by Ditsa Keren

Early Detection Of Alzheimer's Disease Can Save Your Brain, Cytox CEO Explains

Early Detection Of Alzheimer's Disease Can Save Your Brain, Cytox CEO Explains

Cytox is developing a transformational prognostic technology that assesses an individual’s risk of developing Alzheimer’s disease and aids in the development of new, more effective dementia treatments. In this interview, CEO Richard Pither outlines the genetic and lifestyle factors that affect one’s risk of developing the disease, and explains how early detection can prevent it altogether.

Please tell us a bit about yourself.

I’m the CEO of Cytox. I’ve been running the company since 2012. Originally it was a spin-out from Oxford University, and was based on academic work that started in Oxford. It has since expanded to many other academic collaborators, most notably, the University of Cardiff and University College London (UCL). We work all around the world now.

I was previously the head of R&D for General Electric (GE) medical diagnostics. I’ve been involved in Alzheimer’s disease for about 20 years. When I was introduced to Cytox technology I became quite excited about it, so I decided to leave GE and take over the helm at Cytox. Since then we’ve been developing a genetic test that can predict the risk of cognitive decline due to Alzheimer’s, from a simple saliva sample.

What can you tell us about your main product, genoSCORE?

The genoSCORE product is now available across Europe as genoSCORE-LAB, and has literally just launched in the US and Canada as the IBX Alzheimer’s Risk Test. We announced it on World Alzheimer’s Day, September 21st, so these are really exciting times for us.

Both the European and US test products are underpinned by our genoSCORE technology. It’s a polygenic risk test, which looks at over 100,000 genetic components that contribute to an individual’s risk of developing Alzheimer’s disease in the future. The test could be taken either by someone who’s got early symptoms, or by someone who’s much younger that has a concern about their genetics and whether they may be predisposed to developing Alzheimer’s disease; perhaps because they have a family member who has previously been diagnosed.

The thing about genetics is that we carry this risk from the day we’re born. Understanding that, and more importantly, understanding what you can do about it to mitigate the future risk of developing the disease, is really important, particularly in these days of preventative medicine. Early detection is absolutely critical to the optimal clinical management and treatment of those at risk of Alzheimer’s disease.

The way our test works is that we take a DNA sample through a saliva kit, either at the clinic or in the patient’s home, then send it to a reference lab that extracts the DNA from that sample, and runs the genotyping analysis. Next, we use the data from the genotyping to run the polygenic risk analysis using an algorithm that we’ve developed and validated here at Cytox, which generates the final polygenic risk score.

Within two to four weeks of receiving that sample, a report highlighting the risk of that individual goes back to the clinician for them to discuss with the patient, to understand what they should be doing about their risk profile.

We try to identify people that are at high risk of developing Alzheimer’s disease in the future so that clinicians can manage their lifestyle risks, such as high blood pressure, diabetes, lack of exercise, to delay disease progression and the onset and severity of symptoms, and maybe even offer therapeutic interventions later on.

What kind of clients do you typically work with?

Currently, we only provide our test via clinicians and not directly to consumers, because the information that we are providing is too important to just hand it to patients directly and let them live with the consequences. It has to be handled through medical professionals. For that reason, we sign up and register clinical sites as our main target audience.

Our current focus is in the US which is where we see huge levels of interest. As of recording this interview, we have 23 clinics already registered for using the test, and this is growing daily. Now that we have launched the product, we are able to start the full-scale marketing program in the US, which we are doing with our specialist sales and marketing partners.

Indeed, we have some very important commercial relationships in the US. One of them is with a company called Infinity BiologiX (IBX), which has existing accredited laboratories and significant expertise in this type of test. As such, IBX will be providing laboratory services, including sample processing, analysis using the genoSCORE technology, and reporting back to clinics.

We also work with a US company called Vanguard Pharma, which is effectively our sales and marketing division, which will introduce the test to clinicians and neurologists who see the sorts of patients who would benefit from this test. They are working with us and with IBX to develop market awareness in the US and drive the use of this test.

What are the next steps for patients with a high risk of Alzheimer’s disease?

Some very important studies over the recent years have identified several risk factors, and 12 in particular, that are associated with lifestyle and environmental risks that can be managed to reduce that component. The Lancet Commission published a report last year, which estimates that around 40% of Alzheimer’s disease could be managed through a healthy, active lifestyle, both physically and mentally.

The reason we know that lifestyle changes are effective is largely due to the work of the so-called “finger studies” conducted by Prof. Miia Kivipelto from the Karolinska Institute in Sweden. Over the last few years, Prof Kivipelto and her team have published several studies in randomly controlled cohorts which observed that those who undertook these lifestyle changes actually fared much better and had a far lower incidence of disease symptoms. Even people who entered the study with early symptoms could still be helped to maintain a highly functional lifestyle, compared to expected rates of deterioration seen in those that do not modify their lifestyles.

These practical and effective actions are not yet well understood by the public, but they are becoming more understood by clinical professionals. The motivation to understand risk at an early age is therefore becoming more compelling, as we build our understanding of how to avoid and mitigate the risks.

Alongside lifestyle changes, there is the potential of interventional therapeutics to treat Alzheimer’s, such as Biogen’s new drug, approved by the FDA back in June. Physicians are divided about the merits of that drug on the data presented to date. It’s also worth noting that the expense of the drug, about $56,000 per patient per year, raises further challenges for reimbursement. However, it is most likely that administration of this drug would be most effective in the very early stages of the disease, probably even pre-clinically, because it is designed to maintain neurons rather than replace those that have already been lost in the late stages of the disease. So the efficacy of this recently approved drug, and many more in development using similar interventional approaches, will likely be dependent upon early detection and early treatment, which is exactly what our test offers.

How can early detection change the course of Alzheimer’s disease?

I see these lifestyle interventions, at least in the near term, offering the most promise for patients. While it is good news that new drug therapies are in development and being approved, it is clear that a comprehensive suite of therapeutic interventions is still some time away.

However, with either approach, the point is that they have to happen very early in the development of the disease, ideally before symptoms appear. The evidence now is inarguable. Early intervention will have a real clinical benefit in many people. I think that is the prize, that’s why people should be interested in whether they carry an increased risk of Alzheimer’s disease because there are things that can be done to mitigate that risk and reduce the probability that they will develop symptoms.

We’ve known for a long time that Alzheimer’s disease has a strong genetic component, but it’s not genetics alone that drives the disease, it’s genetics plus lifestyle. If you can manage the lifestyle component, even those with high genetic risk could see definite benefits to their disease progression.

As you probably know, there are two forms of Alzheimer’s disease. There’s the early-onset form, which is very rare and accounts for less than 1% of the whole of Alzheimer’s disease. Early-onset Alzheimer’s disease (EOAD) occurs due to specific genetic mutations in one of three genes: the amyloid precursor protein gene, the Presenilin-1 or Presenilin-2 gene. If you inherit one of the causative mutations in those genes, you will develop EOAD. In those people, it’s a purely genetic disease, but fortunately, it’s rare.

What we’re talking about is late-onset Alzheimer’s disease, which has very complex genetics. The component that perhaps most people are familiar with is the APOE gene, which comes in several variants or alleles. If you carry the so-called APOE-4 variant, you’re considered to be at elevated risk of Alzheimer’s disease. Conversely, if you carry the APOE-2 variant, you’re considered to be at lower risk, but the APOE is not the whole story. We know that plenty of people that carry the E4 risk variant never develop Alzheimer’s disease. Conversely, about 40% of diagnosed Alzheimer’s cases do not have E4 at all.

Our test looks for about 112,000 different genetic variants that have all been linked to either increased or reduced risk of Alzheimer’s disease. We add all those variants up in a weighted algorithm to generate a single polygenic risk score, taking into account all the genetic variants that an individual carries. This gives a much more comprehensive picture of whether they’re likely to be at high genetic risk of Alzheimer’s disease or not.

How definite are polygenic risk scores?

The algorithm was originally trained in huge data sets of about 70,000 cases and controls. Then we validated performance in independent data sets. We’ve relied on something called the ADNI — the Alzheimer’s Disease Neuroimaging Initiative — which has been running for about 15 years and was set up by Prof. Mike Wiener at the University of California, San Francisco. We were able to take samples from those individuals who entered the study without symptoms or with mild cognitive symptoms and test our ability to predict an individual’s likelihood of progression. In those studies, we found an accuracy of about 84% in our ability to predict those at high risk of cognitive decline due to Alzheimer’s disease, whether they start with mild symptoms or they’re cognitively normal at the time of testing.

Many people develop mild cognitive impairment (MCI) but only about 25% of them decline to Alzheimer’s disease. For those who don’t decline, those MCI symptoms may be due to anxiety, stress, or depression. We were able to pick out with high accuracy those who went on to develop Alzheimer’s disease. This is a very accurate test from a very simple non-invasive sample. The way we see this being used is that it’s an early, upfront test to say whether someone is in the higher risk category or not. If they are, the clinician will be taking a close look at these people regularly to see whether that risk has developed into something symptomatic, which suggests that a disease process may be active. None of these tests are used in isolation, they’re all used in an overall clinical management picture.

How do you expect Alzheimer’s detection and treatment to evolve in the future?

I think there are many lessons to be learned from oncology and cancer drug development. About 25 years ago, prostate cancer, breast cancer, or liver cancer were all seen as a single disease. Now, however, through a greater understanding of the underlying genetics of cancer, we recognize that there are about 10 types of breast cancer and a similar number of liver and prostate cancer variants. Alongside that increased understanding of the genetics behind cancer, the oncology field has moved from having a single drug for every type of cancer to a much more customized, personalized spectrum of drugs, and combinations of drugs, to provide the efficacy we see today. Through this approach, we have seen many cancer patients move into long-term remission.

Similarly, in the future, Alzheimer’s disease will be seen as a multiplicity of diseases. While they all lead to the same clinical symptoms and phenotypes, we will better understand the multiple genetic variants causing the disease.

Indeed, already today if you look at the different pathways associated with Alzheimer’s, it is evident that there are at least six different forms of Alzheimer’s disease. Going forward, as drugs get more specific in their mechanisms, it’s unlikely that one drug is going to be equally useful across all those different subtypes of Alzheimer’s disease.

Where we see this moving is that there will be very specific targeted drugs that will be useful for some individuals with specific genetic characteristics, and we’ll need to be able to combine genetic stratification of people with specific drug mechanisms to be able to treat many more people in a much more personalized way.

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About Author
Ditsa Keren
Ditsa Keren

Ditsa Keren is a technology blogger and entrepreneur with a strong passion for biology, ecology and the environment. In recent years, Ditsa has been specializing in technical and scientific writing, covering topics like biotechnology, algae cultivation, nutrition, and women's health.

Ditsa Keren is a technology blogger and entrepreneur with a strong passion for biology, ecology and the environment. In recent years, Ditsa has been specializing in technical and scientific writing, covering topics like biotechnology, algae cultivation, nutrition, and women's health.