CSF and plasma lipid profiling predicts risk of cognitive impairment in cognitively unimpaired older adults
Takahisa Kanekiyo, Launia J. White, Hongping Ye, Yingxue Ren, Jason D. Ulrich, Ana‐Caroline Raulin, Alla Alnobani, Chengjie Xiong, Yan W. Asmann, Maria Vassilaki, Alicia Algeciras‐Schimnich, Junmin Peng, Fatima S. Amtashar, Suzanne E. Schindler, David M. Holtzman, Guojun Bu, Ronald C. Petersen, Michael G. Heckman, Xianlin HanAbstract
INTRODUCTION
Age‐related cognitive decline and Alzheimer's disease (AD) are strongly influenced by lipid metabolism, yet how central and peripheral lipid profiles relate to disease risk before symptom onset remains unclear.
METHODS
We performed comprehensive shotgun lipidomics in cerebrospinal fluid (CSF) and plasma from cognitively unimpaired older adults, with longitudinal follow‐up for Clinical Dementia Rating (CDR) conversion.
RESULTS
CSF lipidomes were primarily associated with age and established CSF AD biomarkers, whereas plasma lipid profiles were strongly influenced by sex. Specific CSF phosphatidylethanolamine subspecies showed robust positive associations with CSF total tau, phosphorylated tau 181, neurogranin, and chitinase‐3 like‐1. CSF triacylglycerol TAG(C49:6), phosphatidylglycerol PG(18:0‐18:1), cholesteryl ester CE(20:3), and phosphatidylethanolamine PE(D16:0‐18:1) independently predicted CDR conversion, improving risk prediction. Plasma sphingomyelin subspecies were modestly associated with cognitive decline risk.
DISCUSSION
These findings identify distinct CSF and plasma lipid signatures linked to preclinical cognitive decline and highlight brain lipid metabolism as a promising source of predictive biomarkers and therapeutic targets.