Bridging Integrator 1 (BIN1, rs6733839) and Sex Are Moderators of Vascular Health Predictions of Memory Aging Trajectories

Abstract

A promising risk loci for sporadic Alzheimer's disease (AD), Bridging Integrator 1 (BIN1), is thought to operate through the tau pathology pathway. We examine BIN1 risk for a moderating role with vascular health (pulse pressure; PP) and sex in predictions of episodic memory trajectories in asymptomatic aging adults. The sample included 623 participants (Baseline Mean age = 70.1; 66.8% female) covering a 44-year longitudinal band (53-97 years). With an established memory latent variable arrayed as individualized trajectories, we applied Mplus 8.5 to determine the best fitting longitudinal growth model. Main analyses were conducted in three sequential phases to investigate: 1) memory trajectory prediction by PP, 2) moderation by BIN1 genetic risk, and 3) stratification by sex. We first confirmed that good vascular health (lower PP) was associated with higher memory level and shallower decline and males were more severely affected by worsening PP in both memory performance and longitudinal decline. Second, the PP prediction of memory trajectories was significant for BIN1 C/C and C/T carriers but not for persons with the highest AD risk (T/T homozygotes). Third, when further stratified by sex, the BIN1 moderation of memory prediction by PP was selective for females. We observed a novel interaction whereby BIN1 (linked with tauopathy in AD) and sex sequentially moderated a benchmark PP prediction of differential memory decline in asymptomatic aging. This multi-modal biomarker interaction approach, disaggregated by sex, can be an effective method for enhancing precision of AD genetic risk assessment.