CSF Proteome Changes Depend on APOE Genotype in Prodromal AD

Abstract

AbstractBackground APOE Ɛ4, the major genetic risk factor for sporadic Alzheimer’s disease (AD), has a dose‐dependent effect on the risk of development of AD. It remains unclear how APOE Ɛ4 dose affects different pathophysiological processes in AD, and therefore we studied APOE genotype effects on the CSF proteome of prodromal AD individuals.MethodCSF proteomics was performed using TMT‐MS in 77 prodromal AD individuals (mean age 70±7 years, 42 (55%) female, n=25 Ɛ3Ɛ3, n=38 Ɛ3Ɛ4, n=14 Ɛ4Ɛ4) and 41 cognitively normal individuals used as a reference group (mean age 64±7 years, 21 (51%) female, biomarker A‐T‐, all Ɛ3Ɛ3) from the EMIF cohort. APOE Ɛ2‐carriers were excluded due to the low number. In total, 2535 proteins were detected, of which we selected 1143 observed in at least 70% of the individuals. APOE genotype effects on CSF protein concentrations were tested with linear regressions adjusting for age and sex in comparison to our reference group.ResultIn total, 134 (12%) proteins showed APOE genotype dependent differences in prodromal AD individuals compared with the reference group (P < 0.05, Fig. 1). Of these, 6 proteins, including SMOC1 and YWHAB, showed differences in all prodromal AD individuals, reflecting general disease processes. Comparing each genotype to the reference group, 23 proteins differed in Ɛ3Ɛ3 prodromal AD, of which 21 showed higher concentrations, without enrichment for any specific biological pathways; 54 proteins differed in Ɛ3Ɛ4 prodromal AD, of which 51 proteins, enriched for glucose metabolism, showed higher concentrations; and 110 proteins differed in Ɛ4Ɛ4 prodromal AD, of which 98 proteins, enriched for glucose metabolism, (oxidative stress‐induced) apoptosis and interleukin‐12 signaling, showed higher concentrations and 12 proteins, enriched for complement activation, showed lower concentrations. Comparing APOE Ɛ4 dose within prodromal AD, 21 proteins showed differences between Ɛ3Ɛ4 and Ɛ4Ɛ4, of which 7 proteins, enriched for complement activation, showed downregulation in Ɛ4Ɛ4.ConclusionThe CSF proteome of prodromal AD individuals showed APOE genotype dependent alterations, which were associated with distinct biological processes, including glucose metabolism, apoptosis and complement activation. Most of these alterations were Ɛ4 dose‐dependent. These differences should be considered in selection of future therapy targets.