How and why some brains resist Alzheimer's disease symptoms

Alzheimer’s disease typically manifests with noticeable cognitive decline, but some individuals defy this expectation, showing no symptoms despite having the disease.

This intriguing phenomenon raises a vital question: how do certain individuals maintain their health well into old age, free from Alzheimer’s symptoms?

Factors like genetics, lifestyle, and environment certainly play a role, but recent research sheds new light on this resilience.

Typical symptoms of Alzheimer’s disease

Alzheimer’s disease presents a range of symptoms that gradually worsen over time. In the early stages, memory loss becomes noticeable, particularly with recently learned information.

The person struggles to remember important dates or events and increasingly relies on memory aids. They may repeatedly ask the same questions and need frequent reminders.

As the disease progresses, individuals experience confusion and disorientation, often getting lost in familiar places.

They have trouble understanding visual images and spatial relationships, which may affect their ability to read, drive, or judge distances. They may lose their sense of smell and/or taste.

Alzheimer’s patients find it difficult to make decisions and solve problems, and they may withdraw from work or social activities.

They experience changes in mood and behavior, becoming suspicious, depressed, fearful, or anxious. Communication becomes challenging as they struggle to find the right words, follow conversations, or engage in discussions.

In advanced stages, Alzheimer’s patients require full-time care as they lose awareness of their surroundings and the ability to perform basic tasks like dressing, eating, and using the bathroom independently. They may experience changes in sleep patterns, wandering, and episodes of aggression or agitation.

Identifying Alzheimer’s cases with no symptoms

Researchers Luuk de Vries, Joost Verhaagen, Dick Swaab, and Inge Huitinga explored this mystery using brain tissue from the Netherlands Brain Bank, a unique repository housing brain tissue from over 5,000 deceased donors, complete with precise neuropathological diagnoses and detailed medical histories.

Among the samples, the researchers identified a rare subgroup of individuals who had Alzheimer’s disease processes in their brains but showed no clinical symptoms during their lifetimes.

This group, termed the ‘resilient’ group, challenges our understanding of Alzheimer’s.

“What is happening in these people at a molecular and cellular level was not clear yet. We therefore searched for donors with brain tissue abnormalities who did not show cognitive decline in the Brain Bank,” Luuk de Vries explained.

“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,” he continued.

Role of lifestyle in resilience

Research suggests that lifestyle factors significantly impact the delay of Alzheimer’s disease onset. Regular exercise, cognitive activity, and social engagement all contribute positively.

Moreover, individuals in cognitively demanding jobs may accumulate more Alzheimer’s pathology before exhibiting symptoms.

Understanding the molecular basis of this resilience could pave the way for developing medications that replicate these protective processes in Alzheimer’s disease patients.

Key findings in gene expression

The team’s analysis revealed several altered processes in the resilient group. Notably, their astrocytes produced more of the antioxidant metallothionein.

Astrocytes, which act as the brain’s garbage collectors, play a protective role, but they often enlist the help of microglia, which can exacerbate inflammation.

In the resilient group, a microglia pathway commonly linked to Alzheimer’s was less active.

Moreover, the resilient individuals exhibited a relatively normal “unfolded protein response,” which removes misfolded toxic proteins, unlike Alzheimer’s patients.

Indicators also suggested an increase in mitochondria in their brain cells, enhancing energy production.

Future of Alzheimer’s disease research

These findings are promising but raise further questions about causality. Determining whether these processes initiate the disease or are a response requires more research, particularly through cell or animal model experiments.

As Luuk de Vries noted, “It remains difficult to determine from human data which process initiates the disease process. You can only demonstrate this by changing something in cells or animal models and seeing what happens next. That is the first thing we have to do now.”

Understanding the molecular and cellular mechanisms behind this resilience could pave the way for new treatments or even vaccines, offering hope to millions affected by Alzheimer’s disease.

The full study was published in the journal Acta Neuropathologica Communications.

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