensate quite well for this.

One of the underlying processes that drive Alzheimer’s disease has to do with an imbalance between the production and clearance of a peptide called amyloid-beta. As its name suggests, this peptide is a central part of amyloid plaques. However, amyloid-beta does far more than lump together into plaques. Certain forms of the amyloid peptide are highly neurotoxic and even minute amounts are capable of disrupting signaling between cells in the brain. In sum, current evidence lead us to the interpretation that breaking down amyloid plaques in the brain would not halt the underlying formation of amyloid-beta peptides, and it is therefore unlikely that such an approach would prevent Alzheimer’s disease.

 

Can breaking down brain plaques prevent Alzheimer’s?

Leanne M Stevens has answered Unlikely

An expert from Dalhousie University in Psychology, Neuroscience, Pedagogy

The question asks whether breaking down plaques could prevent Alzheimer’s. Once plaques and tangles exist (at a pathological level) you are no longer preventing but treating. Alzheimer’s is a complex disease related to amyloid-beta plaques, neurofibrillary tangles, and inflammation (among other factors). It is unlikely that targeting any single one of these components will cure Alzheimer’s. Current research often focuses on identifying/diagnosing Alzheimer’s symptoms early, slowing/lessening symptoms, and preventing the disease (e.g., looking at the risk factors, lifestyle, etc. that may increase or decrease the chances of developing the disease in the first place).

 

Can breaking down brain plaques prevent Alzheimer’s?

David R Borchelt has answered Unlikely

An expert from University of Florida in Alzheimer’s Disease, Proteins, Pathology

I think that whether this strategy would work as a preventative would greatly depend on when the treatment was applied.  The question as phrased suggests that amyloid deposition has already begun at which time it may already be too late to be preventative.  Simply breaking them down with also destroying the peptide and preventing new peptide from being generated would quite possibly make things worse.

 

Can breaking down brain plaques prevent Alzheimer’s?

Bruce G Jenkins has answered Unlikely

An expert from Massachusetts General Hospital in Neuroimaging

As others have noted there are different types of plaques and they are mostly a consequence of the ongoing pathological processes. If one reframes the question to “Can breaking down brain plaques improve Alzheimer’s symptoms?” then the answer is almost certainly no. Numerous trials addressing this issue have failed and some have even shown using PET imaging that the plaque burden has been reduced in spite of a lack of amelioration of symptoms. The trial data are reviewed by Christopher van Dyck in :

http://dx.doi.org/10.1016/j.biopsych.2017.08.010

We already know that most people with Down’s syndrome develop AD. The extra dose of amyloid precursor protein seems to predispose them to development of AD pathology at much earlier ages than control populations:

https://www.ncbi.nlm.nih.gov/pubmed/25285303

This fact, along with many others, suggests that lowering beta-amyloid levels at an early age might lower risk of late development of AD. Unfortunately, the amyloid-lowering drugs used so far have too many side-effects to propose their use in general populations.

 

Can breaking down brain plaques prevent Alzheimer’s?

Amanda Heslegrave has answered Unlikely

An expert from University College London in Neurodegenerative Disease

Once amyloid plaques have been deposited in someone who is predisposed to get AD for whatever reason, then I don’t think you could prevent it. If early enough maybe you could slow the course of disease, but there are other toxic factors too which need to be taken into account.

 

Can breaking down brain plaques prevent Alzheimer’s?

Thomas E Mahan has answered Likely

An expert from Washington University in St. Louis in Neuroscience, Biochemistry, Cell Biology

The answer to this question is very much context dependent. Clearing amyloid beta plaques from the brain before downstream damage has occurred has the potential to help delay and prevent the cognitive impairments of Alzheimer’s. However, if damage from the plaques has resulted in neuronal damage and the accumulation of significant amounts of tau tangle pathology and signs of cognitive impairment are already present, breaking down plaques is unlikely to prevent the progression of Alzheimer’s. This has been shown in failed clinical trials that have targeted plaques in individuals that already have cognitive impairments and significant tau pathology. However, because plaques can accumulate 15-20 years before symptom onset, targeting plaques early in the course of the disease may be able to aid in the prevention of the disease.