Vascular health is associated with locus coeruleus‐related entorhinal tau deposition

Abstract Background Autopsy studies reported that the locus coeruleus (LC) is one of the first sites of tau accumulation. In addition, LC‐mediated norepinephrine (NE) signaling is thought to play a role in blood‐brain‐barrier maintenance and neurovascular coupling through its projections to the microvasculature, suggesting that the NE‐LC system interacts with cerebrovascular disease and Alzheimer’s disease (AD) pathology. Since vascular risk factors are prevalent in older individuals and contribute to vascular pathology, a common co‐pathology of AD, understanding interrelationships among vascular health, tau and LC integrity as early as possible, can guide prevention. Method We included 124 individuals (Table1) from the Harvard Aging Brain Study with MRI and 18 F‐Flortaucipir and 11 C‐Pittsburgh‐Compound‐B PET‐imaging within one year of each other. LC‐MRI signal intensity was extracted from 5 maximum‐intensity voxels and normalized to pontine tegmentum. White matter signal abnormalities (WMSA intracranial volume adjusted) were obtained from FreeSurfer6. PET measures were partial‐volume corrected. The Framingham‐Risk‐Score (FRS‐CVD, likelihood of a cardiovascular event in 10 years) was calculated. Structural Equation Models were used to test hypothetic models (1: WMSA mediate the relationship between FRS‐CVD and LC, leading to entorhinal (EC) tau; 2: FRS‐CVD is associated with WMSA and LC, and the LC influences WMSA, both leading to EC tau) against the null model (independent paths of LC and WMSA between FRS‐CVD and EC tau;Figure1). Models were bootstrapped (n = 2000). Model fit measures determined which model described the data best (CFI >0.90, RMSEA <0.08, SRMR <0.08). Age and sex were included as covariates. Result Models null and 2 had poor fit. Model‐1 had an excellent fit, suggesting that a higher likelihood of a cardiovascular event in ten years is positively associated with WMSA, WMSA is associated with LC intensity, which in turn is associated with EC tau (Table2). Posthoc, global Aβ (DVR) was added as covariate in model‐1, this did not change the model‐fit or outcomes. Conclusion Previous work demonstrated that LC‐intensity correlates strongly with entorhinal tau. Our findings now suggest that presence of increased cardiovascular risk is associated with lower LC‐intensity through its effects on white‐matter damage, emphasizing the importance of mitigating risk factors earlier in life.