Viral Mimicry of Alzheimer’s Disease: Innate Sensing of Self-Nucleic Acids as a Driver of Glial Senescence

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder defined by progressive memory loss and synaptic failure. For decades, therapeutic development has focused on clearing amyloid-beta plaques, yet the repeated clinical failures of this approach necessitate a fundamental paradigm shift toward the brain’s immunometabolic landscape. The “Viral Mimicry” hypothesis posits that AD represents a state of sterile autoimmunity where the innate immune system mistakenly identifies self-nucleic acids as viral pathogens. This “ghost war” is ignited by the convergence of metabolic dysfunction and genomic instability: specifically, the leakage of mitochondrial DNA into the cytosol and the epigenetic derepression of ancient retrotransposons (LINE-1, HERVs). These endogenous ligands activate the cGAS-STING cytosolic sensing axis, a pathway that drives a chronic interferon response. Consequently, microglia and astrocytes are transformed into senescent, pro-inflammatory phenotypes that release a toxic Senescence-Associated Secretory Phenotype (SASP), directly fueling synaptic elimination. Crucially, major genetic risk factors, including APOE4 and TREM2 variants, exacerbate this cascade by compromising mitochondrial integrity and lipid metabolism, thereby sensitizing the brain to innate surveillance failure. By reconceptualizing AD as an acquired interferopathy driven by the “enemy within,” this framework highlights novel therapeutic targets. Specifically, repurposing Nucleoside Reverse Transcriptase Inhibitors (NRTIs) to block retrotransposition and deploying senolytics to clear dysfunctional glia offer promising strategies to arrest the progression from healthy aging to cognitive decline. This review synthesizes current research on the molecular mechanisms of viral mimicry, detailing the impact of genetic risk factors and evaluating emerging therapeutic interventions targeting this innate immune axis.

Graphical Abstract

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The Shift from Molecular Containment to Viral Mimicry in Alzheimer’s Disease. The figure contrasts the physiological state of healthy aging with the pathological state of Alzheimer’s Disease. (Left) In the healthy brain, "Molecular Containment" is maintained: immunogenic mitochondrial DNA is sequestered within the organelle, and ancient retrotransposons are epigenetically silenced within the nucleus. (Right) In Alzheimer’s Disease, the convergence of genomic instability and metabolic failure leads to a "loss of inhibition". The derepression of retroelements (LINE-1 (long interspersed nuclear element-1) dsDNA, HERV dsRNA) and the leakage of mitochondrial DNA into the cytosol activate the cGAS-STING innate immune axis. This viral mimicry transforms microglia into a senescent, Lipid-Droplet Accumulating phenotype, driving a chronic Type I Interferon response that fuels neurodegeneration