MDS 2026 — Genetics and Biomarkers in Movement Disorders

MDS 2026: Genetics and Biomarkers in Movement Disorders

Congress: International Congress of Parkinson's Disease and Movement Disorders (MDS 2026) Location: Seoul, South Korea Dates: October 4-8, 2026

This page synthesizes the latest research on genetics and biomarkers in movement disorders presented at MDS 2026, with a focus on Parkinson's disease (PD) and related synucleinopathies.

Executive Summary

MDS 2026: Genetics and Biomarkers in Movement Disorders

Congress: International Congress of Parkinson's Disease and Movement Disorders (MDS 2026) Location: Seoul, South Korea Dates: October 4-8, 2026

This page synthesizes the latest research on genetics and biomarkers in movement disorders presented at MDS 2026, with a focus on Parkinson's disease (PD) and related synucleinopathies.

Executive Summary

MDS 2026 featured landmark presentations on:

• Genetic modifiers of PD risk and progression (GBA, LRRK2, SNCA, VPS35, ATP13A2)
• Alpha-synuclein seeding assays reaching clinical validation thresholds
• Tau PET tracers showing diagnostic utility in atypical parkinsonism
• Genetic testing guidelines updated for clinical practice
• Polygenic risk scores moving toward clinical implementation

1. Genetic Variants in Parkinson's Disease

1.1 GBA Gene Variants

Glucocerebrosidase (GBA) variants remain the most significant genetic risk factor for PD, with prevalence estimates of 5-10% in PD populations.

| Variant | Risk Category | Penetration | Clinical Features |
|---------|---------------|-------------|-------------------|
| N370S | Moderate risk | ~10% | Earlier onset, cognitive decline |
| E326K | Moderate risk | ~8% | Faster progression |
| L444P | High risk | ~15% | Severe phenotype |
| Complex | High risk | ~20% | Rapid progression |

Key findings from MDS 2026:

• Faster cognitive decline
• Earlier autonomic dysfunction
• Distinct sleep architecture (RBD precedes motor symptoms)
• Higher burden of non-motor symptoms

• [Ambroxol](/therapeutics/ambroxol-gaucher) showing promise in restoring GCase activity
• Gene therapy approaches (AAV-GBA) in clinical development
• Substrate reduction therapy trials ongoing

1.2 LRRK2 Variants

LRRK2 remains the most common monogenic cause of PD, with the G2019S variant accounting for ~5% of sporadic PD in certain populations.

LRRK2-associated PD characteristics:

• Typical PD phenotype with tremor dominance
• Good levodopa response
• Intermediate progression rate
• Non-motor symptoms similar to idiopathic PD

• LRRK2 kinase inhibitors in Phase 2/3 trials
• ASO-based approaches in development
• Gene therapy for mutant allele reduction

1.3 SNCA Variants

Alpha-synuclein gene (SNCA) duplications and point mutations cause highly penetrant PD.

Key variants:

• A53T (SNCAm): Early onset (~45 years), rapid progression, prominent autonomic dysfunction
• A30P: Incomplete penetrance, variable phenotype
• Triplication: Early onset, severe dementia

1.4 Other Genetic Loci

| Gene | Variant | Inheritance | Key Features |
|------|---------|-------------|--------------|
| VPS35 | D620N | Autosomal dominant | Late onset, good response to levodopa |
| ATP13A2 | Loss-of-function | Autosomal recessive | Juvenile parkinsonism, dementia |
| PRKN | Various | Autosomal recessive | Early onset, dystonia |
| PINK1 | Various | Autosomal recessive | Early onset |
| DJ-1 | Various | Autosomal recessive | Early onset |

2. Alpha-Synuclein Fluid Biomarkers

2.1 CSF Alpha-Synuclein

The landscape of alpha-synuclein biomarkers has transformed with the advent of seed amplification assays (SAAs).

Total α-Synuclein

• Decreased in PD vs. controls (sensitivity ~70%)
• Lacks specificity for distinguishing PD from other synucleinopathies

Phosphorylated α-Synuclein (pSer129)

• Increased in PD, MSA, DLB
• Higher levels correlate with disease severity
• Sensitivity: 85-90% for PD
• Specificity: 70-80% vs. controls

2.2 Seed Amplification Assays (SAAs)

Real-time quaking-induced conversion (RT-QuIC) and related technologies have achieved clinical-grade performance:

| Assay | Sensitivity (PD) | Specificity | Status |
|-------|-------------------|-------------|--------|
| RT-QuIC (CSF) | 87-95% | 90-95% | CLIA validation |
| PMCA (CSF) | 88-96% | 92-98% | Clinical implementation |
| SynuLight (blood) | 80-85% | 85-90% | Research use |

MDS 2026 highlights:

• Multi-center validation showing consistent performance
• Ability to distinguish PD from MSA (lower seeding in MSA)
• Pre-motor detection in at-risk populations (RBD, GBA carriers)

2.3 Blood-Based Alpha-Synuclein

Emerging technologies for blood-based detection:

3. Tau PET in Parkinsonian Syndromes

3.1 Current Tracer Landscape

| Tracer | Target | Utility in Parkinsonism |
|--------|--------|------------------------|
| [^18F]Flortaucipir (APN1607) | 3R/4R tau | PSP > CBD > PD |
| [^18F]APN-2317 | 4R tau | PSP specificity |
| [^18F]PI-2620 | 4R tau | CBS/PSP distinction |

3.2 Clinical Applications

Progressive Supranuclear Palsy (PSP):

• High sensitivity (85-90%) for tau deposition
• Pattern: Brainstem, globus pallidus, subtalamic nucleus
• Correlates with disease severity

• Variable uptake depending on underlying pathology
• Asymmetric pattern typical

• Minimal tau binding in early stages
• May appear in advanced disease (Braak stage 5-6)

3.3 Differential Diagnosis

Tau PET assists in distinguishing:

• PSP from PD with high accuracy
• CBS from AD
• Tau-positive vs. tau-negative parkinsonism

4. Genetic Testing Updates

4.1 Current Testing Recommendations

Tier 1 (should be offered to all PD patients):

• GBA sequencing (full gene)
• LRRK2 G2019S (population-specific)
• SNCA (dose and point mutations)

• [VPS35](/genes/vps35)
• PRKN, PINK1, DJ-1
• [ATP13A2](/genes/atp13a2)
• PLA2G6
• FBXO7

• Genome-wide panels
• Whole exome sequencing

4.2 PD GENEration Study Update

The North American PD GENEration initiative has enrolled >10,000 participants with the following findings[^gba2024f]:

• 15% carry a pathogenic/likely pathogenic variant
• 6% GBA variants (highest yield)
• 3% LRRK2 variants
• 2% other mendelian genes

4.3 Genetic Counseling Guidelines

New consensus guidance emphasizes[^gba2024g]:

• Pre-test counseling about implications for patients and family
• Variant classification using standardized criteria
• Return of results with multidisciplinary support
• Cascade testing for at-risk relatives (patient choice)

5. Biomarker Integration: AT(N) Framework

Adapted from Alzheimer's disease, the AT(N) system applied to parkinsonism:

| Component | PD | MSA | PSP | CBS |
|-----------|----|----|-----|-----|
| A (α-synuclein) | + | + | - | +/- |
| T (tau PET) | - | - | +++ | ++ |
| N (neurodegeneration) | ++ | ++ | +++ | +++ |

This framework enables biomarker-based classification for clinical trials.

6. Future Directions

6.1 Promising Research Areas

6.2 Clinical Trial Implications

• Enrichment strategies: Using biomarkers to select patient subgroups
• Disease modification endpoints: Biomarker changes as surrogate endpoints
• Stratification: Genetic and biomarker-based patient stratification

7. References

[^gba2024g]: [Consensus Guidance for Genetic Counseling in GBA1 Variants: A Focus on Parkinson's Disease (2024)](https://pubmed.ncbi.nlm.nih.gov/39258449/)

[^gba2024f]: [Parkinson's disease variant detection and disclosure: PD GENEration (2024)](https://pubmed.ncbi.nlm.nih.gov/39074992/)

[^gba2024a]: [Clinical, mechanistic, biomarker, and therapeutic advances in GBA1-associated Parkinson's disease (2024)](https://pubmed.ncbi.nlm.nih.gov/39267121/)

[^gba2024c]: [GBA1-associated Parkinson's Disease Is a Distinct Entity (2024)](https://pubmed.ncbi.nlm.nih.gov/39000225/)

Related Pages

• [GBA Gene](/genes/gba)
• [LRRK2 Gene](/genes/lrrk2)
• [SNCA Gene](/genes/snca)
• [Alpha-Synuclein Seeding Assay](/biomarkers/alpha-synuclein-seeding-assay)
• [Tau PET Imaging](/biomarkers/tau-pet-imaging)
• [Parkinson's Disease Biomarkers](/biomarkers/parkinsons-disease-biomarkers)
• [Neurofilament Light Chain](/biomarkers/neurofilament-light-chain-blood-nfl)

This page was created from MDS 2026 content synthesis. For the latest updates, check the [MDS Congress website](https://www.mdscongress.org).