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 aging and AD pathogenesis. The outcome of our research will provide deeper understanding of role
of lipids in brain aging and in AD and will lead to novel therapeutic approaches.