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

Individuals who carry two copies of the apolipoprotein E {epsilon}4 (APOE {epsilon}4) allele are at high risk of developing Alzheimer's disease (AD), yet the effects of APOE {epsilon}4 homozygosity on biological pathways related to AD over the lifespan are unknown. Here we analyzed the plasma proteomes of APOE {epsilon}4/{epsilon}4 individuals with and without AD-related cognitive impairment (n=413) and compared them to the proteomes of cognitively unimpaired individuals with APOE {epsilon}3/{epsilon}3 genotype (n=2764) from ages 20 to 90. Multiple biological pathways were altered in young adulthood in {epsilon}4 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 {epsilon}4 homozygotes at preclinical and clinical AD stages. Targeting metabolic and other pathways for therapeutic intervention in {epsilon}4/{epsilon}4 individuals by at least age 50 will likely be the most effective approach to decrease risk for AD in this special population.