Understanding the Pattern of Cognitive Decline in GBA1-Related Parkinson's Disease: An Exploratory Longitudinal Multi-Cohort Study

GBA1

Heterozygous pathogenic GBA1 variant as a risk factor for accelerated cognitive decline in Parkinson's disease

Parkinson's disease patients carrying a pathogenic GBA1 variant are at higher risk of cognitive impairment, but the pattern and evolution of that decline remained poorly described. This longitudinal multicohort study, described as exploratory by the authors, standardized neuropsychological assessments across 546 healthy controls, 903 non-carrier patients and 211 carriers from the PPMI, ABC-PD and NCER-PD cohorts. Carriers performed worse in executive function, attention, visuocognitive skills and memory at baseline, with a more rapid and widespread decline and an increased risk of clinically relevant cognitive impairment. Processing speed and visuoperceptual function were affected earliest, respectively 1.2 and 2.5 disease years before non-carriers; a rapidly declining subgroup was more often male, reported depressive symptoms and carried a severe GBA1 mutation.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The clinically useful result is the timing: knowing which domains decline first, and how far ahead, helps target neuropsychological assessment in carriers rather than announcing an overall risk. The authors themselves call the analysis exploratory, trajectory subgroups are derived post hoc, and the three cohorts have heterogeneous follow-up durations. Variant severity as a risk modifier deserves confirmation in a dedicated sample.

Analysis by Dr Thibaut Benquey