Plasma Proteomic Analysis of APOE ε4 Homozygotes Identifies Preclinical Alzheimer’s Disease Alterations Potentially Modulated by Semaglutide

Abstract Individuals who carry two copies of the apolipoprotein E ε4 ( APOE ε4) allele are at high risk of developing Alzheimer’s disease (AD), yet the effects of APOE ε4 homozygosity on biological pathways related to AD over the lifespan are unknown. Here we analyzed the plasma proteomes of APOE ε4/ε4 individuals with and without AD-related cognitive impairment ( n =413) and compared them to the proteomes of cognitively unimpaired individuals with APOE ε3/ε3 genotype ( n =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. One Sentence Summary Dammer et al . characterize proteomic changes in APO E ε4 homozygotes from ages 20 to 90 and identify disease pathways potentially treatable with GLP-1 receptor agonists.