Region-specific brain structural modulation and amyloid-β pathology associated with dietary biotin: insights into dementia neuropathology.

BACKGROUND: The association and mechanisms between biotin and dementia remain unclear. METHODS: We investigated the association through a population and animal study. UK Biobank data were used to evaluate the association of biotin with incident dementia and brain structural alteration. To validate our findings, we established a biotin-deficient mouse model, and performed behavioural tests, immunofluorescence, RT-qPCR, Western blotting, and molecular docking. FINDINGS: In humans, higher biotin intake was significantly associated with reduced risks of all-cause dementia (moderate: 0.83 [0.74-0.94]; high: 0.78 [0.68-0.89]), Alzheimer's disease (AD, moderate: 0.74 [0.61-0.89]; high: 0.79 [0.64-0.98]), and delayed-onset dementia (DOD, moderate: 0.810 [0.715-0.918]; high: 0.776 [0.672-0.896]), but not vascular dementia (VD) and early-onset dementia (EOD). Neuroimaging results revealed a "pseudo-atrophy" pattern-reduced cortical volume with increased tissue intensity-resembling structural remodelling rather than neurodegeneration. In mice, biotin deficiency triggered region-specific alteration of APP, PSEN1, and APOE in the hippocampus and prefrontal cortex. It was accompanied by elevated Aβ42 levels and an increased Aβ42/40 ratio. Molecular docking suggested that biotin physically interacts with the catalytic pocket of PSEN1 and the receptor-binding domain of APOE. INTERPRETATION: Dietary biotin is associated with a lower risk of dementia, especially AD, potentially by inhibiting amyloidogenic processing and modulating APOE-mediated clearance. The observed neuroimaging and molecular patterns suggest that maintaining adequate biotin intake is a viable strategy for dementia prevention. FUNDING: This work was supported by the National Natural Science Foundation of China (No. 82273619).