AAN 2025: Precision Medicine and Pharmacogenomics in Neurological Care

Precision medicine and pharmacogenomics are transforming the neurology landscape, said William David Freeman, MD, FAAN, professor of neurology, College of Medicine, Mayo Clinic, during a plenary session at the 2025 American Academy of Neurology Annual Meeting, held in San Diego, California. By providing critical insights, neurological drug therapies can be optimized, and adverse events (AEs) can be minimized.

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Freeman began the presentation by emphasizing that neurology care must shift from a “one-size-fits-all” treatment mentality to a personalized approach, catering therapies to the individual patient. Precision medicine involves delivering targeted interventions based on individual molecular disease drivers. This way, patients are receiving treatments based on their genetic makeup. Additionally, revolutionizing diagnosis, treatments, and the management of one’s neurological disorders can be supported with the leveraging of genetic knowledge, biomarker development, and emergent targeted therapies, such as RNA and gene editing.

The goal of pharmacogenomics is to improve therapeutic efficacy and minimize AEs and potential side effects by moving beyond the current established “trial and error” method of treatment and instead to a genetically-informed precision prescribing. Throughout the presentation, Freeman discussed specific neurological diseases and how pharmacogenomics is key to current and future therapies.

Alzheimer and Parkinson Disease

Genetic makeup influences the therapeutic response in Alzheimer and Parkinson diseases to donepezil via APOE, ATP-binding cassette (ABC) transporter, butyrylcholinesterase acetylcholine receptor subunit α7, choline acetyltransferase, estrogen receptor gene, or paraoxonase. Additionally, the APOE ε4 allele is a significant risk factor for Alzheimer disease. CYP2D6 variants affect the metabolism of donepezil, according to Freeman.

In Parkinson disease, genetic polymorphisms can influence the response and AEs of antiparkinsonian medications. Additionally, COMT gene variations can affect the dosage of levodopa and, therefore, the risk of dyskinesia. Emerging multigenetic pharmacogenomics-guided treatments show promise in these fields, according to Freeman.

Stroke

Genetic variations can impact drug metabolism and response in patients who are being treated for stroke, said Freeman. In stroke, pharmacogenomics and precision medicine are particularly helpful when guiding antiplatelet and anticoagulant therapies. Specifically, for antiplatelets, Freeman noted that CYP2C19 genotyping is recommended for clopidogrel efficacy, with the clinical trial CHANCE-2 (NCT04078737) demonstrating a lower risk of ischemic stroke or transient ischemic attack at 90 days in high-risk Asian populations with loss-of-function CYP2C19 on ticagrelor plus aspirin when compared with clopidogrel plus aspirin. There were no differences in major bleeding between the 2 groups.

Migraine and Multiple Sclerosis (MS)

For migraine, a complex interplay of genes influences an individual’s responses to migraine medication, and CYP enzymes metabolize migraine drugs. Robust genetic markers for predicting triptan efficacy in migraine are lacking, according to Freeman, who cited 5-HT1B gene studies that demonstrated negative results. Despite these findings, a polymorphism in the GNB3 gene has indicated some promise for predicting triptan response in cluster headache; however, he acknowledged that further research must be conducted to establish clear genotype-phenotype relationships.

A key biomarker that guides disease-modifying therapies (DMTs) in MS is interferon beta (IFNβ). Approximately 20% to 50% of patients lack a response to DMTs, primarily due to the genetics of genes MXA, IL10, and CCR5, which are associated with IFNβ responsiveness.

Further, glatiramer acetate nonresponder rates are estimated to range up to 50% because of HLA class I/II genetics and the TRBb and CTSS genes. Polymorphisms in ABC transporter genes are potential pharmacogenetic markers for mitoxantrone response in MS. Freeman noted that there is ongoing research to identify clinically actionable pharmacogenetic biomarkers, such as neurofilament light chain, that monitor disease activity.

Advancements and Navigating Challenges

Freeman notes multiple advancements that can offer great contributions when fueling precision neurology: next-generation sequencing and genome-wide association studies, which can accelerate genomic discovery; artificial intelligence (AI) and machine learning, which analyze complex data, predict possible outcomes, and accelerate drug discovery to further guide therapies; CRISPR gene editing to target therapies for genetic roots of neurological diseases; wearable devices and AI-powered diagnostics to promote continuous monitoring and personalized treatments; advanced neuroimaging to detect diseases early and monitor them effectively; as well as multi-omics and systems biology.

As far as navigating roadblocks, Freeman said that the lack of a global expertise network with limited understanding of pharmacogenomic phenotypes and rare genetic variants may lead to translational and educational gaps. Additionally, standardized orders and reporting in electronic health systems are significant challenges. Ethical, legal, and social issues, along with inconsistent policies and reimbursement frameworks, need addressing to make proper progress. There is also an existing need for trained personnel to ensure equitable access while addressing health disparities.

Finally, high costs of genetic testing, data interpretation, and the rapid pace of technology pose obstacles, with variability in clinical decisions, lack of fully validated treatment algorithms, and insufficient evidence of cost-effectiveness also presenting as potential roadblocks.

A New Approach

To help support this new approach to neurological treatment, Freeman suggested that health care professionals, researchers, and patient advocates should establish collaborative networks to expand and build upon inclusive datasets. Additionally, embracing technology, such as AI and machine learning, can serve as a useful and accurate diagnostic tool.

Freeman noted that the future holds great promise, with more targeted therapies, earlier diagnoses, and personalized individual care being factors that can pave the way for neurological treatment. Additionally, he acknowledged that practical challenges remain despite the progress that has been made—particularly in Alzheimer disease, migraine, and rare diseases—and continued education, research collaboration, and technological integration are critical for development.

REFERENCE

Freeman W. Frontiers in Neuroscience Plenary Session—Precision Medicine in Neurology: Cutting-Edge and Emerging Pharmacogenomics for Personalized Neurological Care. Presented at: American Academy of Neurology Annual Meeting; San Diego, California. April 5-9, 2025.