Circulating lipids uncover early membrane disruption as a primary event preceding Alzheimer’s disease onset

Alzheimer’s disease (AD) is not a single entity but a biologically heterogeneous disorder, with substantial inter-individual variability in clinical presentation, molecular drivers, and disease trajectories. This heterogeneity limits current diagnostic and therapeutic strategies, which largely rely on late-stage protein biomarkers that, while sensitive to prodromal impairment, remain insufficient for primary prevention and patient stratification. Lipids are fundamental to brain structure and function, yet their role in the earliest stages of AD remains poorly defined. Here, we identify a robust, early-life lipid signature in serum from asymptomatic carriers of the PSEN1-E280A mutation, detectable from childhood. Using latent profile analysis, we resolve distinct lipid states associated with risk and resilience to dementia, modulated by genetic status, sex, and APOE genotype, and supported by concordant changes in circulating protein biomarkers. Mechanistically, these lipid alterations point to early and sustained disruptions in cholesterol and sphingolipid metabolism, suggesting that impaired lipid turnover is a primary event in AD pathogenesis rather than a downstream consequence. Our findings position circulating lipids as dynamic reporters of disease-relevant cellular pathways and reveal a previously unrecognized metabolic dimension of the presymptomatic phase of AD. Together, this work reframes AD as a disorder of early metabolic dysregulation and highlights lipidomic profiling as a powerful approach for early detection, risk stratification, and mechanistic insight.