APOE and TREM2 variants differentially influence glial fibrillary acidic protein and neurofilament light in plasma of UK Biobank participants

Plasma levels of protein biomarkers glial fibrillary acidic protein (GFAP) and neurofilament light (NEFL) are key dementia biomarkers, but it is unclear how risk genes for Alzheimers disease (AD) influence levels of these biomarkers. We investigated the association of the established high-effect variants for AD in APOE and TREM2 with these biomarkers, using data from 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. Higher levels of both GFAP and NEFL in midlife are significantly associated with greater risk for incident dementia. In contrast, the protective APOE2 allele showed no effect on GFAP or NEFL. In conclusion, we find that major genetic risk factors for AD differentially affect dementia protein biomarkers across age, indicating gene specific pathways with potential therapeutic implications.