Immune protein BAFF tracks delayed memory differently in first-episode schizophrenia

People experiencing schizophrenia for the first time, before any antipsychotic treatment, show lower blood levels of two immune regulators than healthy adults, and the direction of the link between one of these proteins and delayed memory differs sharply between the two groups. That is the central finding of a case-control study published in Translational Psychiatry, which examined serum B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL) in 90 first-episode, drug-naïve schizophrenia patients and 90 matched healthy controls.

Cognitive impairment is a core feature of schizophrenia and has previously been linked to immune dysregulation, but the contribution of humoral immune regulators, the signalling molecules that steer B-cell development and antibody responses, has remained unclear. The research team set out to test whether circulating BAFF and APRIL relate to cognition and symptom severity in the earliest, untreated stage of the illness.

Participants completed the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), a standardised neuropsychological instrument covering domains such as immediate and delayed memory, attention and language. Symptom severity was rated with the Positive and Negative Syndrome Scale (PANSS). Serum concentrations of BAFF and APRIL were quantified using Luminex technology, a bead-based multiplex assay that measures multiple proteins in small sample volumes.

After statistical adjustment for age, sex, education, body mass index and smoking status, both proteins were significantly lower in the patient group than in the controls. For BAFF the between-group difference yielded F = 131.935 with P < 0.001, and for APRIL F = 59.772 with P < 0.001. Because the patients had never received antipsychotic medication, the reduced levels cannot be attributed to drug effects, a common confound in immune studies of schizophrenia.

The hypothesis-driven primary analysis focused on RBANS delayed memory, the ability to recall material after a delay, which is among the cognitive functions most consistently affected in psychotic disorders. Here the researchers found a significant Group × BAFF interaction (F(1,171) = 13.524, P < 0.001). Among healthy controls, higher BAFF was associated with better delayed memory, with a positive slope of B = 0.015 (P = 0.017). In the schizophrenia patients the slope ran in the opposite direction, B = -0.022, so higher circulating BAFF accompanied poorer delayed-memory performance.

This crossover pattern was robust in sensitivity analyses, meaning it persisted when the researchers varied the modelling assumptions. It suggests that BAFF does not simply relate to memory in the same way in everyone; instead, its cognitive correlates appear to depend on clinical status, raising the possibility that immune signalling is perturbed in early psychosis in a way that alters how BAFF levels relate to brain function.

Broader, exploratory analyses of other cognitive domains were more cautious in their yield. A nominal Group × BAFF interaction emerged for the RBANS total score (F = 5.866, P = 0.016), but after correction for multiple comparisons across the exploratory tests the false-discovery-rate-adjusted value was q = 0.082, which the authors interpreted cautiously rather than as a confirmed finding. No analogous interaction was observed for APRIL, indicating that the memory-related pattern is specific to BAFF rather than a general property of this cytokine family.

Immune measures also did not map onto symptoms. BAFF and APRIL levels were not significantly associated with any PANSS symptom dimensions, so the proteins do not appear to track positive symptoms, negative symptoms or general psychopathology in this sample. The cognitive association therefore stands apart from the clinical symptom picture.

The authors frame the results as cross-sectional and hypothesis-generating. The study identifies peripheral BAFF as a correlate of delayed memory in early untreated schizophrenia, but it cannot establish temporality, causality or any central immune-cognitive mechanism. BAFF measured in blood may reflect peripheral immune activity, and whether it relates to processes within the brain remains unknown. The case-control design also captures a single time point, so it cannot show whether immune changes precede cognitive changes or follow them.

Even with those limits, the work adds a specific molecular handle to the immune-cognition question in schizophrenia. A measurable blood protein, differing between patients and controls and showing an inverted relationship with delayed memory in the earliest stage of illness, offers a candidate biomarker for future longitudinal studies of how humoral immunity and cognition interact in psychosis.

Subject of Research: Serum BAFF and APRIL levels and their relationship to delayed memory in first-episode drug-naïve schizophrenia

Article Title: Serum B-cell activating factor and delayed memory in first-episode drug-naïve schizophrenia: a case-control study

Article References: Yang, Q., Jin, T., Jin, S., Jiang, F., Qiu, J., Yang, X., Wang, P., Yan, Q., Tian, Q., & Zhang, X. (2026). Serum B-cell activating factor and delayed memory in first-episode drug-naïve schizophrenia: a case-control study. Translational Psychiatry. https://doi.org/10.1038/s41398-026-04546-w

Image Credits: AI Generated

DOI: 10.1038/s41398-026-04546-w

Keywords: schizophrenia, BAFF, APRIL, delayed memory, cognitive impairment, first-episode psychosis, immune dysregulation, RBANS, PANSS, case-control study, Luminex assay, Translational Psychiatry