Novel Genetic Loci Linked to Cognitive Decline in Parkinson's Disease

No existing therapy slows the progression of Parkinson's disease (PD) from motor to cognitive symptoms, and the pace of progression to dementia varies considerably between patients. This heterogeneity has made it hard to determine the efficacy of PD drugs in clinical trials.

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The International Genetics of Parkinson's Disease Progression Consortium has linked five genetic loci to PD dementia (PDD) and devised the first polygenic score for predicting whether a patient with PD will have an aggressive course. Clemens R. Scherzer, MD, director of the Laboratory for Neurogenomics at Massachusetts General Hospital, served as senior author of the group's research letter in Nature Genetics.

Study Cohorts

The researchers performed a genome-wide survival study of 11.2 million variants in 3,821 patients with PD who were prospectively tracked in 31,053 visits in North America or Europe for up to 12 years. They assigned 2,650 patients to the discovery population and 1,171 patients to the replication population.

Novel Loci

• RIMS2—In an analysis that combined the discovery and replication populations, the lead variant rs182987047 showed a hazard ratio of 4.77 for progression to PDD (genome-wide significance, P=2.78 × 10⁻¹¹). RIMS2 is involved in the docking and priming of presynaptic vesicles, and the knockout of RIMS2 in mice leads to critical defects in memory
• TMEM108—The rs138073281 variant was associated with HR of 2.86 (P=2.09 × 10⁻⁸) in the combined analysis. TMEM108 has been implicated in synaptic spine formation and cognition
• WWOX—The rs8050111 variant was associated with HR of 2.12 (P=2.37 × 10⁻⁸) in the combined analysis. WWOX is mutated in autosomal recessive ataxia with mental disabilities and epilepsy, and it has been associated with Alzheimer's disease

Confirmation of Previously Identified Prognostic Loci

• GBA—Patients carrying a pathogenic mutation for Gaucher's disease or protein-coding variants in GBA that previously have been associated with PD had HR of 1.93 for PDD (P=0.0002)
• APOE—Patients carrying the ε4 allele had HR of 1.48 (P=0.001)

MMSE Scores

Meta-analyses of serial Mini Mental State Exam scores confirmed that for each variant, carriers had significantly more rapid cognitive decline than non-carriers.

Susceptibility Variants Not Linked to Cognitive Decline

The researchers created a polygenic risk score (PRS) that aggregated 90 susceptibility variants for PD. Unexpectedly, they found no association between that score and PDD. Furthermore, when considered individually, none of the 90 variants predicted PDD or motor progression.

Polygenic Hazard Score for Progression to Dementia

The team then used the five loci to develop a polygenic hazard score (PHS) to predict PDD:

• The PHS was significantly more accurate than chance (P=2.68 × 10⁻²²) or the PRS (P=0.0009) in estimating whether a patient would develop dementia within 10 years from disease onset
• 90% of patients with PHS of 0 remained free of dementia for 10 years after the onset of PD, compared with 73% whose score was in the highest quintile
• The association of the PHS with PDD was replicated in three independent cohorts (EPIPARK, De Novo Parkinson Cohort and HBS2)

A New Paradigm for Drug Development

The PHS could be used to enrich trials with patients who have a more aggressive disease course and are therefore likely to experience the greatest benefit. Because dementia is one of the most debilitating manifestations of PD, disease-modifying drugs that target genetic loci of PDD and turn fast progressors into slow progressors, would substantially improve quality of life.

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