Study Identifies Impact of Parkinson Disease Variations on Progression Risk


Patients with the GBA mutation of Parkinson disease (PD) were shown to exhibit more severe cognitive decline than patients with idiopathic PD and those with both the GBA and LRRK2 G2019S mutations of PD.

Patients with Parkinson disease (PD) who have the GBA genetic mutation may be prone to more severe cognitive decline than patients with idiopathic PD and those with both the GBA and LRRK2 G2019S variants, according to study findings published last week in JAMA Network Open.

As 2 common genetic forms of PD, GBA and LRRK2 have been hypothesized to have a combined deleterious association with disease pathogenesis. “These are consistent with limited clinical reports suggesting earlier age at onset of PD and increased penetrance in carriers of LRRK2/GBA,” noted researchers.

Although, prior cross-sectional analyses have conversely presented a milder disease course for patients with both variations when compared with those with GBA PD alone, including less severe motor symptoms, less dementia, and less severe nonmotor features.

Expanding on these findings, the researchers conducted a longitudinal cohort study evaluating the association of LRRK2 G2019S and GBA variants with cognitive and motor decline in PD.

They recruited 1193 patients with PD (mean [SD] age, 66.6 [9.9] years; 490 [41.2%] women), who were classified by mutation or type of PD:

  • LRRK2 PD (n = 155): mean (SD) age, 68.4 (9.2) years; mean (SD) duration of motor symptoms at baseline, 8.3 (6.5) years
  • GBA PD (n = 128): mean (SD) age, 64.8 (9.7) years; mean (SD) duration of motor symptoms at baseline, 6.9 (5.9) years
  • LRRK2/GBA PD (n = 21): mean (SD) age, 65.7 (9.0) years; mean (SD) duration of motor symptoms at baseline, 6.0 (6.7) years
  • Idiopathic PD, patients who have neither the GBA or LRRK2 mutations (n = 889): mean (SD) age, 66.5 (10.0) years; mean (SD) duration of motor symptoms at baseline, 5.5 (4.9) years

Each participant was examined on the rate of decline observed in Montreal Cognitive Assessment (MoCA) and Movement Disorders Society-Unified Parkinson Disease Rating Scale–Part III scores, determined via linear mixed effects models with PD duration as the time scale.

Participants included those who were and were not of Ashkenazi Jewish descent, which increases the risk for both LRRK2 and GBA variants. The mean (SD) duration of study participation was 2.85 (1.43) years.

Among the study cohort, patients with GBA PD exhibited faster estimated rates of decline in MoCA than patients with LRRK2/GBA PD (B [SE], −0.31 [0.09] points/y; P < .001), LRRK2 PD (B [SE], −0.33 [0.09] points/y; P < .001), and idiopathic PD (B [SE], −0.23 [0.08] points/y; P = .005).

Moreover, patients with GBA PD had significantly worse motor progression compared with those with idiopathic PD (B [SE], 0.49 [0.22] points/y; P = .03) or LRRK2 PD (B [SE], 0.77 [0.26] points/y; P = .004).

There was no difference in rate of cognitive change between participants with LRRK2 PD and those with LRRK2/GBA PD (B [SE], 0.01 [0.07] points/y; P = .85), which researchers say indicates that the LRRK2 variant may prove dominant when paired with the GBA variant, except for cases of severe GBA mutation.

A LRRK2 G2019S and GBA interaction in MoCA decline was observed when including severe GBA variations (B [SE], 0.22 [0.11] points/y; P = .04), but not without (B [SE], 0.12 [0.11] points/y; P = .28).

“However, the biological basis of a dominant association or interaction is not clear and is apparently contrary to basic investigations,” concluded researchers. Study of a larger cohort of individuals with severe GBA variation is warranted.”


Ortega RA, Wang C, Raymond D, et al. Association of dual LRRK2 G2019S and GBA variations with Parkinson disease progression. JAMA Netw Open. Published online April 21, 2021. doi:10.1001/jamanetworkopen.2021.5845

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