Plasma lipid dysregulation reflecting cerebrospinal fluid profile predicts Alzheimer’s disease progression

Lipidomics offers potential for the early detection of Alzheimer's disease (AD) and for elucidating the molecular mechanisms driving the progression from mild cognitive impairment (MCI) to AD. In this study, we investigated and validated the association between 139 cerebrospinal fluid (CSF) lipids and MCI-to-AD conversion. We included 400 MCI participants from the Ace Alzheimer Center Barcelona (ACE) cohort, all free of type 2 diabetes, comprising both ATN+ and ATN- individuals. After a median follow-up of 2.1 years, 142 participants progressed to AD dementia. We identified a multi-lipid signature of 11 lipids (including phosphatidylcholines, lysophosphatidylcholines, triglycerides, phosphatidylethanolamines, lysophosphatidylethanolamines and phosphatidylinositols) in CSF, which was associated with increased AD progression (HR = 1.85, 95% CI: 1.53-2.27). This signature was validated in paired plasma samples, a less invasive biofluid (HR = 1.26, 95% CI: 1.04-1.52) and in plasma samples from an external cohort of 189 participants (149 with subjective cognitive decline, 40 with MCI; β = 0.261, 95% CI: 0.022-0.500), demonstrating moderate-to-high predictive accuracy for MCI-to-AD progression. Counterfactual-based mediation analysis revealed that plasma phosphorylated tau-181 mediated up to 47% of the association between the lipid signature and AD dementia, highlighting glycerophospholipid metabolism as a key pathway. Exploratory Mendelian randomisation analyses suggested a potential causal association of lipid signature and AD, with two instrumental single-nucleotide polymorphisms mapped to loci implicated in neurodevelopmental and metabolic regulation (RBFOX1 and CDKAL1). In conclusion, our findings support the growing evidence of lipid metabolism dysregulation as an early marker of AD and identify plasma lipids reflecting CSF profiles that may be promising prognostic markers for AD dementia.