Alzheimer's disease can be asymptomatic. How is that possible?

Each person ages differently, and the process is influenced by factors such as genetics, lifestyle and environment. Some people live to be 90 or even 100 years old in good health, without medications or brain disease. But how do these people maintain their health as they age?

Luke de Vries from Joost Veraagen's group, as well as his colleagues Dick Swaab and Inge Huitinga, examined the brain at the Netherlands Brain Bank. The Netherlands Brain Bank stores brain tissue from more than 5,000 deceased donors with a wide range of different brain diseases.

What makes the Netherlands Brain Bank unique is that in addition to storing tissues with very precise neuropathological diagnoses, they also store a documented medical history and a detailed clinical course with symptoms for each donor.

Stable group

The team found a subgroup of people who had Alzheimer's disease processes in their brains, but did not show clinical symptoms during their lifetime. This is the so-called “stable” group. But how is it possible that they did not experience any symptoms while others did?

Luke de Vries explains: “What is happening in these people at the molecular and cellular level has not yet been clear. Therefore, we looked for donors with brain tissue abnormalities who did not have cognitive decline in the Brain Bank. Of all the donors, we found 12, so this is a rather rare case. We think that genetics and lifestyle play an important role in resistance, but the exact mechanism is still unknown."

“Exercise or cognitive activity and having lots of social contacts may help delay the onset of Alzheimer's disease. It has also recently been found that those who receive a lot of cognitive stimulation, such as through demanding jobs, may accumulate more Alzheimer's pathology before symptoms appear.

“If we can find the molecular basis of resistance, then we will have new starting points for the development of drugs that could activate the processes associated with resistance in Alzheimer's patients,” adds de Vries.

Infographic: "Alzheimer's disease without symptoms. How is this possible?" Author: Netherlands Institute of Neuroscience

Alzheimer's disease versus resistant group

“When we looked at gene expression, we saw that several processes had changed in the resistant group. First, astrocytes appear to produce more of the antioxidant metallothionein. Astrocytes are like scavengers and serve a protective role for the brain. Astrocytes often also ask microglia for help, but because they can be quite aggressive, they sometimes exacerbate inflammation,” continues de Vries.

“In the resistant group, the microglia pathway, which is often associated with Alzheimer's disease, appeared to be less active. In addition, we saw that the so-called “misfolded protein response,” a reaction in brain cells that automatically removes misfolded toxic protein, was impaired in Alzheimer's patients but was relatively normal in resistant individuals. Finally, we found indicators that the brain cells of resilient people may have more mitochondria, leading to better energy production."

But what do these differences in processes mean? And are they cause or effect?

“It is difficult to determine from human data which process initiates the disease. This can only be demonstrated by changing something in cells or animal models and seeing what happens next. That's the first thing we need to do now,” says de Vries.

The results were published in the journal Acta Neuropathologica Communications.