Evidence for the roles of lipids in brain aging and Alzheimer (AD) and its related dementias (ADRD) is building. Lipidomics is providing new insights related to altered lipid turnover and metabolism in AD and their roles in brain aging. Our AD Metabolomics Consortium (ADMC) led by MPI Kaddurah-Daouk is part of the Accelerating Medicines Partnership-AD (AMP-AD) with centers of excellence in AD research, metabolomics/lipidomics, informatics, machine learning, and modeling. Over the last eight years we invested major effort exploring the AD metabolome with high-quality metabolomics/lipidomics datasets across different cohorts with rapid and broad data sharing and transparent reporting of methods, to maximize rigor and reproducibility. We defined metabolic failures across the trajectory of disease, connecting peripheral and central changes, delineating genetic modulation of metabolic changes in AD effort that lead to novel targets for drug development. MPI Arnold led the construction of the first molecular atlas for AD, a data integration resource for investigating AD and its biomarkers in a multi-omics context. MPI Meikle, a world-renowned expert in lipidomics, has created over 50,000 plasma lipidomic profiles from landmark studies, including AD cohorts (ADNI, AIBL, NSHDS) and the most advanced lipidomic profiling of human brain samples from the ROS/MAP cohorts. Our recent work, incorporated lipidomic GWAS with lipidomic profiling in AD cohorts and identified peripheral ether lipids associated with the ApoE risk and resilience variants. Lipid metabolism changes with age, potentially mediating the effects of age, the strongest risk factor for LOAD, on AD. However, it is unclear how age and lipid metabolism interact to affect the aging brain and AD susceptibility. An improved understanding of these relationships will open up new opportunities for early interventions to modify lipid metabolism pathways that modulate the immune system and preserve brain health. We will use state-of-the-art lipidomics to enable three complementary and one exploratory aim. Aim 1 derive reproducible peripheral and central lipidomic signatures for metabolic resilience and vulnerability to cognitive decline and calculate metabolic risk scores (MRS) that inform on AD risk and brain aging. Aim 2 catalogue the lipid-mediated effects of AD risk genotypes linked to vulnerability and resilience. Building on our methods to characterize the lipidome associated with APOE alleles, we will use GWAS, mediation analysis and Mendelian randomization analyses to uncover genetically modulated lipid alterations causally linked to AD and brain aging. Aim 3: evaluate the effects of lifestyle interventions on our derived lipidomic signatures to identify those interventions that can ameliorate lipid dysregulation to sustain brain health and prevent cognitive decline. Exploratory aim: perform lipidomic profiling of peripheral (immune) cells to capture a cellular lipidome and relate this to brain a...