Plasma Biomarkers Modulate <i>APOE4</i> Genotype Risk in Cognitive Decline: Insights from a Large Memory Clinic Cohort

Abstract Background The apolipoprotein E ( APOE ) 4 genotype is a major genetic risk factor of late‐onset Alzheimer's disease (AD). We examined the link between APOE4 carriage, cognitive decline and AD plasma biomarkers in a large memory clinic cohort with annual assessments spanning up to three decades. Method Participants at the University of Pittsburgh Alzheimer's Disease Research Center (Pitt‐ADRC) underwent baseline blood collection and cognitive function assessment using the Clinical Dementia Rating (CDR) Sum of Boxes, followed by annual CDR assessments for a median follow‐up of 3.0 years (IQR 1.9‐5.9). APOE genotyping was determined using TaqMan assays. Plasma p ‐tau181, p ‐tau217, brain‐derived tau (BD‐tau), GFAP and NfL, were measured using SIMOA assays. Linear regression and Kaplan‐Meier analysis were employed for statistical inference. Result This study included 4,073 participants (59.9% female; 90.2% non‐Hispanic White), aged 71.9 ± 9.8 years, with 2160 being non‐demented (CDR≤0.5) at baseline. APOE4 , but not APOE2 , carrier status was significantly associated with worse (higher) CDR scores ( p &lt;0.001) and higher levels of p ‐tau181, p ‐tau217, BD‐tau, and GFAP (all p &lt; 0.001), but not NfL. The significance of these associations was not influenced by the number of APOE4 alleles. APOE4 carriers experienced a faster decline in cognitive function, with a median cognitive stable time of 5.0 years compared to 6.1 years for non‐carriers (log‐rank p &lt;0.001). However, this APOE4 ‐dependent cognitive decline was only apparent in participants with &lt;=median plasma biomarker concentrations but disappeared in individuals with &gt;median biomarker levels. Conclusion This study shows that the APOE4 genotype exerts a significant, biomarker‐dependent risk on cognitive decline at early stages of the disease. These findings can guide personalized risk assessment and improve clinical management of AD.