Differential associations of APOE and TREM2 variants with glial fibrillary acidic protein and neurofilament light in plasma of UK Biobank participants support distinct disease mechanisms.

Plasma levels of glial fibrillary acidic protein (GFAP) and neurofilament light (NEFL) are key dementia biomarkers. GFAP and NEFL represent different underlying disease processes, i.e. astrocytic activation vs. neuronal damage. The associations of established genetic risk variants with these biomarkers may reflect time course and mechanisms by which the respective genes influence disease risk. Therefore, we investigated the association of the established high-effect dementia variants in APOE and TREM2 with these biomarkers, in a large population cohort of over 50,000 participants from the UK Biobank (UKB). The results show that APOE4 is associated with elevated levels of plasma GFAP, and to a lesser extent, NEFL. The APOE4 effect on GFAP increases with age and the number of APOE4 alleles. The risk variants R47H and R62H in TREM2 are associated with higher NEFL levels, but not with GFAP, and the effect sizes do not increase with age. In contrast, the protective APOE2 allele showed no effect on GFAP or NEFL. In conclusion, we find that major genetic risk factors for Alzheimer's disease exhibit distinct patterns of effect on these biomarkers, with APOE4 primarily affecting astrocyte activation starting in midlife, while TREM2 variants affect NEFL but not GFAP, and the protective effects of APOE2 are not captured by either of these biomarkers.