Polyol pathway dysregulation in CSF links glucose metabolism to tau pathology inde-pendently of amyloid and genetic predisposition

Dementia affects approximately 60 million people worldwide, yet molecular mechanisms linking early neuropathological changes to clinical progression remain poorly understood. We performed targeted and untargeted metabolomics in plasma and cerebrospinal fluid (CSF) from 166 memory clinic patients spanning no cognitive impairment, mild cognitive impairment due to Alzheimers disease (AD), AD dementia, and mixed AD-cerebrovascular dementia. Using a data-driven approach, we identified a CSF polyol signature characterized by elevated sorbitol, meso-erythritol, and d-glucose/erythritol ratio consistently associated with phosphorylated tau (pTau) and total tau (tTau), but not amyloid-{beta}. This as