Is the Alzheimer’s “Amyloid Hypothesis” Wrong?

Check out this answer from Consensus:

The amyloid hypothesis has significantly shaped our understanding of Alzheimer’s disease, but its limitations and the failure of Aβ-targeting therapies have prompted a reevaluation. While Aβ may play a role in the early stages of AD, it is likely not the sole cause of the disease. Future research should adopt a more holistic approach, considering other factors such as tau pathology and synaptic dysfunction, to develop more effective treatments for Alzheimer’s disease.

The amyloid hypothesis has been a cornerstone of Alzheimer’s disease (AD) research for over two decades. It posits that the accumulation of amyloid-beta (Aβ) peptides in the brain is the primary cause of AD. Despite its dominance, the hypothesis has faced significant scrutiny and controversy, particularly due to the repeated failure of Aβ-targeting therapies in clinical trials. This article explores the arguments for and against the amyloid hypothesis, examining whether it remains a valid framework for understanding and treating Alzheimer’s disease.

Arguments Supporting the Amyloid Hypothesis

The amyloid hypothesis is supported by several lines of evidence. Genetic studies have shown that mutations in the amyloid precursor protein (APP) and presenilin genes, which are involved in Aβ production, are linked to early-onset familial AD. Additionally, individuals with Down’s syndrome, who have an extra copy of the APP gene, develop Aβ deposits and AD-like pathology early in life6. Soluble Aβ oligomers have been shown to impair synaptic function and memory in animal models, further supporting the hypothesis6.

Criticisms and Controversies

Despite the supporting evidence, the amyloid hypothesis has several unresolved issues. One major criticism is the presence of Aβ deposits in cognitively normal individuals, which suggests that Aβ accumulation alone may not be sufficient to cause AD1. Additionally, the correlation between plaque load and cognitive decline is weak, raising questions about the direct role of Aβ in neurodegeneration1. The failure of Aβ-targeting therapies in clinical trials has also led to skepticism about the hypothesis4 5.

Alternative Perspectives

Some researchers argue that Aβ is not the primary cause of AD but rather a trigger for other pathogenic processes, such as tau aggregation, which may be more directly responsible for neurodegeneration2. Others suggest that Aβ may play a role in brain homeostasis and that its accumulation is a secondary effect rather than a cause of AD8. The tau hypothesis, which posits that tau protein abnormalities are the main drivers of AD, has gained traction as an alternative to the amyloid hypothesis5.

Therapeutic Implications

The repeated failure of Aβ-lowering agents in clinical trials has led to calls for a broader approach to AD research. Some suggest focusing on rescuing synaptic dysfunction directly, rather than targeting Aβ itself4. Others advocate for a more comprehensive understanding of the disease, considering multiple factors and pathways involved in AD pathogenesis1 3.

Is the Alzheimer’s “Amyloid Hypothesis” wrong?

Cynthia Picard has answered Likely

An expert from Douglas Mental Health University Institute in Alzheimer’s Disease, Genetics, Biochemistry

The familial form of Alzheimer’s disease (FAD) is typically caused by mutations in APP, PSEN1 or PSEN2 genes, which all lead to the overproduction of amyloid (Aβ) plaques. The cleavage of Aβ by γ-secretase allows the amyloid precursor protein intracellular domain (AICD) to translocate to the nucleus and activate the transcription of APP and BACE1, exacerbating the situation. The concomitant activation of GSK3β contributes to the phosphorylation of Tau, leading to the formation of intracellular neurofibrillary tangles. Another target gene of nuclear AICD is LRP1, coding for a receptor that can bind HDL particles. Recently, mutations in another HDL receptor (SORL1) were identified in 3 families with FAD. These findings, together with the failure of anti-Aβ therapies, suggest that the amyloid hypothesis was incomplete. The importance of cholesterol metabolism should be considered, as evidenced in the late onset form of Alzheimer’s disease (LOAD). Genome-wide association studies of LOAD have revealed the implication of many cholesterol-related genes (APOE, CLU, ABCA7, PICALM, BIN1 and SORL1) as important LOAD risk factors. APOE, CLU and ABCA7 play a role in cholesterol transport via HDL particles that have the ability to bind receptors such as LDLR, LRP1 and SORL1. PICALM and BIN1 facilitate the endocytosis of the receptor bound complexes which can release cholesterol inside the cells. In conclusion, genes associated with both the familial form (FAD) and the sporadic form (LOAD) of Alzheimer’s disease share common pathways associated with the amyloid cascade and cholesterol metabolism.

Is the Alzheimer’s “Amyloid Hypothesis” wrong?

George Perry has answered Likely

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

As causative agent, amyloid has been debunked. The idea is wrong. I explain the issue in my MOOC, it is free to audit: Course | AD001x | edX

Also I bring together a number of my papers on this issue together in Open Science:

ScienceOpen interview series: Prof. George Perry, world expert on Alzheimer’s Disease – ScienceOpen Blog

Search – ScienceOpen

‘Beyond amyloid’: A look at what’s next in Alzheimer’s research

Is the Alzheimer’s “Amyloid Hypothesis” wrong?

Gunnar K Gouras has answered Unlikely

An expert from Lund University in Alzheimer’s Disease

The Alzheimer’s amyloid hypothesis that posits that the main component of the hallmark amyloid plaques in the brain with the disease, the beta-amyloid amyloid peptide, plays an important role in the disease, is in my opinion correct. However, the simple conclusion drawn from this hypothesis that removing beta-amyloid peptides will cure the disease is turning out to be much more challenging than initially envisioned and possibly might even be incorrect. Having been in this field for many years, I believe that the many very bright people in our field have not just been led astray. Nevertheless, I certainly have worried that there is too little debate in our research field and also too much complacency with following what is only a hypothesis. As someone who works hard to better understand Alzheimer’s disease, my view is that neurodegenerative diseases of aging (Alzheimer’s, Parkinson’s, etc.) are particularly difficult to cure because they develop in what is such a complex entity: our brain. In particular, synapses appear to be where these diseases initiate. I do see a lot of progress in our field over the years, although to really move us forward more rapidly towards a meaningful therapy, we should work together better and face our controversies more head-on. Research on Alzheimer’s is needlessly slow because of dogmas, and even a lack of courage and confidence in challenging them. Thus, it is important to question our perceptions and research. Beta-amyloid will end up being one of many players in this complex disease; we already know many others (apoE, TREM2, presnilins, tau, etc.). I also don’t think that the failed clinical trials targeting beta-amyloid should lead us to dismiss beta-amyloid’s role, but rather should highlight our still insufficient understanding of beta-amyloid’s role in the disease . (I also want to note that beta-amyloid peptides and the end-stage lesion, the amyloid plaques, are not the same.) In conclusion, we need to press on with our work, while also taking time to question and be questioned, and responding to doubts.

Is the Alzheimer’s “Amyloid Hypothesis” wrong?

Giuseppe Sorrentino has answered Likely

An expert from University of Naples Parthenope in Alzheimer’s Disease

Although widely explored, the pathogenesis of Alzheimer’s disease (AD) has yet to be cleared. Over the past twenty years the so call amyloid cascade hypothesis represented the main research paradigm in AD pathogenesis. In spite of its large consensus, the proposed role of Aβ remain to be elucidated. Many evidences are starting to cast doubt on amyloid as the primary causative factor in AD. For instance, Aβ is deposited in the brain following many different kinds of injury. Also, concentration of Aβ needed to induce toxicity in vitro are never reached in vivo. In this job we propose an amyloid-independent interpretation of several AD pathogenic features, such as synaptic plasticity, endo-lysosomal trafficking, cell cycle regulation and neuronal survival.

See: Sorrentino p et al. FEBS Letters 588 (2014) 641–652

Is the Alzheimer’s “Amyloid Hypothesis” wrong?

Robert G Struble has answered Near Certain

An expert from Southern Illinois University in Neurodegenerative Disease, Neuroscience

The amyloid cascade hypothesis of dementia troubled many of us studying AD in the early 80s. The committee decision to use senile plaques as a criteria for AD dx was a simplistic assumption given the absence of dementia in cases of severe senile plaque formation and the absence of plaques in severe cases of dementia. However, the amyloid hypothesis was extremely enticing since it presented a simple etiology of a major disease and one to generate coherent research questions for funding. The failure of removing amyloid by antibodies (and other approaches) tended to either be ignored or was justified by modifying a mechanistic hypothesis. Moreover, to neuropatholists, the amyloid transgenic models looked little like human AD and the behavioral deficits seen in these models were supported by weak statistical analysis. This is not to say that an insoluble material in the brain could not cause brain dysfunction, but the magnitude of dysfunction did not fit well with the the clinical data. Finally, the in vitro studies of amyloid toxicity did not translate well to clinical differences. Amyloid deposition in the brain certainly did neural function no favors but the magnitude of effect was too small to explain the disease. In sum, amyloid deposition was a characteristic of defined AD, and might be a fellow traveler with the etiology of the disease but did not appear to be a causative factor. Hence the amyloid cascade hypothesis was probably not the cause of AD dementia.

Is the Alzheimer’s “Amyloid Hypothesis” wrong?

Ramon Trullas has answered Unlikely

An expert from Consejo Superior de Investigaciones Científicas in Neurodegenerative Disease, Neurobiology

Alzheimer’s (AD) is a disease that may be caused by different factors. For example, familial AD linked with mutations in PSEN1 or APP genes is almost certainly caused by Amyloid accumulation. Sporadic AD, caused but not yet known factors is unlikely to be related to Amyloid accumulation.

Is the Alzheimer’s “Amyloid Hypothesis” wrong?

Gregory M Rose has answered Unlikely

An expert from Southern Illinois University in Alzheimer’s Disease, Cognitive Science, Pharmaceutics

While there is clearly no known direct relationship between amyloid and the behavioral symptoms of AD (i.e., amyloid = dementia), there is an emerging consensus that some form of amyloid is a risk factor. The problem now is to explain what happens in the decade or so between the measurement of elevated amyloid in CSF or plaques in the brain and the emergence of cognitive impairment.