Plasma proteomics of APOE genotype: age-specific analyses in UK population-based cohorts

Background: The apolipoprotein E (APOE) locus is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). Variation in APOE isoforms is known to have diverse pleiotropic effects on circulating lipids and other metabolites, but effects on the circulating proteome across the life course are not well characterised. We investigated the specific effects of APOE {epsilon}4 and APOE {epsilon}2 carriage on the circulating proteome in middle-age and later life. Methods: In primary modelling, we analysed associations of APOE {epsilon}4 and {epsilon}2 carriage (reference {epsilon}3/{epsilon}3) with circulating proteins in UK Biobank participants (N = 42,642; age = 39.1 to 70.9 years). Using multivariable linear regression, we conducted ancestry-specific analyses of 2,922 assayed plasma proteins across individuals of European (EUR), African (AFR), and South Asian (SAS) ancestry. To identify age-dependent effects, stratified analyses were performed with the sample split into age groups. We then performed replication analyses of APOE-associated proteins in age-matched groups, using data from two independent UK-based cohorts. Results: We identified 351 proteins associated with {epsilon}2 carriage and 480 with {epsilon}4 carriage among individuals of European ancestry (n = 40,092); 130 of these were associated with both {epsilon}2 and {epsilon}4 carriage (with either consistent or inverse association directions). These included established biomarkers of neurodegeneration (GFAP and NEFL) and other proteins implicated by AD genetic risk loci (e.g., TREM2, CTSB, IDUA, SORT1, GRN). Many of these proteins are linked to other neurodegenerative diseases besides AD. In multiple age groups, {epsilon}4 carriage was strongly associated with consistent differences in circulating APOE, MENT, and PLA2G7 levels across ancestries and cohorts. Conclusion: APOE {epsilon}4 and {epsilon}2 exert broad, often age-dependent effects on the plasma proteome, detectable decades before typical ages of AD diagnoses, highlighting a potential early window for monitoring and intervention.