Exercise might help prevent cognitive decline in high-risk patients with early Parkinson’s disease (PD), new research suggests.

Investigators found PD patients who were APOE ε4 carriers had greater cognitive decline compared to non-APOE ε4 carriers, but the findings also revealed higher physical activity appeared to slow cognitive decline in this higher risk group.

“The main finding of the current study is that higher physical activity was related to slower APOE ε4-associated cognitive decline in early PD patients, which was shown to be robust in sensitivity analyses,” the researchers, led by Ryul Kim, MD, Inha University Hospital, Incheon, Korea, write.

The study was published online March 31 in the journal Neurology.

Unclear Mechanism

The APOE ε4 allele is known to be a “major risk factor” for Alzheimer’s disease (AD), but “accumulating evidence shows that this allele also has a potential role in cognitive impairment in PD,” the authors note.

Previous research shows physical activity has beneficial effects in PD, but the mechanism underlying these effects are “not well understood.” Additional data suggest physical activity modifies the APOE ε4 effect on the development and progression of AD.

“These observations led us to hypothesize that physical activity also plays a role in modulating the association between APOE ε4 and cognition in PD,” but no studies have yet reported on this interaction in PD patients, the authors note.

To investigate, they drew on data from the Parkinson’s Progression Markers Initiative (PPMI) — a cohort study conducted to identify PD progression markers.

The current analysis included 173 patients recently diagnosed with PD but not yet treated for the condition. The cohort’s mean age was 63.3 ± 10.0 years, age of PD onset was 59.4 ± 10.0 years, and 68% were male. Of these participants, 46 were APOE ε4 carriers.

Dopamine transporter (DAT) activity was assessed using imaging at enrollment, and again at years 2 and 4. Cognitive function was assessed at years 2, 3, and 4 using the Montreal Cognitive Assessment (MoCA) test.

Protective Effect

Although APOE ε4 carriers tended to be younger than noncarriers, the age of PD onset did not differ between the 2 groups, and there were also no significant differences between the groups in demographic and clinical variables.

There were larger declines in MoCA scores in the APOE ε4 carriers vs the noncarriers (0.21 ± 1.40 and 0.08 ± 1.15, respectively).

The APOE ε4 allele was associated with a “steeper” rate of cognitive decline, compared to the non-APOE ε4 allele (estimate −1.33 [95% CI, −2.12 to −0.47,
P = .002).

There was a significant interaction of physical activity, APOE ε4, and time: higher physical activity was associated with slower APOE ε4-related cognitive decline (estimate 0.007 [0.003 to 0.011, P = .001).

However, the researchers found no significant main effects of the APOE ε4 allele or physical activity on the change in the MoCA score.

“Considering that dopaminergic treatment may affect cognitive function, particularly in the early stage of PD, we additionally included the levodopa daily equivalent dose (LEDD) and its interaction with time as covariates in the model,” the investigators note.

They found that the interactive association between physical activity and the APOE ε4 allele on cognitive decline remained significant, even when participants who had normal cognitive performance at year 2 were included in the study population or when LEDD variables were included as covariates in the model.

Both high- and low-intensity exercise were significantly associated with slower APOE ε4-related cognitive decline.

There was no significant interaction between physical activity and APOE ε4 with changes in striatal DAT activities.

“Increased physical activity attenuated APOE ε4-related vulnerability to early cognitive decline in PD patients,” the authors note, adding that the effect “did not appear to be mediated by striatal dopamine activity.”

They hypothesize that physical activity may “offer a greater protective effect” on cerebral amyloid accumulation in APOE ε4 carriers. It is also possible that physical activity will counteract the negative impact of the APOE ε4 allele through improved brain mechanism and decreased neuroinflammation.

“The Next Blockbuster Drug”

Commenting on the study for Medscape Medical News, Bastiaan R. Bloem, MD, PhD, director of Center of Expertise for Parkinson & Movement Disorders, Radboud University Medical Center, Nijmegen, the Netherlands, said exercise might be seen as “the next blockbuster drug.”

Bloem, who was not involved in the study, noted there is “quite robust evidence now that exercise acts as symptomatic therapy, like a drug, alleviating sleep [disturbances], depression, constipation, and motor symptoms.”

The study “sheds new light on the idea of exercise as not only alleviating symptoms but actually as a potential disease modifier,” said Bloem, whose research has focused on the beneficial effects of a rigorous exercise program, combined with tablet-based gamificaton and a reward system in stabilizing motor symptoms in patients with PD over time.

“The reward system created additional motivation for the patients with PD who often experience depression and apathy that interfere with motivation,” he said.

The current study has important take-home messages for practicing clinicians. “Physicians should encourage exercise in patients, and patients should also take the lead themselves,” Bloem said.

“It doesn’t matter what type of exercise you do, but it should have an aerobic component, should be safe so the patient doesn’t fall down, should have enough intensity to cause the patient to pant, and should be individualized and enjoyable so the patients stick to it,” he emphasized.

Bloem noted that yoga and mindfulness are also helpful. “If we’ve learned anything from the COVID-19 crisis it’s that chronic stress is deleterious to all of us and particularly bad for people with PD because you need dopamine to be able to handle stress, and the lack of dopamine in people with PD makes them deteriorate faster.”

The study was supported by a research grant of National Research Foundation by the Ministry of Science and ICT (MSIT) in Korea. The authors and Bloem have disclosed no relevant financial relationships.

Neurology. Published online March 31, 2021. Abstract

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