The protective PLCG2 variants delay Alzheimer's disease onset age in APOE ϵ4 carriers

INTRODUCTION We investigated the impact of protective PLCG2 -P522R and PLCG2 -3'UTR variants, and the TREM2 -R62H risk variant on Alzheimer's disease (AD) onset age in relation to APOE ϵ4 status. Plasma-based biomarkers of the different variants were also explored. METHODS Kaplan-Meier and survival analyses were performed using FinnGen genotype and clinical endpoint data to assess the onset ages of AD, anxiety, and type 2 diabetes. Plasma biomarkers related to metabolism and inflammation were analyzed in 145 FINGER cohort participants. RESULTS PLCG2 -P522R and PLCG2 -3'UTR variants delayed AD onset, including among APOE ϵ4 carriers. PLCG2 -P522R carriers showed elevated plasma ghrelin levels. TREM2 -R62H variant associated with an earlier onset of AD in APOE ϵ4 carriers. DISCUSSION Protective PLCG2 variants may mitigate APOE ϵ4-mediated risk of AD, which coincide with increased plasma levels of ghrelin. These findings highlight the further need to explore biomarkers and mechanisms associated with the protective variants in relation to APOE ϵ4.