Plasma Proteomic Analysis of <i>APOE</i> ε4 Homozygotes Identifies Preclinical Alzheimer’s Disease Alterations Potentially Treatable with Semaglutide

Individuals who carry two copies of the apolipoprotein E ε4 (<i>APOE</i> ε4) allele are at high risk of developing Alzheimer's disease (AD), yet the effects of <i>APOE</i> ε4 homozygosity on biological pathways related to AD over the lifespan are unknown. Here we analyzed the plasma proteomes of <i>APOE</i> ε4/ε4 individuals with and without AD-related cognitive impairment (<i>n</i>=413) and compared them to the proteomes of cognitively unimpaired individuals with <i>APOE</i> ε3/ε3 genotype (<i>n</i>=2764) from ages 20 to 90. Multiple biological pathways were altered in young adulthood in ε4 homozygotes including metabolism and glucagon-like peptide 1/insulin growth factor (GLP-1/IGF), mitochondrial, microtubule, proteostasis, and synaptic pathways. Semaglutide-a GLP-1 receptor agonist-demonstrated reversal effects on metabolic and synaptic pathway alterations in ε4 homozygotes at preclinical and clinical AD stages. Targeting metabolic and other pathways for therapeutic intervention in ε4/ε4 individuals by at least age 50 will likely be the most effective approach to decrease risk for AD in this special population.