Post by Sarah Hill
What's the science?
Is the medical field ready to recommend physical activity to prevent memory loss in aging and Alzheimer's disease? A recent report from the National Academies would suggest not, citing inconsistent support from cognitive outcomes in randomized controlled trials and a need for more evidence about how long intervention benefits last. However, pre-clinical studies involving animal and human subjects have consistently demonstrated physical activity-induced memory maintenance and improvements and enhanced hippocampal structure and function. How can we make sense of these discrepancies? This week in Trends in Cognitive Sciences, Voss and colleagues weigh the evidence for and against physical activity in preventing or counteracting cognitive decline, proposing a cross-species approach to evaluate whether exercise can be recommended for memory loss in aging and dementia.
What do we know?
Thus far, several experimental studies have suggested physical activity can improve memory performance, though this depends on the type of exercise prescribed and the methods used to assess memory function. In both normal and Alzheimer's disease rodent models, voluntary wheel running and forced treadmill training appear to accelerate the generation of adult-born neurons in the hippocampus (the region in the brain associated with memory formation), leading to improvements in spatial memory and pattern separation (i.e. the ability to distinguish between similar objects/contexts). The production of new neurons in the hippocampus is particularly advantageous because adult-born neurons are more susceptible to mechanisms of learning and memory (as they become integrated into existing circuitry) and form new synaptic connections more readily than developmentally-born neurons. Physical activity-induced enhancements in spatial memory, pattern separation and wayfinding have also been observed in young and middle-aged adults, though few studies have looked at these same effects in older human subjects. How physical activity or associated changes in cardiorespiratory fitness translates to functional changes in the brain is currently an active area of research, though multiple human neuroimaging studies have shown changes in hippocampal volume and strengthened connectivity in a particular hippocampal-cortical brain network known as 'the default network' following physical activity. Taken together, these studies suggest a strong link between physical activity and improved hippocampal memory function. However, some memory processes seem to be more sensitive to aging and effects of physical activity than others. Specifically, the authors identified relational memory, wayfinding, and pattern separation as important outcomes for future study.
Though the evidence in favor of physical activity-mediated memory maintenance is relatively consistent, several questions remain. First, what are the molecular and cellular mechanisms through which physical activity exerts its neuroprotective effects? Secondly, can these signaling pathways be harnessed for use in treatment strategies or as biomarkers of cognitive improvement? Brain-derived neurotrophic factor (BDNF), a trophic factor associated with synaptic plasticity, neurogenesis and cell survival, appears to be a key player involved as it acutely increases in the bloodstream of human subjects following a single session of physical activity, and long-term elevated BDNF blood levels associate with increased hippocampal volume and default network functional connectivity. This is further supported by evidence from animal studies, whereby blockade of BDNF signaling eliminates beneficial effects of exercise on learning and memory, as well as neurogenesis. While changes in BDNF are measurable in the human bloodstream, the factor is undetectable in mouse serum or plasma and its expression levels in the rat bloodstream do not appear to change following physical activity. Identification of other central and peripheral signaling partners involved in mediating exercise effects on cognition is currently underway, with factors including VEGF, IGF-1, and AMPK additionally implicated.
The most important question under current investigation is likely what the most effective exercise regimen for eliciting improvements in cognitive function may be. A majority of studies involving human subjects showed that moderate to high-intensity exercise enhanced performance on measures of cognition known to decline in aging, particularly when cardiorespiratory fitness was improved. While cardiovascular and resistance training both associate with improved spatial learning and synaptic plasticity in a rodent model, they appear to act via different signaling pathways, with aerobic exercise upregulating hippocampal IGF-1, BDNF, TrkB, and CaMKII, and resistance training increasing peripheral and hippocampal IGF-1, as well as activating the hippocampal Akt signal pathway. Further, a recent analysis reported that multimodal training (combining elements of various types of exercise) may be more effective in strengthening episodic memory than either aerobic exercise or resistance training. Though there is clearly still much to be done in terms of identifying the ideal exercise regime, the biggest takeaway from these studies seems to be that consistency is key: for lasting improvements in hippocampal memory function to occur, physical activity that gets the heart rate up needs to be kept up with for weeks to months.
What's the bottom line?
The authors concluded that regular physical activity shows promise as a viable treatment strategy for cognitive decline. Evidence supporting physical activity-induced cognitive improvement is strongest for aerobic exercise, with a majority of studies demonstrating that exercise at or above 60% maximum heart rate (for 1 hour, 3X per week) is beneficial to areas of the brain supporting memory function. Much is still unknown with regard to physical activity and memory, and future studies are needed to uncover whether other types of exercise (such as weight training) are as beneficial as aerobic exercise, as well as how to tailor an individualized exercise regimen for maximum memory effects.
Voss et al. Exercise and Hippocampal Memory Systems. Trends in Cognitive Sciences (2019). Access the original scientific publication here.