This aligns with our recent analysis of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) data showing that APOE’s reduced ability to off-load excess cholesterol, as well as the redistribution of cholesterol and other fatty acids across cell types in the brain, disrupts metabolic support for neurons by interfering with G protein-coupled receptor (GPCR) signaling in the astrocyte-neuron lactate shuttle [25]. Here, APOE is linked to early-onset autosomal dominant Alzheimer disease.