The 100-Foot Ladder to Tackle Global Alzheimer’s

60% of the 55 million families affected by Alzheimer’s globally live in low- and middle-income countries—yet the vast majority of genetic research on the disease has been limited to westerners.

The Davos Alzheimer’s Collaborative, a new effort to tackle Alzheimer’s globally, aims to change that. DAC, formed last January and incubated by the World Economic Forum, marks the first major effort to improve understanding of dementia and Alzheimer’s disease worldwide, with a 6-year budget of $750 million and a global coalition of scientists, researchers, and health systems.

“You can’t scale a 100-foot wall with ten 10-foot ladders—you really need a 100-foot ladder,” says former US NIH director Elias Zerhouni of early efforts to build collaborative programs to tackle Alzheimer’s. Zerhouni realized that many people were doing many different things, but none of them at scale. That knowledge heavily informed DAC’s foundational pillars.

Zerhouni, a professor emeritus of Johns Hopkins University, and George Vradenburg, DAC’s chair, share takeaways from DAC’s first, proof-of-concept year, and what’s ahead.

How has the lack of genetic diversity in clinical trials impeded research so far?

EZ: It’s amazing to see that in the same family, or the same population—patients with basically the same genetics—some develop the disease, others don’t, pointing to differing genetic drivers of disease.

But you can only analyze these differences if you compare populations with different genomic bases—to determine what’s background versus what’s the disease—to find aggravating and protective genes. That understanding is essential to attacking a disease like Alzheimer’s. [It’s] very much like what happened with the 1948 Framingham Heart Study. Over a period of ~70 years, we learned that cholesterol had a role, then smoking, hypertension, and so on. That’s what I’m hoping for here—that we’ll understand the different classes of Alzheimer’s [and] how to slow down and stop the disease.

The diversity and inclusion elements are a clear-eyed scientific imperative, not just a nice, let’s-all-come-together feature.

What can you tell us about plans for the first Alzheimer’s clinical trial in Africa?

GV: In Africa, we’re working with a cohort that has done clinical trials on malaria and HIV, but this would be the first neurological disease trial in Central Africa. We’re exploring that, and we have a company that’s putting forward a drug to be tested.

EZ: So far, we’ve taken pilot cohorts around the world and tested whether or not we can use polygenic risk scores to identify the right population, use blood tests that can be sterilized, and genomic testing that can be standardized across the world. To scale across the world, first you need a foundational phase—to find the people, to standardize the algorithms, to capture the data in a standardized form.

What countries are involved in the pilot, and how were they chosen?

GV: We’re working with health systems in 6 different countries to see how they introduce biomarker and testing capabilities into normal clinical practices, so that we can distinguish who should get which medicine, at what stage of disease.

We chose those countries for their diversity, but also, it was a question of who put up their hands to participate: Brazil, Jamaica, Mexico, Scotland, Japan, and the US. We’ll add 6 more countries next year, including China. As we learned with COVID, it’s one thing to get the vaccine, it’s another to get it into people’s arms. How do you do that, if you don’t talk to health systems at the same time as you’re talking to the discovery scientists?

How can pharmaceutical companies can be incentivized to include LMICs in their plans for diagnostics and treatments?

GV: This is a very large, prevalent disease, so there’s natural incentive to try and serve that population. But it’s very costly and very complicated. We hope to simultaneously reduce the cost, and the time, of developing drugs—and get other governments and other populations involved. We can entice pharmaceutical companies by establishing a clinical trial network with good clinical practices and regulatory excellence. That’s what we did with HIV drug development, with the NIH’s Warp Speed COVID vaccine trial—but you can’t do it unless you pre-position the talent and rigorous approaches.

EZ: To make sure that major companies are attracted, we need to make sure that we are attractive in the context of rigorous clinical trial conduct—that’s what we’re trying to accomplish. It’s essential that we work with pharmaceutical companies. We want to encourage companies from the world over, not just the US or Europe, to come together in the search for a cure or disease-modifying approach.

How has COVID-19 changed your approach?

EZ: Surprising and disappointing to me was the fact that in 2003 we had SARS, and we developed a global pandemic preparedness plan. And then we had H1N1, then MERS. It’s not that COVID came as a total surprise to many—but the world didn’t take it seriously. We don’t want the Alzheimer’s response to suffer similarly from a lack of foresight, planning, and collaboration.

GV: The growth of Alzheimer’s prevalence is as predictable as it can get. This is not one we’re going to be surprised by. Shame on us if we know what’s coming over the next 30 years, and don’t do anything. And, the cost to the globe in the next 10 years is a predictable $20 trillion.

EZ: From the lack of COVID-19 preparedness, we saw the need for a forward-looking strategy. From the COVID-19 response, we saw what works: convergence of talents from government, academia, and industry. But it’s not perfect. We’ve vaccinated 80% of the people in the North—and just 2% in the South. COVID has been a great revealer of strengths—but also weaknesses.

Are new drugs the best hope for addressing Alzheimer’s?

EZ: Testing and diagnostics are important, not just therapeutics. By the time the disease is established, the damage is essentially done—it’s much easier to manage if we intervene early. We know that if we delay the loss of cognitive function by 5 years, we reduce the burden of the disease by 50%—keeping a person healthier for a longer period of time.

GV: There are 4 drugs now aimed at early Alzheimer’s, to slow the disease. Biogen’s Aduhelm has been approved; it’s controversial, but right behind it are other companies with stronger, potentially safer drugs. But out of all the cognitively normal people in the world, how do you identify those who will actually develop Alzheimer’s? So, detection and testing is the first need; then you can test drugs, slow the disease down, and potentially get to the point of vaccines.

EV: I don’t want to create false expectations—but I believe that we will learn so much in 10-15 years that we will be able to start to intervene. Just like the Framingham study: It took about 10 years to get the initial results—and then 2 years later, the drugs. That would be the dream.