Investigating the role of long-term latent herpes simplex virus infection on APOE4-associated Alzheimer's disease pathogenesis

This research project focuses on investigating the role of long-term latent herpes simplex virus (HSV) infection in APOE4-associated Alzheimer’s disease (AD) pathogenesis. This work addresses an urgent gap in our understanding of how persistent viral infections might interact with well-established genetic risk factors to influence the onset and progression of late-onset AD. APOE4 is the strongest common genetic risk allele for late-onset AD, and growing evidence suggests that environmental and infectious exposures may modulate genetic susceptibilities.

The study is designed to probe whether and how chronic, latent HSV infection modifies molecular, cellular, and tissue-level processes associated with APOE4 that are thought to drive neurodegeneration. The project frames the central hypothesis that long-term latent HSV presence in the CNS alters neuronal and glial homeostasis in ways that exacerbate APOE4-driven pathways implicated in AD, including synaptic dysfunction, neuroinflammation, tauopathy, and cellular senescence. By focusing on the intersection of persistent viral latency and genetic risk, the research aims to reveal mechanistic links that have implications for disease prevention, biomarker development, and therapeutic intervention. The study will employ a combination of approaches appropriate for dissecting interactions between infection and genetic risk. These approaches include longitudinal characterization of latent HSV in model systems harboring APOE4, assessment of cellular responses to viral latency in neurons and glia, and evaluation of molecular signatures associated with neurodegenerative processes.

Identifying alterations in inflammatory signaling, antiviral responses and pathways associated with protein aggregation and neuronal resilience will be a key area of emphasis for this proejct. The research will also consider sex as a critical biological variable, given mounting evidence that AD risk and biological responses can be sex-dependent. The intended outcome is a multi-layered picture of how long-term viral latency may shift the trajectory of APOE4-associated neurodegeneration, either by priming injurious inflammatory states, compromising proteostasis, promoting tau-related pathology, or accelerating cellular senescence. Beyond mechanistic insight, Hensley-McBain’s project seeks to inform translational opportunities.

If persistent HSV infection is shown to meaningfully interact with APOE4 to drive pathogenic processes, it could point toward preventive or therapeutic strategies that target viral latency, modulate host antiviral pathways, or mitigate downstream inflammatory and proteostatic consequences. The work could also yield candidate biomarkers reflective of latent infection–driven pathophysiology in APOE4 carriers, enabling earlier detection or stratification of individuals at elevated risk. Overall, the research is positioned at the nexus of genetics, infection biology, and neurodegeneration, with the potential to refine models of late-onset AD etiology and to broaden avenues for intervention. As a contribution from Hensley-McBain and collaborators, the project aligns with efforts to unpack complex risk interactions underlying Alzheimer’s disease and to translate mechanistic discoveries into strategies that may reduce the burden of cognitive decline associated with APOE4.