Solving the Alzheimer’s Puzzle

Plenty of exercise, an active social life, a balanced diet, mentally stimulating hobbies, being well educated and having a high socioeconomic status – these factors can all help lower the risk of Alzheimer’s disease. However, each one affects the brain differently, and their impact varies from one person to the next.

Lack of physical activity, for example, can lead to the accumulation of harmful proteins that characterize Alzheimer’s disease, such as beta-amyloid and tau. An active lifestyle, on the other hand, influences the brain’s functional networks and helps preserve cognitive abilities.

Sex is a central characteristic underlying these differing effects, according to Valerie Treyer, who co-leads the UZH Center for Prevention and Dementia Therapy at the Institute for Regenerative Medicine (IREM). She and her colleague Anton Gietl have conducted several studies showing that protective factors like exercise, along with risk factors related to metabolic or cardiovascular function, have different effects on men and women.

This means that studies on Alzheimer’s risk need to be evaluated differently according to sex. “When we analyze our data, we have to use different statistical models so that the different effects on women and men are taken into account,” notes Treyer.

The research team sees these separate analyses for men and women as an initial step towards personalized prevention strategies that effectively reduce Alzheimer’s risks. However, this approach still has to account for a range of other factors. “In the end, whether or not a person develops Alzheimer’s is always determined by a combination of many individual factors,” explains Gietl.

Gietl, a geriatric psychiatrist and clinical lead of the research group, is involved in a prevention program at the University Hospital of Psychiatry Zurich that places heavy emphasis on patients’ personal life circumstances. Without addressing patients’ specific needs and strengths, he says, effective prevention is hardly achievable.

Even if people exhibit clear pathological indicators of Alzheimer’s, it doesn’t necessarily mean that cognitive impairment is inevitable. Many elderly people over age 80 can live independently, drive a car and maintain a high overall quality of life, even with severe plaque deposits in the brain.

“It seems that there are mechanisms that neutralize, offset or reduce the effect of plaque accumulation on cognitive function,” explains Treyer. “That’s what we mean when we talk about cognitive reserve.”

In a study of people aged 84 to 94, the researchers found that consistent healthy activities during youth have a positive effect on later cognitive abilities. This applies especially to executive functions such as organizing or planning tasks, which are essential for independence in day-to-day life.

“This means that Alzheimer’s prevention measures aimed at promoting healthy lifestyles should start as early as possible,” says Treyer. For this to work, it is important to identify people at high risk of Alzheimer’s before any cognitive decline sets in.

The immune system may be crucial in this regard. In one study, the team’s neuroimmunologist, Christoph Gericke, found evidence that a certain kind of immune cell becomes more numerous when amyloid deposits are present in the brain. This happens even if no cognitive decline has set in.

In another study, the group found two blood markers that can be combined with targeted cognitive assessments to improve detection of people at increased risk of cognitive decline. “We hope that our findings will improve the planning and implementation of clinical trials, especially in prevention research,” says Gietl.

These many different approaches show that Alzheimer’s research often feels like a puzzle: different areas of expertise are needed to understand how the individual pieces fit into the overall picture. For this reason, the research group brings together a wide range of field-specific knowledge, from imaging and neuroimmunology to statistics and clinical practice.

It’s not only this multidisciplinary approach that sets the team apart. They’re also notable for a longitudinal study in which they’ve been monitoring participants aged 50 to 89 over the course of a decade. These individuals showed either no cognitive problems at the start or the study, or only minor impairments.

With its long time frame, the study makes it possible to track changes that can lead to Alzheimer’s disease. At the same time, factors indicating an elevated risk for developing the disease can be identified at an early stage – allowing for early detection of at-risk groups and early influence on how the disease progresses.

The researchers are confident that prevention delivered at the right moment can make a big difference – with lower costs and minimal risk. “However, if the disease has already set in, it can usually only be delayed with current therapies, but not reversed,” says Treyer. Successful prevention depends on a complete picture that draws on findings from multiple studies, not just individual pieces of the puzzle.