Alzheimer’s without symptoms: Unraveling the mystery

Scientists have identified a rare group of individuals with Alzheimer’s pathology but no symptoms, suggesting genetics and lifestyle as key factors in their persistence, with potential implications for new Alzheimer’s treatments. Credit: SciTechDaily.com

Everyone experiences aging in their own unique way, with factors such as genetics, lifestyle and environment playing a role in the process. Some individuals reach the age of 90 or even 100 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 looked at brains from the Brain Bank in the Netherlands. The brain bank in the Netherlands stores brain tissue from more than 5,000 deceased brain donors with a wide range of different brain diseases. What makes the Netherlands Brain Bank so unique is that, in addition to stored tissue with very precise neuropathological diagnoses, they also keep the documented medical history and detailed disease course with symptoms of each donor.

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The team found a subset of people who had Alzheimer’s disease processes in their brains, but showed no clinical symptoms while they were alive. A so-called ‘resistant’ group. But how is it possible that they did not experience any symptoms while others did?

“What is happening to these people at a molecular and cellular level was not yet clear,” explained de Vries. “Therefore we looked for donors with abnormal brain tissue who did not show cognitive decline in the Brain Bank. Out of all the donors we found 12, so it is quite rare. We think that genetics and lifestyle play an important role in resilience, but the exact mechanism is still unknown.”

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“Exercising or being cognitively active and having lots of social contact can 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 a complex job, can build up more Alzheimer’s pathology before they show symptoms. If we can find the molecular basis for resilience, then we have new starting points for developing drugs that can activate processes related to resilience in Alzheimer’s patients.”

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

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“When we looked at gene expression, we saw that a number of processes were altered in the resilient group,” said de Vries. “First of all, astrocytes appeared to produce more of the antioxidant metallothionein. Astrocytes are like garbage collectors and provide a protective role for the brain. Astrocytes often seek help from microglia as well, but because they can be quite aggressive, they sometimes exacerbate inflammation. In the resilient group, a microglia pathway often associated with Alzheimer’s disease appeared to be less active.”

In addition, we saw that the so-called ‘unfolded protein response’, a reaction in brain cells that automatically removes a toxic misfolded protein, was affected in Alzheimer’s patients but was relatively normal in resilient individuals. Finally, we found indications that there may be more mitochondria in the brain cells of resilient individuals, which provides better energy production.”

But what do these changes in processes mean? And is there cause or effect?

“It remains difficult to determine from human data which process initiates the disease process. You can demonstrate this just by changing something in cells or animal models and seeing what happens next. That’s the first thing we have 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 changes in unfolded protein response” 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, 25 Apr 2024, Acta Neuropathologica Communications.
DOI: 10.1186/s40478-024-01760-9