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

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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 Alzheimer's 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-β. This association was validated in an independent CSF metabolomics (n=687) and proteomics (n=737) cohorts. Structural equation modelling confirmed that polyol metabolites predict tau burden, with less than 3% attenuation following genetic adjustment, establishing a non-genetic, metabolically driven mechanism. These findings define a tau-dominant, amyloid-independent metabolic axis in neurodegeneration, implicating the polyol pathway as a potentially modifiable therapeutic target.

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