Alzheimer’s without symptoms: unraveling the mystery

Everyone experiences aging in their own way, with factors such as genetics, lifestyle and environment playing a role in this process. Some individuals reach 90 or even 100 years of age, in good health, without medications or brain disease. But how do these individuals maintain their health as they age?

Luuk de Vries from Joost Verhaagen’s group and his colleagues Dick Swaab and Inge Huitinga examined brains from the Dutch brain bank. The Netherlands Brain Bank stores brain tissue from more than 5,000 deceased brain donors with a wide range of different brain diseases. What makes the Dutch brain bank so unique is that in addition to stored tissues with highly accurate neuropathological diagnoses, it also keeps the documented medical history and detailed disease course with symptoms of each donor.

Resilient group

The team found a subgroup of people who had Alzheimer’s pathological processes in their brains, but showed no clinical symptoms during their lifetime. A so-called “resilient” group. But how is it possible that they didn’t experience any symptoms while others did?

“What is happening in these people at the molecular and cellular level is not yet clear,” de Vries explained. “We therefore searched the brain bank for donors with brain tissue abnormalities and without cognitive decline. Out of all the donors, we found 12, so it’s quite rare. We believe that genetics and lifestyle play an important role in resilience, but the exact mechanism is still unknown. »

Keep challenging yourself

“Exercising or being cognitively active and having plenty of social contact can help delay the onset of Alzheimer’s disease. It has also recently been discovered that those who receive a lot of cognitive stimuli, for example in complex work, may develop more Alzheimer’s pathology before developing symptoms. If we can find the molecular basis of resilience, then we will have new starting points for the development of drugs that could activate resilience-related processes in patients with Alzheimer’s disease.

Alzheimer’s disease without symptoms. How is it possible? Credit: Netherlands Institute for Neuroscience

Alzheimer’s group versus resilient group

“When we looked at gene expression, we found that a number of processes were altered in the resilient group,” de Vries said. “First, astrocytes appeared to produce more of the antioxidant metallothionein. Astrocytes are like garbage collectors and play a protective role for the brain. Astrocytes often also ask microglia for help, but because they can be very aggressive, they sometimes make inflammation worse. In the resilient group, a microglial pathway often linked to Alzheimer’s disease appears to be less active.

In addition, we found that the “unfolded protein response,” a reaction in brain cells that automatically eliminates a misfolded toxic protein, was affected in Alzheimer’s disease patients but was relatively normal in individuals resilient. Finally, we found indicators that there may also be more mitochondria in the brain cells of resilient individuals, ensuring better energy production.

But what do these differences in processes mean? And is there a cause or an effect?

“It remains difficult to determine from human data which process triggers the disease process. You can only demonstrate this by changing something in cells or animal models and seeing what happens next. This is the first thing we need to do now.

Reference: “Gene expression profiling of Alzheimer’s disease-resilient individuals reveals higher expression of genes related to metallothionein and mitochondrial processes and no change in the protein response deployed” by Luuk E. de Vries, Aldo Jongejan , Jennifer Monteiro Fortes, Rawien Balesar, Annemieke JM Rozemuller, Perry D. Moerland, Inge Huitinga, Dick F. Swaab and Joost Verhaagen, April 25, 2024, Acta Neuropathology Communications.
DOI: 10.1186/s40478-024-01760-9