Identifying Proteomic Pathways to Cognitive Impairment in Psychotic Disorders

Cognitive impairments are among the earliest and most disabling features of psychotic disorders, often emerging years before the first clinical episode. To design interventions that can prevent or slow cognitive decline, we need to understand the biological changes that occur long before symptoms appear.

This research, part of the Wellcome-funded programme 'The Glue That Holds the Pieces Together: Unlocking Cognitive Health in Psychotic Disorders', focuses on uncovering proteomic predictors of cognitive impairment using the Avon Longitudinal Study of Parents and Children (ALSPAC).

The UCL Workstream: ALSPAC Proteomics and Causal Inference

Led by Professor Neil Davies at UCL in collaboration with Dr Joseph Hayes and Professor Ville Karhunen (University of Cambridge), this workstream aims to identify protein-level changes in adolescence that predict cognitive impairment and later psychotic disorders.

The study uses ALSPAC plasma samples collected at age 15, Olink Explore HT assays quantifying over 5,000 proteins, and cognitive data from ages 5 to 24. By linking proteomic profiles with later cognitive decline and psychosis, we can pinpoint early biological pathways involved in disease progression.

Analytical Approach

• Describe developmental trajectories of cognition from age 5 to 24 in participants who later develop psychosis, compared with matched controls.
• Identify proteomic predictors of these trajectories using wide-spectrum proteomic data.
• Apply causal inference methods such as drug-target Mendelian randomization to evaluate which proteins could be viable treatment targets.
• Triangulate findings with experimental proteomic data from mouse models to identify shared molecular pathways.

Why ALSPAC?

ALSPAC provides an unparalleled resource for this work: long-term follow-up from birth to adulthood, repeated cognitive and mental health assessments, and high-quality biological samples with detailed genetic, clinical, and social data. This allows the team to study how molecular changes in adolescence predict cognitive and psychiatric outcomes decades later.

Expected Outcomes

• A new prospective ALSPAC proteomics dataset that will become available to researchers.
• Identification of proteins and drug targets associated with cognitive impairment in psychotic disorders.
• Improved understanding of the timing and biology of early cognitive decline.
• A foundation for drug repurposing and early intervention trials in psychosis.

Research Team

Principal Investigator: Professor Esther Walton - University of Bath

Co-investigators

• Professor Neil M Davies - UCL Division of Psychiatry
• Professor Joseph Hayes - UCL Division of Psychiatry
• Professor Ville Karhunen – MRC Biostatistics Unit, University of Cambridge
• Professor Anthony Isles – Cardiff University
• Professor Jason Lerch – University of Oxford

Funding

Funded by the Wellcome Trust under the ‘Applying Neuroscience to Understand Symptoms in Anxiety, Depression and Psychosis’ programme (Award Ref: 315898/Z/24/Z).