Physical Frailty Shows Association With Incident Parkinson Disease, Modified by Genetic Risk

Chen Liangkai, PhD

Findings from a prospective cohort study of middle-aged and older adults followed up for 12 years showed a higher rate of new-onset incident Parkinson disease (PD) in those with physical prefrailty or frailty. Additionally, this association was modified by the genetic risk of PD, where the highest risk of PD was observed in those with frailty and high genetic risk.

To the authors knowledge, this was the first large prospective study assessing the longitudinal association between frailty and the incidence of PD and exploring the genetic interaction in such association. Among a final cohort of 314,998 participants, investigators found that prefrailty and frailty were associated with a 26% (HR, 1.26; 95% CI, 1.15-1.39) and 87% (HR, 1.87; 95% CI, 1.53-2.28) increased risk of PD, respectively.

Senior investigator Chen Liangkai, PhD, Department of Nutrition and Food Hygiene, Huazhong University of Science and Technology, and colleagues assessed physical frailty through the Fried criteria. This included 5 domains of weight loss, exhaustion, low physical activities, slow walking speed, and low grip strength. The polygenic risk score (PRS) showed the association between genotype and risk of PD by score points and was composed of 44 single-nucleotide variants (SNVs).

During a mean follow-up of 12.3 years, 1916 PD cases were documented. After adjustment for covariates, the absolute rate differences per 100,000 person-years were 1.6 (95% CI, 1.0-2.3) for prefrailty and 5.1 (95% CI, 2.9-7.3) for frailty compared with non-frail participants. Those with prefrailty and frailty were more likely to be older and female, more deprived, and current smokers, and had higher body mass index and more long-term morbidities than those with nonfrailty.

When looking at the subdomains of the Fried criteria, full adjusted models showed that exhaustion (HR, 1.41; 95% CI, 1.22-1.62), glow gait speed (HR, 1.32; 95% CI, 1.13-1.54), low grip strength (HR, 1.27; 95% CI, 1.13-1.43), and low physical activity (HR, 1.12; 95% CI, 1.00-1.25) were significantly associated with incident PD, while the null association was observed for weight loss. Notably, there was a positive linear association between the accumulative number of frailty components and the incidence of PD (P for noninferiority = 0.79), with an HR increasing by 21% (95% CI, 1.15-1.27) each additional component of the frailty phenotype.

"Frailty phenotype, such as slow gait speed, may also associate with the function of the brain and muscle through the vascular system, which often influences the cerebra and muscles when aging and cognitive impairment is associated with cerebral vasculature as well," Liangkai et al wrote. "As for exhaustion, the nigrostriatal pathway is a possible way to link frailty and PD, as it is the basic pathological mechanism of PD and related to the regulation of exercise fatigue."

There was an positive association of PD-PRS tertiles with the risk of PD, as those with frailty and the highest tertile of PRS had the highest risk of PD (HR, 3.22; 95% CI, 2.35-4.41) relative to those with nonfrailty and the lowest tertile of PRS. When using frailty as a reference, those with nonfrailty had decreased risk of incident PD by 43% (HR, 0.57; 95% CI, 0.39-0.84), 55% (HR, 0.45; 95% CI, 0.32-0.65) and 42% (HR, 0.58; 95% CI, 0.42-0.79) in low-, intermediate-, and high-PRS groups, respectively.

The study authors wrote, "Our results suggest that improvement of physical frailty would benefit individuals even with a high genetic risk of PD.” They added, “integrating frailty assessment into the primary prevention of PD may favor the identification of high-risk individuals."

REFERENCES
1. Zheng Z, Lv Y, Rong S, Sun T, Chen L. Physical frailty, genetic predisposition, and incident Parkinson disease. JAMA Neurol. Published March 13, 2023. doi:10.1001/jamaneurol.2023.0183