Association of Physical Activity and APOE Genotype With Longitudinal Cognitive Change in Early Parkinson Disease

Abstract

Objective:To determine whether greater physical activity could modify the negative association of APOE ε4 with longitudinal cognitive changes in early Parkinson’s disease (PD) and to uncover the disease-specific mechanism for explaining such benefits of physical activity.Methods:We used data from the Parkinson’s Progression Markers Initiative cohort. Because self-reported physical activity, measured by the Physical Activity Scale of the Elderly, was initiated at 2 years after enrollment, this longitudinal analysis was based on assessments performed at years 2, 3, and 4. Cognitive function was measured annually with the Montreal Cognitive Assessment (MoCA). Dopamine transporter (DAT) imaging was performed at years 2 and 4. We assessed the interactive associations between physical activity and the APOE ε4 allele on the longitudinal changes in MoCA scores and striatal DAT activities.Results:A total of 173 early PD patients (age 63.3±10.0 years; 27% APOE ε4 carriers) were included. The APOE ε4 allele showed a steeper rate of cognitive decline than the non-APOE ε4 allele (estimate -1.33; 95% CI, -2.12 to -0.47; p=0.002). However, there was a significant interaction between physical activity and APOE ε4, such that higher physical activity was related to slower APOE ε4-related cognitive decline (estimate 0.007; 95% CI, 0.003 to 0.011; p=0.001). No significant interaction was found between physical activity and the APOE ε4 allele regarding the change in striatal DAT activities.Conclusion:Increased physical activity attenuated APOE ε4-related vulnerability to early cognitive decline in PD patients. This protective effect did not appear to be mediated by striatal dopaminergic function.Classification of evidence:This study provides Class II evidence that increased physical activity was associated with decreased APOE ε4-related early cognitive decline in PD patients.

Long-term Effect of Regular Physical Activity and Exercise Habits in Patients With Early Parkinson Disease

“…Previous observational studies have preferentially focused on the effect of baseline physical activity levels and have shown that high baseline exercise habits and regular overall physical activity levels are associated with better clinical course of PD over a few years. 13 - 17 Therefore, we were initially surprised by our observation that not their baseline level but the maintenance of their level is the key factor associated with better clinical course of PD over a longer period of time. However, given the gradual decline in physical activity levels in patients with PD ( Figure 1A ) and the reported gradual decline in the effectiveness of interventional exercise, 43 , 44 it seems quite plausible that the focus should be on a sustained increase in exercise and regular physical activity levels to improve long-term clinical outcomes.…”

“…It remains possible that we have overlooked some of effects of regular physical activity if it has different effects on different genotypes, as suggested by a recent important observational study showing the interaction effects among regular physical activity, APOE genotype, and global cognitive function. 17 …”

“…Previous observational studies have shown that not only exercise habits but also overall regular physical levels at baseline are associated with slower motor and cognitive decline over a few years. [14][15][16][17] However, again, the short follow-up period and the lack of sufficient adjustment of confounding factors remain important issues. Therefore, no reliable conclusions have yet been drawn regarding the longterm disease-modifying effects of exercise and high daily physical activity levels in patients with PD.…”

Lower Circulating Lymphocyte Count Predicts ApoEε4‐Related Cognitive Decline in Parkinson's Disease

“… 4 Inspired by these observations, we aimed at assessing whether low lymphocyte count is associated with the subsequent development of the key milestones in PD's disease course, specifically cognitive impairment, with a particular attention to the apolipoprotein E (ApoE) ε4 allele, a crucial modifying factor in cognitive impairment. 5 , 6 …”

Plasma MIA, CRP, and albumin predict cognitive decline in Parkinson’s Disease

“…11,12,13,14,15 Extracellular-vesicle-associated tau and amyloid β42 have also been reported to correlate with cognition in PD. 16 Additionally, genetic variants have been linked to cognitive trajectory in PD, 17,18,19 with the most well-replicated effects on cognition seen for the APOE E4 allele 20,21,22,23 and PD-associated GBA variants. 17,24,25,26 Studies to date, however, have limitations that hamper translation of biomarkers of PD cognitive decline into clinical contexts.…”