To Prevent Parkinson's Disease, We Need New Biomarkers

By Andrea Pfeifer, cofounder and CEO, AC Immune

The approval of the first disease-modifying treatments for Alzheimer’s disease (AD) marked a significant landmark in transforming the way we address neurodegeneration. Can this progress in AD be extended to Parkinson’s and other neurodegenerative diseases driven by proteinopathies? I am convinced that it can.

Clinical trials in AD provided the first evidence confirming that targeting pathological endogenous proteins in the brain can slow neurodegenerative disease progression. With a significant volume of data demonstrating that earlier intervention is better, clinical trials have now shifted toward biomarker-defined early-stage and preclinical populations. In other words, the goal now is to intervene when positive biomarker screening detects proteinopathies, well before irreversible and debilitating clinical symptoms appear.

Patients with Parkinson’s disease (PD), the second most common and the fastest-growing neurodegenerative disorder, are still waiting for a truly effective treatment. Current treatments, such as levodopa, manage symptoms, but they lose effectiveness over time and often cause side effects like involuntary muscle movements called dyskinesias.

Following in the footsteps of AD, emerging PD therapies increasingly target underlying mechanisms, such as the hallmark protein α-synuclein, to block or clear the toxic clumps that drive neuron loss in PD. Other approaches address mitochondrial dysfunction and gene-specific pathways.

PD research also is undergoing a similar transformation toward prevention and prodromal intervention — and we have an opportunity to apply what we learned in AD research to improve the chances of success in PD.

Our work will depend on development of new multimodal biomarker sets that detect disease in prodromal and very early phases, track biological change over time, and differentiate between a true slowing of progression and mere symptomatic benefit.

Current tools are too insensitive, late-stage, or nonspecific to support this shift to early precision intervention. The success of truly disease-modifying and preventive therapies will depend on having validated PD-specific biomarkers, recognized as standard clinical measures, that can identify at-risk individuals and measure biological response. Fortunately, work on identifying and developing these tools is underway.

Eyes On The Target

PD is caused by the loss of dopamine-producing neurons in the brain, leading to motor symptoms like tremors, rigidity, bradykinesia, and postural instability, as well as non-motor issues such as cognitive decline and sleep disturbances.

Those symptoms remain the cornerstone of diagnosis. Yet, by the time symptoms are evident and diagnosis is made, a large fraction of dopaminergic neurons has already been lost and there is less substrate left to protect. In short, it is already too late.

The first challenge in developing therapies that can slow or stop PD before symptoms fully appear is identifying patients early enough when the disease is at the earliest stages. There is a starting framework, with patient advocacy organizations and drug sponsors already validating PD biomarkers in clinical studies, including the α-synuclein seed amplification assay (αSyn-SAA).

Genetic studies in autosomal dominant PD and from autopsy studies in idiopathic PD show clearly that α-synuclein misfolding and aggregation are the molecular drivers for PD and other α-synucleinopathies, including dementia with Lewy bodies and multiple system atrophy (MSA).

Under physiological conditions, α-synuclein exists in an equilibrium between cytosolic and membrane-bound states and appears to be either unfolded or to adopt a coil-shaped alpha helical structure. In a disease state, however, α-synuclein can misfold, and this leads to aggregation of the protein. In PD, the aggregated species of α-synuclein accumulate in the brain. These aggregates interfere with synaptic function, are toxic to neurons, and can be released into the extracellular space and spread to neighboring cells. This seeding and spreading of α-synuclein potentially drives disease progression.

The Michael J. Fox Foundation's Parkinson's Precision Medicine Initiative (PPMI) study showed in 2023 that αSyn-SAAs can identify early PD, and rule out PD, with a high degree of accuracy. Based on those data, the FDA issued a Letter of Support in 2024 to encourage drug developers to use αSyn-SAAs for patient selection in clinical trials. These tests are not approved for use as diagnostics, but they are commercially available for research use.

The PPMI study is also following the evolution of numerous biomarkers over the natural course of PD progression, which has led to the identification of several that are correlated with worsening disease.

Additionally, a public-private project, launched in 2024 and led by the Foundation for the National Institutes of Health, aims to identify biomarkers associated with PD and includes GSK, Sanofi, and Denali Therapeutics.

This is good progress, but we still need a greater range of widely used and validated biomarkers. Several α-synuclein-targeting therapies, including active immunotherapies, are already in clinical trials in early PD, but assessing these treatments in presymptomatic populations will hinge on biomarkers that can detect biological change before clinical endpoints.

Here, too, the research is making strides, but there is much more to learn about how to measure and interpret these new markers.

Different Biomarkers, Different Behaviors

In AD, the most direct biomarkers use tracers to measure the amounts of toxic amyloid β or tau in the brain via positron emission tomography (PET) imaging. Interpreting changes in amyloid β is relatively straightforward: Aggregates accumulate with disease progression, so a decline in PET signal is evidence of disease modification.

There are PET tracers in development to measure α-synuclein in the brain, and these are very promising but still early-stage. So, in clinical trials of agents targeting α-synuclein in early PD, we look at α-synuclein in cerebrospinal fluid (CSF) as a direct measure of target engagement.

Data from the PPMI study show that in established disease, total α-synuclein in the CSF decreases over time as PD progresses. It is postulated that pathological α-synuclein becomes trapped in the brain as it aggregates and cannot migrate into the CSF, as it does under physiological conditions.

Therefore, in clinical trials of therapies targeting α-synuclein, stabilization of α-synuclein levels in the CSF suggests that aggregation is slowing and/or that existing aggregates are being cleared from the brain.

We also look for evidence that damage to neurons is slowing or stopping by using neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). The PPMI study has shown that, as PD progresses, each of these markers increases. Conversely, dopamine transporter (DaT) SPECT, which measures dopaminergic transport in neurons, decreases as disease progresses.

The damage indicated by these markers is irreversible. Once the neurons are gone, we cannot get them back. Thus, in the setting of PD, stabilization of these measures in clinical trials is an encouraging signal of disease modification.

Looking at these biomarkers in a little more detail helps to show why a comprehensive framework for systematic validation and combination assessments is vital.

NfL is a highly sensitive and reliable biomarker for neuroaxonal damage and is increasingly relevant to help distinguish PD from atypical Parkinsonian syndromes, such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS), and to stratify patients by likely progression rate. Its non-specificity means it will likely serve as part of a multimodal panel rather than a stand-alone diagnostic or monitoring marker.

GFAP reflects astrocytic activation and neuroinflammation and is being explored as a marker of more aggressive courses or co-pathology. In future prevention or early-intervention trials, GFAP may help identify individuals with more rapid cognitive or motor decline who could benefit most from disease-modifying therapies.​

As the name suggests, DaT SPECT imaging detects loss of dopamine transporters, which drop by 50% or more before classic PD tremors or stiffness fully appear. It rules out non-PD causes like essential tremor or medication side effects but cannot distinguish PD from similar disorders like MSA or PSP.

Each of these markers on its own can tell us some important information — but they are hugely more powerful when assessed systematically in combination.

Collaborative And Coordinated Action

Developing and validating robust biomarkers requires large longitudinal cohorts, standardized assays, and regulatory qualification, which no single group can deliver alone.

Collaborative efforts across industry, regulators, patient groups, academic centers, foundations, and other stakeholders are essential to set biomarker performance standards, share data, and validate markers as drug development tools suitable for trial enrichment, surrogate endpoints, and regulatory decision-making. This is why efforts such as those of the Michael J. Fox Foundation and the Foundation for the National Institutes of Health are so important.

This will enable standardization across clinical trials and clearer assessments of which modalities, and which specific treatment candidates, have the greatest potential.

If we can collaborate to achieve this, we will open a new paradigm in how we address PD. Ultimately, these tools should enable us to identify at-risk individuals before any symptoms — even prodromal ones — appear. And the dream of precision prevention of this devastating disease will become reality.

About The Author:

Andrea Pfeifer is cofounder and CEO of AC Immune, a clinical-stage Swiss biotech developing precision prevention therapies for neurodegenerative diseases including Alzheimer’s and Parkinson’s. It has three active immunotherapies in clinical development, including ACI-7104, targeting α-synuclein and being investigated in the Phase 2 VacSYn trial.