Plasma lipid metabolites as biomarkers of early white matter degeneration in Alzheimer's disease

Abstract

INTRODUCTION: Alzheimer's disease (AD) is characterized by progressive white matter (WM) degeneration. Circulating lipid metabolites may serve as early indicators of WM microstructural changes. In this study, we investigated the associations between plasma lipid metabolites and WM integrity across the cognitive continuum. METHODS: We included 173 participants from the Alzheimer's Disease Neuroimaging Initiative (51 cognitively normal CN, 88 mild cognitive impairment MCI, 34 AD) database. Plasma metabolites were quantified using targeted lipidomics, and diffusion tensor imaging (DTI) metrics were derived from 52 predefined WM regions. RESULTS: Regression analyses revealed widespread metabolite–DTI associations in MCI, particularly within the corpus callosum. The callosal body and splenium showed significant inverse associations with phosphatidylcholines (PCs) and multiple lysophosphatidylcholines (lysoPCs) species. In AD group, inverse relationships between PCs and the internal capsule were observed. DISCUSSION: Circulating lipid metabolites are linked to WM microstructure in both prodromal and clinical AD, supporting their potential as sensitive biomarkers of early vulnerability and disease progression. Highlights: Circulating lipid metabolites link to white matter integrity in early Alzheimer's disease (AD) Phosphatidylcholines (PCs), lysophosphatidylcholines (LPCs), and propionylcarnitine associate with tract-specific diffusion magnetic resonance imaging (dMRI) metrics No metabolite–white matter associations detected in established AD Plasma metabolites may serve as biomarkers of early white matter degeneration. © 2025 The Author(s). Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.