Locus coeruleus network architecture of Alzheimer's disease vulnerability

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ABSTRACT: The locus coeruleus (LC) is considered to be one of the earliest regions accumulating hyperphosphorylated tau. The first pretangle deposits occur in young adulthood, and by age 40 the LC is affected in nearly every case at autopsy. These tau aggregates occur before the earliest cortical involvement in the entorhinal cortex around age 50, from where they progress to limbic and other cortical regions. The fact that this highly predictable anatomic pattern of pathology progression occurs along regions that are connected suggests that LC-brain connectivity is one of the mechanisms contributing to the earliest vulnerability of accumulation and propagation of tau in Alzheimer's disease (AD). The LC has widespread projections to the cortex enabling the integration and coordination of communication between segregated regions. However, even though, tau is omnipresent in the LC of every person above age 40, not everyone will head down to an irreversible AD path. Thus, to ensure that prevention trials are more effective in these early stages, it will be critical to distinguish individuals at risk of AD versus those who remain resilient in the face of pathology. To overcome this barrier, we need to discern LC large-scale network architectural patterns associated with AD vulnerability versus those conferring resiliency to AD. This will provide a deeper understanding of network changes related to healthy or pathological aging, improve early detection and contribute to identifying individuals at-risk for inclusion in prevention trials. The overall goal of this proposal is to characterize and understand the biological background of LC's specific vulnerability by identifying specific LC- network patterns contributing to vulnerability to AD versus those that confer resiliency, and map associated genetic traits. We hypothesize that associating the selective degradation of the LC's capacity to integrate brain networks with AD pathology will uncover vulnerable and resilient LC-cortical network architectural layouts, which will be associated with AD-related cognitive decline or resiliency, respectively. To achieve this, we will generate multi- modal LC tau-vulnerable clusters by utilizing a unique large 7T fMRI adult lifespan brainstem cohort with novel plasma AD-biomarker data. The architecture of networks emerging from LC clusters will be examined in this 7T fMRI dataset and in two large-scale NIA-funded, rich multi-modal longitudinal datasets, the Harvard Aging Brain Study and ADNI. We will examine the following aims: 1) To identify the anatomic vulnerability to tau along the rostro-caudal axis of the LC and its association with age, sex and APOE; 2) To relate AD pathology to patterns of LC-cortical network architecture, and identify at-risk versus resilient patterns; 3) To characterize the genetic brain transcriptome of tau spreading profiles associated with at-risk and resilient LC- cortical network patterns. The proposed research is innovative and can result in a significant breakthrough for the field by shifting detection to earlier time points and providing new enrollment strategies or targets for therapeutic approaches administered earlier in the disease trajectory, when brain damage is not yet irreversible.