Tau Mediates Synergistic Influence of Vascular Risk and Aβ on Cognitive Decline

Abstract

Objective: Elevated vascular risk and beta-amyloid (Aβ) burden have been synergistically associated with cognitive decline in preclinical Alzheimer's disease (AD), although the underlying mechanisms remain unclear. We examined whether accelerated longitudinal tau accumulation mediates the vascular risk-Aβ interaction on cognitive decline.

Methods: We included 175 cognitively unimpaired older adults (age 70.5 ± 8.0 years). Baseline vascular risk was quantified using the office-based Framingham Heart Study general cardiovascular disease risk score (FHS-CVD). Baseline Aβ burden was measured with Pittsburgh Compound-B positron emission tomography (PET). Tau burden was measured longitudinally (3.6 ± 1.5 years) with Flortaucipir PET, focusing on inferior temporal cortex (ITC). Cognition was assessed longitudinally (7.0 ± 2.0 years) using the Preclinical Alzheimer's Cognitive Composite. Linear mixed effects models examined the interactive effects of baseline vascular risk and Aβ on longitudinal ITC tau. Additionally, moderated mediation was used to determine whether tau accumulation mediated the FHS-CVD*Aβ effect on cognitive decline.

Results: We observed a significant interaction between elevated baseline FHS-CVD and Aβ on greater ITC tau accumulation (p = 0.004), even in individuals with Aβ burden below the conventional threshold for amyloid positivity. Examining individual vascular risk factors, we found elevated systolic blood pressure and body mass index showed independent interactions with Aβ on longitudinal tau (both p < 0.0001). ITC tau accumulation mediated 33% of the interactive association of FHS-CVD and Aβ on cognitive decline.

Interpretation: Vascular risks interact with subthreshold levels of Aβ to promote cognitive decline, partially by accelerating early neocortical tau accumulation. Our findings support vascular risk reduction, especially treating hypertension and obesity, to attenuate Aβ-related tau pathology and reduce late-life cognitive decline. ANN NEUROL 2022;92:745-755.