Arfan Ikram is a professor and head of the Department of Epidemiology at Erasmus MC. Since 1 August 2022, he has also served as chair of ZonMw and a member of the Executive Board of the Dutch Research Council (NWO). Ikram’s research focuses on the interactions between genetics, lifestyle, and brain diseases, with an emphasis on brain health, ageing, and dementia.

The wonder

“Do you remember tackling a difficult maths problem at secondary school, the kind that really made you think hard? That intellectual challenge drives me. It’s the desire to discover something, to see patterns that no one has seen before.

“When I worked as a radiologist in the clinic, I sometimes dealt with complex cases. I did get a kick out of solving those puzzles, but I noticed it didn’t give me the same sense of satisfaction I saw in my colleagues. As a researcher, you can focus on questions that truly motivate you, rather than waiting for problems to come your way.

“During my PhD in 2007, a new analysis technique emerged called genome-wide association studies. Instead of examining one gene at a time, it became possible to analyse genetic variations across an entire genome on a large scale. That was revolutionary.

“In the field, there had been occasional speculation that head size might be relevant to dementia. A larger cranial capacity is associated with greater brain volume, which could have a protective effect against Alzheimer’s. But there wasn’t much evidence to support this, and the subject didn’t attract much attention – certainly not in connection to genetics. My colleagues didn’t see the value in applying the new technique to head size, but I decided to go ahead with it.”

The research

“I set up a consortium where we collected DNA from over ten thousand people. At the time, that was a huge sample size. We analysed each participant’s DNA for millions of genetic markers – small variations in the DNA. I then linked this data to cranial capacity and Alzheimer’s disease.”

The eureka moment

Afran Ikram 2_Eureka_Hilde Speet
Image credit: Hilde Speet

“I vividly remember sitting at my computer in the old EE tower of Erasmus MC, running the analysis. One gene variation showed a very strong link to head size – a variation in the tau gene. This gene codes for the tau protein, which is one of the proteins that accumulates in Alzheimer’s patients. Inside brain cells, the tau protein becomes tangled, causing the cells to lose their structure and die. So, I had found the link between genetics, head size, and dementia, including Alzheimer’s.

“In that moment, I realised I was the first person in history to know that the tau gene plays a role in cranial capacity. For an entire afternoon, I was the only person in the world with that knowledge. I thought: ‘This is the discovery, this is what I do this for.’”

The result

Afran Ikram 3_Eureka_Hilde Speet
Image credit: Hilde Speet

“The discovery raised a lot of questions. In younger individuals, the tau gene has little impact on brain function, though it does have a small measurable effect on cranial capacity, as far as we can tell. Later in life, the effect of tau gene variations on the brain becomes more apparent. Whether this has a protective role or increases the risk of Alzheimer’s is still unclear. But it is one of the strongest genetic signals influencing head size, brain development, and Alzheimer’s risk.

“It’s also interesting that this gene variant is predominantly found in people of Caucasian descent and much less so in people of Asian or African descent. That needs further investigation as well. If we can understand how the tau gene is involved in brain development, we may be able to better predict why some people are more vulnerable to neurological conditions.

“The research field was ready for this discovery. If I hadn’t done this study, someone else would have within six months. It’s like feeling the first raindrop: someone has to be the first, but the rain would have come anyway. Yet in academia, the person who feels that first drop is often rewarded and celebrated. That’s not how it should work. My greatest reward was that eureka moment.”

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