Title: Tear fluid microRNAs as early biomarkers for Alzheimer’s disease: Preclinical findings with clinical proof-of-principle validation.

Key Results

• Robust transgene expression — Human APP and MAPT were strongly expressed across the brain–eye axis, with progressive APP/Aβ accumulation in both tissues.

• PSEN1 decline — Human PSEN1 expression decreased with age, indicating a model‑specific limitation in amyloid processing.

• Brain–retina amyloid coupling — APP/Aβ burden increased in hippocampus, cortex, and retina, showing significant cross‑tissue associations at mid and late disease stages.

• Tau divergence — pTau showed early dissociation between brain and retina, later shifting toward brain‑dominant accumulation.

• Inflammatory uncoupling — Iba1 and GFAP indicated early inflammatory coupling that weakened with age, reflecting increasing compartmental divergence.

• Gene‑level concordance — AD‑ and immune‑related transcripts showed strong brain–eye concordance despite distinct tissue clustering.

• miRNA architecture — Mature miRNAs displayed a conserved regulatory structure across brain, eye, and tears, with brain–tear similarity exceeding brain–eye similarity.

• Human tear biomarkers — Seven miRNAs were reduced in CSF‑positive AD, and the resulting tear‑based panel showed strong discriminatory performance.