The Temporal Order of Genetic, Environmental, and Pathological Risk Factors in Parkinson Disease

Dr. Margarita Fedorova outlines how genetic, environmental, and pathological factors interact in Parkinson's disease and what this means for patient counseling.

Show citation:

Blauwendraat C, Morris HR, Van Keuren-Jensen K, Noyce AJ, Singleton AB. The temporal order of genetic, environmental, and pathological risk factors in Parkinson's disease: paving the way to prevention. Lancet Neurol. 2025;24(11):969-975. doi:10.1016/S1474-4422(25)00271-6

Show transcript:

Dr. Margarita Federova:

Welcome to Neurology Minute. My name is Margarita Fedorova, and I'm a neurology resident at the Cleveland Clinic. Today we're exploring a framework for understanding how genetic, environmental, and pathological factors interact in Parkinson's disease and what this means for how we counsel our patients.

A personal view paper by Blauwendraat and colleagues, published in The Lancet Neurology in September 2025, addresses a critical question. We've identified over 100 genetic loci for Parkinson's, but how do they act?

The common saying is genetics loads the gun and environment pulls the trigger, but this paper suggests the relationship may be more complex. The key tool here is alpha-synuclein seeding amplification assays or SAAs.

These detect misfolded alpha-synuclein protein in cerebrospinal fluid. Over 90% of Parkinson's patients test positive for misfolded alpha-synuclein using this assay. But here's what's notable. 2% to 16% of neurologically healthy older adults also test positive with prevalence increasing with age.

This means there are more asymptomatic people with detectable alpha-synuclein pathology than people with actual Parkinson's disease. Most of these asymptomatic individuals will never develop symptoms. This raises an important question. What determines who converts to a disease and who doesn't?

By integrating SAA results with genetic data, researchers can examine whether genetic factors drive initial protein misfolding or whether they modulate the response to pathology triggered by environmental or random events.

Preliminary data suggests polygenic risk scores don't strongly associate with SAA positivity in healthy older adults. In other words, people with high genetic risk for Parkinson's aren't necessarily more likely to have misfolded alpha-synuclein if they're healthy.

This suggests most Parkinson's genetic risk factors may not be causing initial misfolding. Instead, they may be determining what happens afterward, such as whether the pathology progresses to clinical disease.

LRRK2 mutations support this model. About 33% of LRRK2 related Parkinson's patients are SAA-negative compared to only 7% in sporadic disease. This means many people with LRRK2 mutations develop Parkinson's without the typical alpha-synuclein pathology.

LRRK2 mutations also show varied pathology. Sometimes alpha-synuclein, sometimes tau, sometimes neither. This suggests LRRK2 may modulate responses to different initiating events rather than directly causing protein misfolding.

What does this mean for us as clinicians? Asymptomatic SAA-positive individuals could represent a window for intervention. If we can understand what protects them from converting to disease or what triggers that conversion, we could enable earlier identification of at risk individuals and potentially intervene before symptoms develop.

The authors call for large scale studies using SAAs in older populations, combined with genetic analysis and longitudinal follow-up. By integrating pathological biomarkers with genetic and environmental data, we can better understand the temporal sequence of events in development of Parkinson's.

This approach could fundamentally change how we think about disease prevention and early intervention, potentially allowing us to identify at risk individuals before symptoms appear and develop targeted prevention strategies.

That's your neurology minute for today. Keep exploring, and we'll see you next time.

If you want to read more, please find the paper by Cornelis Blauwendraat et al titled The Temporal Order of Genetic, Environmental and Pathological Risk Factors in Parkinson's Disease: Paving the Way to Prevention, published online in September 2025 in Lancet Neurology.