Why Multi-target Therapies Are More Effective than Single-target Drugs for Neurodegenerative Diseases

Neurodegenerative diseases are complex and involve multiple underlying mechanisms. Because of this, targeting a single protein or pathway may not be sufficient to effectively treat these conditions. Many patients with cognitive impairment experience overlapping protein deposits, as seen in conditions like Alzheimer’s and Parkinson’s diseases. These diseases are defined as the buildup of misfolded proteins, such as β-amyloid, tau, and α-synuclein, in the brain.

Dr. Jon B. Toledo, an assistant professor of neurology, specializes in studying Lewy body disease, Alzheimer’s, and the intersection of neurodegenerative and non-neurodegenerative disorders.

The fact that multiple protein deposits can occur in a single patient has led researchers to explore whether therapies that target multiple targets simultaneously could be more effective than traditional approaches that focus on a single target. Dr. Toledo provided his insights on this topic. 

Q: Are multi-target therapies more effective than single-target drugs for neurodegenerative diseases?

A: Neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease are complex, with frequent prevalence of co-pathologies. Phosphorylated tau, amyloid β, α- synuclein, and TDP-43 (TAR DNA-binding protein 43) deposits often coexist in older adults and dramatically worsen outcomes by interacting synergistically, accelerating cognitive decline, increasing dementia risk, and shortening lifespan. A single-drug approach will likely prove insufficient to stop cognitive decline. On the other hand, multi-target therapies offer a broader span, synergistic therapeutic effects, higher efficiency, and potentially safer profiles. By targeting various disease mechanisms simultaneously, they aim to slow disease progression and improve symptoms.

Q. Are there examples of clinical trials evaluating therapies that target more than one disease-related protein simultaneously?

A: There are emerging examples of clinical trials evaluating therapies that target more than one disease-related protein. One example is the Alzheimer’s Tau Platform trial led by researchers at the University of California, San Francisco, which will start recruiting this year. This study is designed to test whether combining therapies that target both amyloid-β and tau can slow the trajectory of disease progression more effectively than targeting either pathology alone. Another example is the DIAN‐TU‐001 Tau NexGen trial which is a more advanced trial. This one is testing patients with autosomal dominant Alzheimer’s disease using a combination of anti-amyloid and anti-tau therapy.

Q. Are researchers increasingly interested in combination therapies for Alzheimer’s disease?

A: There is a growing recognition that Alzheimer’s disease involves multiple interacting pathological processes. Amyloid-β accumulation is thought to occur early in the disease cascade, while tau pathology correlates more closely with neuronal injury and cognitive decline. Since these proteins contribute to different stages of the disease process, targeting both simultaneously can potentially provide a more comprehensive therapeutic strategy. Overall, a greater number of clinical trials are now evaluating drug combinations rather than singular agents.

Q. What lessons could combination therapy trials provide for future neurodegenerative disease research?

A: Neurodegenerative diseases are biologically heterogeneous. Because of this, combination trials provide an opportunity to evaluate whether targeting several disease pathways simultaneously can produce a greater clinical impact, relative to single-target therapies. These trials also highlight the importance of biomarker-driven patient characterization. As the field moves towards more personalized approaches to therapy, this type of biological stratification will likely become significant. Additionally, combination trials can also clarify the relative contribution of different pathologies to disease progression.

For further information on neurodegenerative diseases and Dr. Toledo’s work on this topic, please see the following papers: