BACKGROUND:
The apolipoprotein E (APOE) locus is the strongest genetic risk factor for late-onset Alzheimer’s disease and related dementias (ADRD). 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 therefore aimed to compare the specific effects of APOE ε4 and APOE ε2 carriage on the proteome in middle and later life.
METHODS:
We compared the proteomic profiles of APOE ε4 and ε2 carriers with ε3 homozygotes 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 explore age-dependent effects, stratified analyses were performed with the sample split into age tertiles (youngest = 40.2-54.4 years; middle = 54.4-62.6 years; oldest = 62.7-70.9 years). We then performed replication analyses of APOE-associated proteins in age-matched tertiles, using data from two independent cohorts.
RESULTS:
We identified 331 proteins associated ε2 carriage and 443 with ε4 carriage; 149 of these were associated with both ε2 and ε4 carriage. These included established biomarkers of ADRD (GFAP and NEFL), and other proteins implicated by ADRD risk loci (e.g., TREM2, CTSB, IDUA, SORT1, GRN); though many of these proteins have been linked to neurodegenerative diseases more broadly. Several strong associations were consistent across age tertiles and ancestries. In multiple age tertiles, ε4 carriage was strongly associated with directionally consistent differences in APOE, MENT, and SNAP25 levels across ancestries, while ε2 carriers had lower PLA2G7 levels in both EUR and AFR populations.
CONCLUSION:
APOE ε4 and ε2 exert broad, often age-dependent effects on the plasma proteome, detectable decades before typical ADRD diagnosis. Further research is needed to determine their relevance to ADRD pathophysiology and prediction.