PERSPECTIVE article
Front. Cell. Infect. Microbiol.
Sec. Molecular Viral Pathogenesis
This article is part of the Research TopicPerspectives in Molecular Viral Pathogenesis: 2025View all 6 articles
Charting the Research Frontier for Viral Infections, Immunomodulation, and Dementia: A Perspective on Synaptic Biomarkers as Essential Clinical Trial Endpoints
Provisionally accepted
- 1Laboratory Medicine, National University Health System (Singapore), Singapore, Singapore
- 2Medical and Cognitive Research Unit, Austin Health, Heidelberg, Australia
- 3School of Medicine, Western Sydney University, Penrith, Australia
- 4Clinical Microbiology, University Hospitals of Leicester NHS Trust, Leicester, United Kingdom
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The viral-inflammatory hypothesis of Alzheimer's disease offers a new paradigm, yet interventions like antivirals and vaccination present a paradox that challenge therapeutic development. This perspective examines the critical research gap concerning cerebrospinal fluid (CSF) synaptic biomarkers in immunomodulatory therapy trials. Following decades of partially successful amyloid-centric trials, focus has shifted to upstream triggers including viral infections like Herpes Simplex Virus Type 1, Varicella Zoster Virus, and Severe Acute Respiratory Syndrome Coronavirus 2. While large observational and quasi-experimental studies suggest antivirals and vaccines reduce long-term dementia risk, the first major antiviral randomized controlled trial (Valacyclovir for Alzheimer's Disease) was negative. This perspective posits that this paradox arises from a fundamental flaw in trial design: the absence of synaptic integrity biomarkers. Synaptic loss, not amyloid or tau burden, is the strongest correlate of cognitive decline. Therefore, CSF synaptic protein biomarkers such as the prognostic YWHAG:NPTX2 ratio, postsynaptic Neurogranin (Ng), and presynaptic Growth-Associated Protein 43 (GAP-43) are the most clinically relevant endpoints. The paradoxical trial results may arise from omitting these synaptic measures, creating a mechanistic "black box" obscuring their true biological effects. A strategic framework is proposed, centered on the mandatory inclusion of CSF synaptic biomarkers and relevant co-pathology markers like TAR DNA-Binding Protein 43 (TDP-43; a proteinopathy linked to viral triggers) in all antiviral and vaccine trials. This approach is critical to resolve existing paradoxes, elucidate mechanisms of neuroprotection, and accelerate developing effective therapies that preserve synaptic integrity to prevent and treat dementia.
Keywords: Alzheimer's disease, CSF synaptic biomarkers, Dementia, GAP-43, Neurogranin, TDP-43, Viral hypothesis, YWHAG:NPTX2 ratio
Received: 09 Sep 2025; Accepted: 04 Dec 2025.
Copyright: © 2025 Lee, Woodward, Hohenberg and Tang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Julian Tang
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