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Q&A with Dr. Mike Weiner, University of California, San Francisco

Researchers widely accept that amyloid plaques are the hallmark of Alzheimer’s disease. However, for many years, drug development has focused on the solid amyloid plaque as a primary disease culprit. Recent advances show that it is more likely that early stage soluble beta amyloid oligomers play a key role in the pathogenic process of Alzheimer’s disease.

Alzheimer’s expert Mike Weiner, MD, Director of the Center for Imaging of Neurodegenerative Diseases at UCSF VA Medical Center and Professor of Radiology at the University of California, San Francisco, explores the role of oligomers and recent developments in this Q&A.

1. With so many disappointments with clinical trials of Alzheimer’s drugs targeting amyloid, is there any newer research that suggest that targeting amyloid continues to be a valid therapeutic approach for Alzheimer’s disease?

I’ve been in the field of Alzheimer’s research for several decades, and I have seen what may appear to be the ‘ups and downs’ of confidence in the amyloid hypothesis. In reality, what is happening is that we are building our base of knowledge about the very complex disease that is Alzheimer’s disease (AD). We are putting together more and more pieces of the puzzle — sometimes a puzzle piece puts the picture more into view for us; other times, it does not.

One of the new puzzle pieces that has emerged is the role of toxic amyloid beta oligomers in the disease process of Alzheimer’s. During the three years from 2012 to 2015, more than 1,000 scientific papers have studied how toxic amyloid beta oligomers are involved in Alzheimer’s pathogenesis.

All of this taken together continues to support amyloid as a target for treatment trials. At the same time, enthusiasm is rising for anti-tau approaches.

2. Can you explain what these beta amyloid oligomers are and how they emerged as a key actor in the amyloid beta story?

Amyloid beta molecules aggregate to form oligomers. Numerous studies in animals and human autopsy specimens have demonstrated the presence of these amyloid beta oligomers; additional results suggest that they have neurotoxicity. Therefore, it’s possible that amyloid beta oligomers somehow help to promote the development and spread of tau tangles, which are associated with neurodegeneration. It’s also possible that direct neurotoxicity of amyloid beta oligomers may contribute to cognitive impairments.

3. In light of these insights into the role of amyloid beta oligomers, how might they offer new ways for targeting amyloid beta in AD?

Because amyloid beta oligomers are thought to appear early in the disease process of Alzheimer’s, they offer attractive targets for therapeutics, and potentially also diagnostics. This aligns with other emerging research and clinical findings that suggest that targeting amyloid beta in patients who are earlier in the disease process has shown greater efficacy than those whose disease has further progressed. Unfortunately, at the current time, it’s not possible to measure amyloid beta oligomers in living humans. This limits our ability to fully understand the role of oligomers in AD. Nevertheless, amyloid beta oligomers fit with the new insights and therapeutic targeting ‘upstream’ and earlier in the Alzheimer’s disease process. Without question, the disease modification effects of an anti-oligomer treatment is a promising approach to pursue for AD.

4. Other late stage AD candidates in development, particularly antibodies, may also target oligomers, are there any potential advantages to targeting this mechanism with a small-molecule drug?

In general, small molecule drugs have the big advantage that they often can be taken orally and do not require injections, which antibody therapies require. With regard to drugs that can potentially target amyloid beta oligomers and amyloid pathology, new research is uncovering more about the biological pathways and the role of oligomers in Alzheimer’s. This may lead to development of new drugs to intervene with specific mechanisms of action in these pathways.

Depending on the pathways and mechanisms, both small molecules and antibodies can be effective, each with their own advantages in addressing certain targets to have efficacy for treating AD. What’s important is understanding the biology as much as possible, and the mechanism that the drug is targeting. A paper recently published by Alzheon, a company developing medicines for Alzheimer’s disease and other neurological disorders, suggests a new therapeutic mechanism for targeting toxic amyloid beta oligomers with a small molecule [“Elucidating the Aß42 Anti-Aggregation Mechanism of Action of Tramiprosate in Alzheimer’s Disease: Integrating Molecular Analytical Methods, Pharmacokinetic and Clinical Data,” published in the medical journal, CNS Drugs, and available on Open Access here]. This provides an additional approach for human treatment trials.

5. Do you believe that pursuing Alzheimer’s drug development based on the “anti-oligomer” MOA is valuable, particularly in light of earlier drug failures in the amyloid space?

Overall, I would say that treatments that appear to have anti-oligomer activity are clearly worth investigating in human trials. The new research points to this as a potential linchpin in AD pathogenesis, and there are millions of Alzheimer’s patients in need of new treatments.

We need to press forward with science, while learning from the past. There are many reasons for the previous drug failures in Alzheimer’s. Most importantly, until recently almost all AD trials did not use “amyloid phenotyping” to be sure that all the patients in the trial population actually had AD. There are a myriad of other factors in the past drug development – many of which relate to earlier drugs and trials being designed without the new understanding of the biology, genetics, and mechanisms of AD that have emerged.

6. Are you hopeful that discoveries such as this can lead to meaningful therapies that could possibly arrest the progression of this disease?

There is strong evidence that amyloid beta – in some shape or form – plays a key role in AD. New science and clinical results are emerging every day. Anti-oligomer insights are an example of the new research that continues to open new paths for treatments and hope for Alzheimer’s patients. I, as well as other experts in the field, are hopeful that anti-amyloid beta therapies, including anti oligomer therapy, may be shown to slow the progression of AD, leading to more effective treatments.

About Mike Weiner, MD
Mike Weiner, MD, is principal investigator of the Alzheimer’s Disease Neuroimaging Initiative (ADNI), the largest international observational study of Alzheimer’s disease. He is Director of the Center for Imaging of Neurodegenerative Diseases at UCSF VA Medical Center, San Francisco, California, and Professor of Radiology, University of California, San Francisco, California. Dr. Weiner serves on the Scientific Advisory Board of Alzheon, Inc.

Contact Alzheon for more information on the publication mentioned in this article.