• Physical activity may reduce the risk of Alzheimer’s disease and all-cause dementia and slow age-related cognitive decline.
• Aging and neurodegenerative conditions, such as Alzheimer’s disease, have associations with increased inflammation in the brain.
• Animal studies have shown that physical activity may lead to cognitive benefits by reducing the activation of microglial cells, the primary immune cells in the brain.
• A new study involving older adults reports that reducing microglial activation may help support the protective effects of physical activity on cognitive functioning.

A decline in certain cognitive abilities, such as memory and attention, is typical with aging. However, some individuals may experience dementia, which involves a severe decrease in cognitive abilities that impair daily functioning.

Studies show that individuals who exercise regularly have a lower risk of Alzheimer’s disease and all-cause dementia. Moreover, physical activity can slow down the progression of cognitive decline.

Scientists do not fully understand the mechanisms through which physical activity produces these cognitive benefits in humans.

A recent study led by researchers at the University of California San Francisco (UCSF) shows that reducing inflammation in the brain may mediate the cognitive benefits of physical activity.

Specifically, the researchers found that physical exercise had associations with reduced activation of microglia, the primary immune cells in the brain.

The study’s co-author, Dr. Kaitlin Casaletto, a professor at UCSF, told Medical News Today, “Many studies show that physical activity relates to better brain and cognitive health (e.g., estimates indicate that inactivity alone accounts for 13% of Alzheimer’s disease cases worldwide). Yet, we still do not fundamentally understand the mechanisms linking physical activity to cognition in humans. Our study is the first human data showing that microglial activation (“brain inflammation”) may be a meaningful mechanism.”

The study appears in the Journal of Neuroscience.

Physical activity and microglia

The nervous system consists of two major cell types: neurons and glial cells. Neurons are primarily involved in transmitting electrical and chemical signals, whereas glial cells protect and support neurons. More recently, scientists have discovered that glial cells can modulate signal transmission between neurons.

Animal studies suggest that the glial cells in the brain may mediate the beneficial effects of physical activity on cognitive function. Specifically, physical activity is known to alter the activity of microglia, a sub-type of glial cells.

Microglia are the brain’s immune cells and become activated in response to an infection or neuron damage.

Activation of microglia can benefit the immune system as it mounts an inflammatory response against an infection. But an abnormal increase in the activation of microglia can damage neurons.

Chronic low-grade inflammation in the brain is a characteristic of aging and neurodegenerative disorders such as Alzheimer’s disease. Moreover, studies show that these conditions involve an abnormal increase in the number of activated microglia in the brain.

Scientists know that physical exercise in animals reduces the activation of microglia and other brain markers of inflammation.

Microglia can also modulate the structure and function of synapses, which are specialized contact sites through which neurons communicate with each other. Microglia play an important role in the formation and elimination of synapses.

Moreover, they can modulate the strength of these synapses, thus influencing signal transmission between neurons.

Studies in animals show that the cognitive benefits of physical activity have associations with improvements in synaptic health or integrity. Furthermore, these studies suggest that microglia may mediate the effects of physical activity on synaptic integrity and cognitive function.

The present study investigated the relationship between physical activity and microglial activation in older adults. Given the association between physical activity and improvements in cognitive function and synaptic health, the study estimated the extent to which changes in microglial activity may support these effects of physical activity.

The study found that, as in animals, physical activity had associations with reduced microglial activation in older adults. Moreover, the study’s results suggest that reduced microglial activation could be one of the brain pathways through which physical activity protects individuals from cognitive decline, especially in Alzheimer’s disease.

Measuring physical activity

The present study consisted of 167 deceased individuals enrolled in the Rush Memory and Aging Project (MAP). The Rush MAP is a longitudinal study that aims to identify risk factors associated with the development of Alzheimer’s disease.

The Rush MAP includes older adults without dementia at enrollment and involves annual assessments for dementia risk factors. The participants in the project had agreed to donate their brains and other organs for post-mortem analysis.

The present study consisted of individuals with an average age of 87 years at the time of the first physical activity test and 90 years at their death.

The researchers assessed daily physical activity using a wearable sensor called actigraph. Actigraphy provides an objective measure of physical activity by continuously tracking periods of motor activity and rest over multiple days.

In the current study, the researchers conducted actigraphy assessments continuously for up to 10 days. They also conducted yearly tests to assess cognitive function and the ability of the participants to perform various motor tasks.

After the participants’ death, the researchers analyzed the brain tissue to determine the number of activated microglia in four brain regions. They also assessed the levels of proteins associated with synaptic health and brain markers for Alzheimer’s disease, Lewy body dementia, stroke (infarcts), and other conditions.

Physical activity and microglial activation

The researchers found that higher physical activity levels measured using actigraphy had associations with a lower proportion of activated microglia when they considered all four brain regions together.

Factors such as limited motor function and cognitive impairment could potentially restrict the ability of the participants to engage in physical activity.

Consequently, the researchers adjusted their analysis for age, sex, motor, and cognitive function. They found that the association between the proportion of activated microglia and physical activity was independent of these variables.

The researchers then examined this association in individual brain regions. They found that the association between higher physical activity levels and reduced microglial activation reached statistical significance only in two brain regions — the ventromedial caudate and the inferior temporal gyrus.

Furthermore, the relationship between physical activity and reduced microglial activation was stronger in individuals with higher levels of brain pathologies in these two brain regions.

The brain pathologies found in the ventromedial caudate and inferior temporal gyrus consisted of microinfarcts (or mini-stroke) and Alzheimer’s disease-related pathologies, respectively.

In other words, individuals with higher levels of brain pathologies who regularly engaged in physical activity showed lower microglial activation than their counterparts with similar brain pathology levels but lower physical activity levels.

These data suggest that the effects of physical activity on microglial activation were specific to certain brain regions. These results are consistent with data showing that microinfarcts and brain pathologies associated with Alzheimer’s disease tend to be more common in the two brain regions.

Association with cognition and synaptic integrity

The researchers then examined the association between microglial activation and clinically meaningful markers for dementia, namely cognition and the integrity of the synapses.

Microglial activation in the inferior temporal gyrus, but not the ventromedial caudate, had associations with a decline in cognitive functioning and lower levels of synaptic health markers.

Next, the researchers examined the extent to which reduced microglial activation associated with physical activity could improve cognition and the integrity of synapses.

Using a statistical method called mediation analysis, the researchers estimated that the decrease in the proportion of activated microglial in the inferior temporal gyrus contributed to over 30% of the effects of physical activity on cognition and synaptic markers.

Significantly, changes in microglial activation in the inferior temporal gyrus in individuals with higher levels of Alzheimer’s disease-related brain pathologies mediated more than 40% of the effects of physical activity on cognition and synaptic health.

In contrast, in individuals with lower Alzheimer’s disease-related pathologies, changes in microglial activity contributed to only 10% of the effects of physical activity.

Noting the significance of these findings, Dr. Tristan Qingyun Li said:

”This current work by Casaletto et al. is uniquely significant in that it provides the first evidence in humans to show that changes in microglial activation may be the mechanism bridging the beneficial effects of physical activity and healthier brain function. Furthermore, it points to a specific brain region, namely inferior temporal gyrus, that might be the most relevant for future microglia-based interventions.”

Dr. Li is a professor at the Washington University School of Medicine and was not involved in the study.

Study strengths and limitations

One of the study’s strengths included the use of actigraphy, which provides an objective assessment of physical activity levels. This is in contrast to other studies that often estimate physical activity levels using self-reports, which are prone to biases and inaccuracies.

This is the first human study to show that physical activity may improve cognitive functioning by reducing microglial activation.

Dr. Casaletto noted that the study had a few limitations. She said, “A major limitation of this work is the observational design. We cannot determine the directionality of effects, and it is likely that at least some of the relationship between physical activity and brain inflammation is bidirectional (i.e., brain inflammation leading to reductions in physical activity).”

Dr. Casaletto said that her research group intends to address this shortcoming in subsequent studies. She said, “We have a physical activity intervention study ongoing in which we hope to capture complementary markers of in-vivo inflammatory markers to help support causality of effects.”

Among other limitations, Dr. Casaletto noted, “We captured physical activity and cognition in life but brain inflammation and pathology at death. These are likely dynamic processes, and understanding the temporal link between lifestyle behaviors and biological changes is needed.”

Lastly, Dr. Casaletto noted that the study participants were primarily white and from Northeastern Illinois. Thus, the researchers do not know whether they can generalize the findings to a diverse population.

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