Hypothesis: Early tau accumulation in the entorhinal cortex disrupts vagal efferent firing, which drives pathogenic tau seeding in the colonic enteric nervous system and increases intestinal permeability. The resulting gut-derived inflammatory mediators then travel via vagal afferents to reactivate microglial priming in the entorhinal cortex, creating a self‑reinforcing loop that accelerates both CNS and peripheral tau pathology.

Mechanistically, tau pathology in excitatory grid cells reduces their rhythmic output, weakening the parasympathetic tone that normally stabilizes colonic epithelial tight junctions Entorhinal cortex tau and grid cells. Loss of this tonic vagal efferent signal permits misfolded tau to anterogradely transport along vagal fibers to the myenteric plexus, where it seeds aggregation in enteric neurons Vagal efferent tau transmission. Simultaneously, the epithelial barrier becomes leaky, allowing bacterial products such as lipopolysaccharide to reach the lamina propria and trigger IFN‑β and IL‑1β release. These cytokines activate vagal afferent C‑fibers, which convey danger signals to the nucleus tractus solitarius and from there to the paraventricular hypothalamus and ultimately back to the entorhinal cortex via corticotropin‑releasing hormone‑dependent pathways. The ensuing microglial shift toward a pro‑inflammatory phenotype lowers the threshold for further tau seeding, completing the loop.

Predictions: (1) In ADLP^APT^ mice, chemogenetic inhibition of vagal efferents during the pre‑symptomatic stage will block tau appearance in the colon and preserve barrier integrity, whereas inhibition of vagal afferents after gut leakiness has developed will attenuate microglial activation in the entorhinal cortex without affecting colonic tau load. (2) Oral administration of a tight‑junction stabilizer (e.g., larazotide acetate) will reduce circulating LPS, lower afferent vagal firing, and slow the progression of both colonic tau pathology and entorhinal cortical thinning measured by in‑vivo MRI. (3) Patients with mild cognitive impairment who show elevated serum zonulin (a marker of gut permeability) will have faster decline in grid‑cell‑derived navigation scores on virtual maze tasks over 12 months, independent of baseline amyloid burden Gut microbiome‑tau associations Grid cell firing deficits in tauopathy.

Falsifiability: If vagal efferent blockade fails to prevent colonic tau seeding, or if gut barrier repair does not alter afferent signaling or cortical tau accumulation, the proposed bidirectional loop is not supported. Conversely, demonstration that afferent vagal silencing alone reduces cortical tau without affecting peripheral pathology would argue for a primarily afferent model, refuting the hypothesis.