Plasma and neuroimaging biomarkers of small vessel disease and Alzheimer’s disease in a diverse cohort: MESA

Alzheimer’s & Dementia, December 2025

Authors:  Samuel N. Lockhart1, Courtney L. Sutphen1 Jordan Tanley, Fernando Gonzalez-Ortiz, Przemysław R. Kac, Mohamad Habes, Susan R. Heckbert, Nicholas J. Ashton, Michelle M. Mielke, Robert Koeppe, Marc D. Rudolph, Kiran K. Solingapuram Sai, Christopher T. Whitlow, Kevin D. Hiatt, Suzanne Craft, Thomas C. Register, Kathleen M. Hayden, Stephen R. Rapp, Bonnie C. Sachs, Henrik Zetterberg, Kaj Blennow, Thomas K. Karikari, Timothy M. Hughes

Synaptic dysfunction has long been implicated in the cognitive impairment associated with schizophrenia, yet direct in vivo measures of synaptic terminal density have been limited. In this study, the authors use [11C]UCB-J PET imaging targeting synaptic vesicle glycoprotein 2A (SV2A) to quantify whole-brain grey matter synaptic density in patients with schizophrenia and healthy volunteers.

Across 43 patients and 26 controls, whole-brain SV2A binding was significantly lower in schizophrenia, consistent with a global reduction in synaptic terminal density. SV2A levels declined with age in both groups, indicating similar age-related synaptic changes regardless of diagnosis. Notably, synaptic density did not correlate with current or premorbid IQ measures, suggesting that global synaptic terminal loss alone may not explain intellectual impairment in schizophrenia. Together, the findings position SV2A PET as a powerful translational biomarker for synaptic pathology, while refining our understanding of how synaptic changes relate to cognition in neuropsychiatric disease.

Why read this article

• Clarifies biomarker specificity: Helps disentangle which plasma markers truly index Alzheimer’s disease pathology versus those that also capture vascular brain injury.
• Highlights vascular–neurodegenerative overlap: Shows that NfL, GFAP, and p‑tau isoforms may reflect mixed pathology—critical for interpreting biomarker panels in clinical or research settings.
• Strengthens understanding of diverse populations: Uses a racially diverse cohort and reports comparable biomarker–imaging relationships across groups, an important step toward equitable biomarker use.
• Supports clinical trial design: Offers insights on how comorbidities (e.g., kidney function, BMI) influence biomarker levels, a key consideration for trial enrollment and stratification.
• Reinforces the value of multimodal assessment: Demonstrates how plasma biomarkers complement MRI and PET measures to provide a fuller picture of brain health.
• Identifies future research needs: Points to the importance of longitudinal data, additional biomarker modalities, and expanded racial and ethnic representation.

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