Longitudinal tau burden partially mediates synergistic influence of vascular risk and amyloid‐beta on cognitive decline in clinically normal older adults

Abstract

AbstractBackgroundVascular risk is increasingly recognized as an important contributor to late‐life cognitive impairment. Elevated vascular risk and amyloid‐beta (Aβ) burden have been synergistically associated with greater cognitive decline, however the underlying mechanisms remain unclear. We examined the combined effects of baseline vascular risk and Aβ on longitudinal tau burden. We further investigated the extent to which tau accumulation mediates the synergistic effects of increased vascular risk and Aβ on prospective cognitive decline.MethodWe included data from 175 older adults (cognitively unimpaired at baseline) from the Harvard Aging Brain Study (HABS) (Table 1). Baseline Aβ burden was measured with Pittsburgh Compound‐B (PiB) PET. Baseline vascular risk was quantified using the office‐based Framingham Heart Study general cardiovascular disease risk score (FHS‐CVD). Tau burden was measured longitudinally with Flortaucipir‐PET in inferior temporal cortex (ITC), an early site of neocortical tau accumulation and a region of interest based on prior work. Cognition was assessed longitudinally using Preclinical Alzheimer Cognitive Composite (PACC). Using linear mixed effects models, we examined the interactive effects of FHS‐CVD and Aβ on longitudinal ITC tau accumulation, adjusting for age, sex and APOE ε4 status. Next, we examined the FHS‐CVD*Aβ interaction using floodlight/Johnson‐Neyman analysis to determine the level of Aβ at which effects on ITC tau accumulation became significant. Using moderated mediation analysis, we further examined whether tau accumulation mediated the FHS‐CVD*Aβ interactive effects on PACC decline.ResultIndividual ITC‐tau trajectories are shown in Figure 1. We found an interaction between higher baseline FHS‐CVD and elevated Aβ with greater longitudinal ITC‐tau accumulation (Figure 2; Table 2). Floodlight analysis showed the FHS‐CVD*Aβ interaction became significant (p<0.05) at PiB‐DVR>1.22, lower than the conventional threshold for amyloid‐positivity (PiB‐DVR>1.32). Moderated mediation models revealed ITC‐tau accumulation partially mediated (30%) the effect of FHS‐CVD on PACC decline at high (PiB‐DVR=1.85: β=‐0.48, p<0.001) but not low (PiB‐DVR=1.17: β=‐0.16, p=0.09) levels of baseline Aβ (Figure 3).ConclusionVascular risk may interact with Aβ to promote cognitive decline partially through accelerating tau accumulation, even at subthreshold levels of Aβ. Further studies are needed to elucidate other mechanisms that mediate the remaining effects of this clinically important interaction.