Disruptions to lipid metabolism and transport are increasingly recognized as key contributors to aging and Alzheimer’s disease (AD). The APOE gene, the strongest genetic risk factor for late-onset AD, impairs cholesterol transport in the brain. Similar disruptions linked to early-onset familial AD have also been observed in mutations in PSEN1, PSEN2, and APP. Preliminary studies in mice and human postmortem samples have shown striking age- and AD-related effects on lipid content in the brain and cerebrospinal fluid (CSF), suggesting that lipoprotein-mediated lipid transport is essential for maintaining brain lipid balance and may provide early biomarkers of AD risk.
Building on these findings, Dr. Tsai and team propose to investigate how CSF lipid composition changes with age, disease, sex, and APOE genotype. They hypothesize that age-related lipid changes in the brain contribute to AD risk, and that these changes in CSF lipids—alone or alongside proteomic changes—could serve as biomarkers of disease progression in a sex- and APOE genotype-specific manner. In Aim 1, they will perform unbiased lipidomic profiling on longitudinal CSF samples from DIAN and Knight ADRC participants. In Aim 2, they will generate a comprehensive atlas of CSF lipid changes and identify candidate biomarkers that predict future brain state. In Aim 3, they will extend this analysis to postmortem brain, mouse choroid plexus, and in vitro neuronal models to complement findings across human, animal, and cellular systems.
These studies will leverage rich longitudinal biological, imaging, and cognitive data collected over years in the DIAN and Knight ADRC cohorts. By linking CSF lipid changes to established AD biomarkers and cognitive measures, the team hopes to reveal early lipid patterns associated with disease onset and progression, thereby laying the foundation for lipid-based biomarkers and therapeutic targets in AD.
