Plasma Proteomic Analysis ofε4 Homozygotes Identifies Preclinical Alzheimer's Disease Alterations Potentially Treatable with Semaglutide.

Individuals who carry two copies of the apolipoprotein E ε4 (ε4) allele are at high risk of developing Alzheimer's disease (AD), yet the effects ofε4 homozygosity on biological pathways related to AD over the lifespan are unknown. Here we analyzed the plasma proteomes ofε4/ε4 individuals with and without AD-related cognitive impairment (=413) and compared them to the proteomes of cognitively unimpaired individuals withε3/ε3 genotype (=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.