{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:12:30Z","timestamp":1787026350549,"version":"build-2736575974"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T00:00:00Z","timestamp":1767571200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>The viral-inflammatory hypothesis of Alzheimer\u2019s 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\u2019s 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 \u201cblack box\u201d 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.<\/jats:p>","DOI":"10.3389\/fcimb.2025.1701760","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T06:37:46Z","timestamp":1767595066000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Charting the research frontier for viral infections, immunomodulation, and dementia: a perspective on synaptic biomarkers as essential clinical trial endpoints"],"prefix":"10.3389","volume":"15","author":[{"given":"Chun Kiat","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Woodward","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark I","family":"Hohenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian W","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.14508","article-title":"The Alzheimer\u2019s Association Global Biomarker Standardization Consortium (GBSC) plasma phospho-tau Round Robin study","volume":"2","author":"Ashton","year":"2025","journal-title":"Alzheimers Dement."},{"key":"B2","unstructured":"Deaths in Australia\n          \n          2024"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1992","DOI":"10.1016\/j.neurobiolaging.2008.02.013","article-title":"PSEN1 polymorphisms alter the rate of cognitive decline in sporadic Alzheimer\u2019s disease patients","volume":"12","author":"Belbin","year":"2009","journal-title":"Neurobiol. 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