Dementia And Physical Activity (DAPA) trial of moderate to high intensity exercise training for people with dementia: randomised controlled trial

Lamb et al.[1] report potentially negative results of exercise interventions on cognition in patients with mild to moderate dementia. This appears counterintuitive, considering the beneficial effects of physical activity in a broad range of diseases, including various chronic diseases[2] and neurodegenerative diseases[3]. To better understand the risks and benefits of physical activity, more systematic studies are necessary. These studies should assess the impact of different types of exercises and take into account the heterogeneity of dementia and the individuals’ tolerance to exercise interventions.

Physical exercise benefits health and brain function, by processes at least partially mediated via preconditioning tissues, organs or organisms to later insults. In preconditioning, a stimulus below the threshold of damage induces a tolerance against subsequent similar or different harmful stimuli[4].

This concept however, implies the necessity of a certain reserve capacity. The smaller this reserve, the more likely the preconditioning stimulus exceeds the threshold, resulting in direct damage rather than increasing tolerance. We propose that such buffering reserves may be reduced in the brain of patients suffering from neurodegenerative diseases, like Alzheimer’s disease, and should be considered when designing exercise-based intervention strategies.

Interestingly, several physiological parameters that are positively affected by regular physical activity are compromised in neurodegenerative diseases: e.g. mitochondrial function, the antioxidative defense systems, neuroinflammation and neuronal proteostasis[4 5]. We argue that loss of buffering capacities in dementia patients (such as tolerance to oxidative stress, a well-documented event in early dementia[6] and importantly affected by exercise[7]) might have been responsible for the negative effects on cognition after an intense exercise challenge as applied by Lamb et al.

The study by Lamb et al. highlights important limitations of exercise interventions in patients already affected by dementia and contributes valuable information on the effects of physical activity on dementia patients. But the approach is lacking stratification on the basis of parameters linked to tolerance to physical exercise or consideration of individual threshold levels. Given the small, albeit statistically significant, difference observed in this study, we believe it is crucial to systematically assess to what extent the intensity and type of exercise regimen and individual reserve capacity influence the effect of physical exercise on brain function at different stages of disease progression. Accordingly, submaximal (below the reserve threshold) personalized exercising routines should not be excluded as useful interventions for neurodegeneration patients, in particular if combined with other novel approaches to enhance reserve capacities in controlled ways, for instance by intermittent hypoxic-hyperoxic training[8].

Please find a supporting figure here: https://imgur.com/a/jFdA3AE

1. Lamb SE, Sheehan B, Atherton N, et al. Dementia And Physical Activity (DAPA) trial of moderate to high intensity exercise training for people with dementia: randomised controlled trial. BMJ (Clinical research ed.) 2018;361:k1675 doi: 10.1136/bmj.k1675[published Online First: Epub Date]|.
2. Kujala UM. Benefits of exercise therapy for chronic diseases. British journal of sports medicine 2006;40(1):3-4 doi: 10.1136/bjsm.2005.021717[published Online First: Epub Date]|.
3. Hoffmann K, Sobol NA, Frederiksen KS, et al. Moderate-to-High Intensity Physical Exercise in Patients with Alzheimer's Disease: A Randomized Controlled Trial. Journal of Alzheimer's disease : JAD 2016;50(2):443-53 doi: 10.3233/jad-150817[published Online First: Epub Date]|.
4. Dirnagl U, Becker K, Meisel A. Preconditioning and tolerance against cerebral ischaemia: from experimental strategies to clinical use. The Lancet. Neurology 2009;8(4):398-412 doi: 10.1016/s1474-4422(09)70054-7[published Online First: Epub Date]|.
5. Lawler JM, Rodriguez DA, Hord JM. Mitochondria in the middle: exercise preconditioning protection of striated muscle. The Journal of physiology 2016;594(18):5161-83 doi: 10.1113/jp270656[published Online First: Epub Date]|.
6. Nunomura A, Perry G, Aliev G, et al. Oxidative damage is the earliest event in Alzheimer disease. Journal of neuropathology and experimental neurology 2001;60(8):759-67
7. Radak Z, Chung HY, Goto S. Systemic adaptation to oxidative challenge induced by regular exercise. Free radical biology & medicine 2008;44(2):153-9 doi: 10.1016/j.freeradbiomed.2007.01.029[published Online First: Epub Date]|.
8. Bayer U, Likar R, Pinter G, et al. Intermittent hypoxic-hyperoxic training on cognitive performance in geriatric patients. Alzheimer's & dementia (New York, N. Y.) 2017;3(1):114-22 doi: 10.1016/j.trci.2017.01.002[published Online First: Epub Date]|.