Tools & Techniques Drug delivery, Drug discovery

In Search of Lost Memory

Alzheimer’s disease is a puzzle that has confounded researchers for decades. Despite well-documented attempts from high-profile companies to comprehend the intricate nature of the disease, all promising developments have consistently led to disappointing outcomes. And though current therapeutic options can alleviate certain symptoms, they fall short of halting the progression of Alzheimer’s altogether. We spoke with Peter St George-Hyslop, a professor of neurology at the University of Cambridge and one of the most cited authors in the field of Alzheimer's research, to learn more about the complexities of the disease.

How did you become interested in Alzheimer’s research?

In my third year of study as a medical student, I was asked to interview a lady who had Alzheimer’s disease. I was unaware of the condition at the time, and I remember feeling completely mystified by her responses. How could a person capable of normal physical movement and answering simple questions have no idea why she was in hospital? Most of her responses were very vague too. I remember reporting to a neurologist afterwards, but frankly, I didn’t have a clue what was going on. For the most part, she seemed fine.

The neurologist said, “Did you ask what the date was?” I hadn't, so I asked the question and she did not know. Then the neurologist asked whether I had checked to see if she knew who the Prime Minister of Canada was. Again, I had not asked, and when I did, she thought she knew the answer but was wrong. 

The neurologist then said, “This is called Alzheimer's disease. I think it's going to be very common in the future. You had better go and learn about it.” 

It was a very provocative moment for me. I remember running to the library to find out more, but to my surprise there was only a short paragraph by Alois Alzehimer, which outlined the basic characteristic features of the disease – that was it. I asked myself, how could this strange illness attack and steal the patient of elements we regard as intrinsically human? Their ability to remember, to think and to reason were essentially lost, and yet they maintained the ability to walk around, feed themselves, and do many other such things. It was completely unfair. 

Over the years, I received more training; first in internal medicine, then in neurology. I soon realized that Alzheimer’s disease was not as rare as had previously been suggested. In fact, it was actually quite common. My curiosity led me to a charismatic neurologist from the Department of Medicine and Neurology in Toronto called Donald Crapper McLachlan. He was also investigating the illness, and it was here that I realized there were some genetic cases that nobody seemed to be following up. 

Most of the field at the time was interested in the composition of proteins that accumulated in the brain called amyloid and tau, which contribute to amyloid plaques and neurofibro tangles. These were elements that Alois Alzheimer had detailed when he described the illness in the early 1900s. I thought this was a clever pursuit, but it didn’t really answer the overarching mystery of why it happens. I reasoned that if we found that the cause was a defective gene, then we could work forward to understand how that gene causes the illness and leads to the accumulation of amyloid, and so on.

Working out the genetic roots of the illness became my priority. It turned out there was a group at Harvard looking for genetic markers using recombinant DNA technology. Though their research focused on Huntington's disease, I asked whether I could use the same idea to root out the cause of Alzheimer's. Eventually, this pursuit revealed that chromosome 21 was the amyloid precursor protein gene. However, we soon realized that it only described a small proportion of families with familial forms of Alzheimer’s, meaning there must be other genes. 

Using increasingly sophisticated methods to map and clone the genes of various different loci, we identified the apolipoprotein E in collaboration with Allen Roses, and after that, we discovered the presenilin-1 and presenilin-2 genes. These specific genes are enzymes that cut the protein made by the amyloid precursor protein gene on chromosome 21 to produce amyloid β-peptide (Aβ). Suddenly, we had a real understanding that if a person has a mutation in either of those two genes, plaques would develop and lead to Alzheimer's disease.

We were one of the first groups to show that immunizing transgenic mice, which carried a human APP gene and an illness similar to human Alzheimer's disease, would essentially remove or prevent the formation of the amyloid pathology and improve their cognition. This was the starting point. Now, we're interested in about 12 different genes focused on the role of microglia, which are cells in the brain that remove infectious agents and toxic proteins. Research suggests that mutations in these genes negatively impact the microglia and prevent the clearance and protective function. Personally, I believe manipulating the immune and neuroinflammatory aspects of this disease will be the second therapeutic avenue of approach.

You’ve said that fighting this disease “is more complex than battling cancer.” Why is Alzheimer’s such a difficult area of drug development?

The therapeutic options against cancer are multitudinous. You can attack cancer in various ways, biopsy a physical target, and understand its cellular makeup. With Alzheimers – up until very recently – even the first step of understanding the disease was difficult because the diagnostic tools were quite vague. 

Understanding when someone has dementia is clear, but as there are many different causes it’s difficult to be sure a patient has Alzheimer's disease. This is becoming better understood with improved biomarkers, but one of the reasons early vaccine trials failed is probably because people were recruited using poor diagnostic criteria. Getting clean cohorts where you know what participants have, and you know what you are treating, remains a challenge in many clinical trials.

Furthermore, Alzheimer’s disease has many different causes, including both genetic and environmental. Researchers must account for the problem of inhomogeneity in cohorts, and the likelihood is that some treatments may work for certain types of Alzheimer's disease but not others. On top of this, there are also numerous stages of the disease, with various components that can go wrong. For example, you could target the amyloid, but if tau or inflammation is already present without treatment, it may self perpetuate. Simply put, even if you have successfully engaged in the target you intended, you may not have stopped other aspects of the disease.

Finally, Alzheimer’s is a chronic disease and there is probably a 10 or 15-year preclinical period where the disease progresses without patient awareness from a functional point. By the time the patient requires treatment, they usually have a lot of existing damage, and providing an optimal treatment at that stage is unideal.

Ultimately, the diagnostic difficulties and the multiplicity of the disease process makes it a much more intractable target than cancer. At present, you must follow a large patient population for six to 12 months to see cognitive changes, and these factors together result in highly expensive clinical trials. This is a huge barrier to developing treatments without notable risk.

Where do you think the priorities need to lie – in both academia and industry – if we are to see a real change in treatments for neurodegenerative diseases?

There’s a shared understanding in both academia and industry that treating the disease is dependent on early detection. In fact, there is currently a huge emphasis on developing appropriate biomarkers to do this.

First and foremost, I'm a great fan of the pharmaceutical industry – they achieve things no academic or small biotech company could ever do. However, understanding the very basic aspects of Alzheimer’s disease is where you’re going to generate new insights and targets. We all understand that microglia are misbehaving; we all understand that tau is accumulating; we understand that A beta Tdp43 alphaCNuclean are accumulating. What we don't understand is how they all link together. Understanding what links one to the other, and how to break up those interactions, is going to be very expensive, but ultimately profitable, for the pharmaceutical company – as well as the basic science. In essence, funding is at the crux of everything, and Alzheimer’s is no different.

More positively, ongoing trials from the DIAN (Dominantly Inherited Alzheimer Network) study are approaching people with mutations in single genes (i.e., presenilin, AVP, or TREM2). Their research targets preclinical carriers for treatment and I am excited to learn whether treating just the APP aspects of the disease will be successful.

The Dominantly Inherited Alzheimer's Network (DIAN) study’s efforts, led by Washington University School of Medicine in St. Louis, consist of a long-term observational study that aims to identify the biological changes that occur in the development of Alzheimer's disease to improve early diagnosis and to track progression of the disease. The work is conducted in multiple countries around the world and involves researchers, clinicians, genetic counselors, individuals and families, all of whom can connect with each other via the DIAN Expanded Registry and/or through participating research sites for clinical trials or an observational study. 

The trial will compare the changes that occur in participants with and without mild Alzheimer's symptoms, who may or may not have an Alzheimer's genetic mutation. All results will be stored in the DIAN Central Archive, an international database that allows qualified researchers to access and analyze the information.

What are the most promising therapeutic avenues for interventions or preventive strategies?

There are new cellular models being developed around organoids, assembloids, IPSCs, and mixed models, which require the basic fundamentals of science to be married with application-based science. I think this could be transformative. Indeed, even if we are successful in treating patients in the disease process, there will be people that have a certain amount of injury to the brain. Therefore, parallel work done on repair, whether through the implantation of new cells, or by retraining networks is equally important.Another noteworthy suggestion includes developments coming to the fore from basic neurobiology that focus on transcriptomics or omics. 

What is your view on emerging treatments that target amyloid beta? 

The development and progression of A beta antibody treatments show two things: 1) It may be possible to accelerate the removal, or prevent the accumulation of neurotoxic proteins; and 2) A beta is, in fact, a central player in the disease.

In my opinion, these developments validate the immune approach. It suggests that A beta is a reasonable target and can motivate other strategies for treating the amyloid aspect. However, antibodies alone are insufficient; they can only slow disease progression. Combination treatment, therefore, seems to be the most viable avenue to target different parts of the disease. 

Lecanemab has perhaps established a minimum threshold. If you can do better, you'll probably get registered. Whether it will be a viable therapeutic or prophylactic remains to be seen – and it is quite expensive. However, it is definitely a significant milestone. 

Aside from his usual Alzehimers research endeavors, Peter is also one of 12 esteemed panel members for the third edition of the BIAL Foundation's international award. This year's installment – focused on Biomedicine breakthroughs –  is now underway, with nominations open until June 30. The award carries a €300,000 prize in recognition for work of a broad biomedical nature with exceptional quality and scientific relevance published in the last 10 years.

Candidates for this international award may be nominated by members of the Jury, members of the Scientific Board of the BIAL Foundation, previous BIAL Award winners, scientific societies, boards or deans of medical faculties, heads of leading research institutes, and boards or heads of prestigious academies. Highly qualified researchers may also nominate works, though self-nominations will not be accepted. Visit BIAL's website for more information.

Why do you think the BIAL Awards are so important?

The BIAL Awards are different from many other mainline prizes. Rather than focusing on an individual or individuals, they are focused on a single discovery – which is paradigm shifting from an entire team, not just the senior or last author. This is unique as it celebrates the same degree of excellence of a single moment in time.

Within science, early on in your career you are often faced with the realization that what you are doing is very hard. You will definitely ask yourself, “Why am I doing this?” and the critical culture can make it easy to feel discouraged. So, awards and recognition are highly valuable. It shows that someone is listening and appreciating your work, which I think is absolutely essential to keep people in science.

What qualities do you think are essential for a researcher or a scientist?

Generally speaking, there are three qualities I believe to be particularly important.

  1. Curiosity. This is necessary to motivate you beyond the grain of current understanding, to resist status quo, to persevere, and ultimately fuel your desire to learn more about a selected research topic.
  2. Resilience. There's a joke that research contains the prefix “re” because you keep re-doing things until you find the right answer, and I think that's true. You need to be resilient because many of your questions, approaches, or attempts will fail. But with failure, there is eventually success. It is important to be able to bounce back, and to find new solutions to complex problems.
  3. Creativity. Researchers with the capacity to think outside the box, set aside dogma, and resist following the field in pursuit of innovatory explanations are at the core of what it means to be a scientist.
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About the Author
Jamie Irvine

Associate Editor on The Medicine Maker

I write for the diverse audience of the pharma industry, covering everything from exciting research coming out of academia, to new facility announcements, and more. I'm particularly interested in cell and gene therapeutics, as well as the societal impact of medicinal drug development.

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