Left Frontoparietal Connectivity Counteracts Locus Coeruleus‐Related Attentional Decline in Preclinical Alzheimer’s Disease

Abstract

AbstractBackgroundAutopsy work reported that neuronal density in the locus coeruleus (LC) provides neural reserve against cognitive decline in dementia. Recent neuroimaging and pharmacological studies have also ascribed a protective role of the LC against cognitive decline, possibly mediated by prefrontal functional connectivity (FC). Interestingly, higher left frontoparietal network (LFPN) FC provides resilience against cognitive decline in preclinical sporadic or autosomal Alzheimer’s disease (AD). Given that the FPN and the LC play an important role in attentional control, and attention deficits are affected early in the disease process, we aimed to examine whether LFPN‐FC can counteract the impact of poor LC structural health on attention in the context of AD pathology.Method143 participants from the Harvard Aging Brain study who underwent 3T resting‐state functional MRI, LC structural imaging, PiB(Aβ)‐PET, and up to 4 years of cognitive follow‐ups were included (90 F, mean age = 75±9.88, Table 1). The Digit Symbol Substitution Test (DSST) assessed attentional control. Robust linear regression associated LC integrity or LFPN connectivity to DSST performance at baseline. Robust mixed effect analyses examined the associations between DSST decline and (i) the two‐way interaction between LC integrity (or LFPN‐FC) and PiB (DVR‐PVC), or (ii) the three‐way interaction between LC integrity, LFPN‐FC, and PiB (DVR‐PVC). All analyses were adjusted for age, sex, and years of education.ResultAt baseline, lower LFPN‐FC (p = 0.001) was related to worse performance on the DSST, while no such association was found for LC integrity (p = 0.26). Longitudinally, both, lower LC integrity (p<0.001) and LFPN‐FC (p = 0.026) were associated with faster DSST decline, especially at higher PiB levels (Figure 1). The modulating effect of LFPN‐FC is most prominent under lower LC structural integrity values, where higher levels of LFPN‐FC were associated with less steep decline on the DSST, in particular in individuals with higher PiB (p = 0.036, Figure 2).ConclusionOur findings demonstrate that when LC structural health is poor, higher LFPN‐FC can maintain cognitive performance even at higher levels of Aβ deposition in preclinical AD. These results provide critical insights and targets to support specific brain mechanisms that delay symptom progression in the early stages of the disease.