Trajectory of plasma lipidomes associated with the risk of late-onset Alzheimer’s disease pathogenesis: a longitudinal study in the ADNI cohort

Comprehensive lipidomic studies have demonstrated strong cross-sectional associations between the blood lipidome and late-onset Alzheimer’s disease (AD) and its risk factors. However, the longitudinal relationship between the lipidomic variations and progression of AD remains unknown. Here, we employed longitudinal lipidomic profiling on 4,730 plasma samples from 1,517 participants of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort to investigate the temporal evolution of lipidomes among diagnostic groups. At baseline, there were 1,393 participants including 437 cognitively normal (CN), 713 with mild cognitive impairment (MCI), and 243 AD cases. During follow up, 329 individuals (29 CN and 300 MCI) developed clinical AD (AD converters). We developed an AD-CN classification model to stratify the non-converting MCI group into AD-like and non AD-like MCI based on their lipidomics profiles at baseline. Longitudinal analysis identified associations between the change in ether lipid species (including alkylphosphatidylcholine, alkenylphosphatidylcholine, lysoalkylphosphatidylcholine, and lysoalkenylphosphatidylcholine) in converters relative to non-converting CN and MCI groups. Further, the AD-CN model efficiently classified MCI into low AD risk and high AD risk, with the high AD risk group having two times higher risk of conversion to AD than the low risk group. These findings suggest that the lipidomic profile can serve as a potential biomarker to identify individuals at higher risk for progressing to AD.