A gene-by-physical activity interaction may affect cognitive decline among patients with early Parkinson disease (PD) who are carriers of apolipoprotein E4, according to study findings discussed in a letter published in Neurology.

This study was motivated by observational data that linked physical activity with reduced risk for PD and a reduction in cognitive decline progression. Previous data indicated that mice with PD that were carriers of apolipoprotein E4 exhibit increased swim speeds and exploration times after treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

To explore the relationship between activity and PD, Kim et al. assessed patients with early PD for self-reported physical activity and cognitive decline over a 2-year period. The study investigators observed carriers of apolipoprotein E4 had a more pronounced decline in cognition than nonapolipoprotein E4 carriers.

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Carriers of apolipoprotein E4 who had high levels of physical activity, however, appeared to have cognitive decline mitigated by their physical activity.

The authors of this letter speculated that these results may indicate physical activity could be a valuable tool for delaying PD progression.

Additional studies are needed to determine whether exercise may be incorporated into personalized treatment plans. These future studies should include more comprehensive assessments of cognition such as those quantifying cognitive injury and should incorporate physical activity monitoring via wearable devices. A more broad genetic analysis is needed to assess whether additional genetic mediators are involved in this apparent gene-by-physical activity interaction.

If these observations are replicated among other independent cohorts of patients with PD, it may be possible to moderate cognitive decline associated with other neurodegenerative disorders with physical activity. An expansion of the study of physical activity in other neurodegenerative disorders should be considered.

The letter authors concluded that this study may have uncovered a promising new avenue for personalized treatment plans that aim to delay cognitive decline among patients with PD.


Raber J, Darweesh SKL, Savica R. Physical activity may reduce apolipoprotein E4-associated cognitive decline in Parkinson disease. Neurology. Published online March 31, 2021. doi:10.1212/WNL.0000000000011851