# Contribution of locus coeruleus activity patterns on tau deposition in Alzheimer's disease > **NIH NIH R21** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $249,550 ## Abstract ABSTRACT Alzheimer's disease (AD)'s neuropathologic hallmarks are the accumulation of amyloid-beta (Aβ) and tau proteins. Thus far, therapeutic efforts have been mainly focused on Aβ and showed limited success, underscoring the need for alternative approaches of intervention, particularly those that can target mechanisms related to the initial propagation of pathology. The locus coeruleus (LC) has been identified as one of the earliest regions affected by tau: by the age of 40, 80% of individuals exhibit tau aggregation in the LC, and by the age of 50, 50% of individuals exhibit tau aggregation in the entorhinal cortex (EC), suggesting tau progression from the LC to the medial temporal lobe (MTL). However, the mechanism of tau propagation is yet unknown. Accumulated evidence from animal research suggests that pathologic tau propagates via axons and cell-to-cell transmission and that synaptic and neuronal activity levels facilitate this process. Furthermore, a recent study using a rat model of pretangle tau in LC neurons and optogenetic stimulation suggested that novelty-like phasic LC activation protects against the deleterious changes linked to pretangle tau. In contrast, stress-associated tonic LC activation worsens LC neuronal health and promotes depressive behaviors that have been associated with tau accumulation in the EC. Our own preliminary data shows that lower novelty-related LC activation is related to higher tau deposition in the EC and steeper memory decline in cognitively healthy older individuals. This evidence forms the scientific premise for the hypothesis that phasic versus tonic resting-state LC activity may be associated with mechanisms of tau propagation and ultimately predict cognitive decline. The goal of this proposal is to examine the relationship between the balance between phasic versus tonic LC activity detected in resting- state fMRI data and tau deposition in the EC and the MTL across all stages of the AD continuum and cognitive decline. To achieve this, we will resolve two methodological barriers: (ii) accounting for the hemodynamic blurring in resting-state fMRI using deconvolution in terms of an optimally defined region- and subject-specific hemodynamic response function, and (ii) using novel event-detection techniques for the detection of periods of phasic and tonic activity in the deconvoluted LC. Our methodology for quantifying the balance between phasic versus tonic LC activity will be fine-tuned and validated using simultaneous LC BOLD-fMRI, fiber photometry calcium imaging, and pupil dilation data collected from awake rodents during resting-experimental conditions. Combining these state-of-the-art novel methods with tau-, Aβ-PET, and longitudinal cognitive data from the Harvard Aging Brain Study and the Alzheimer Disease Neuroimaging Initiative, will allow us to examine the following aims: Aim 1) To investigate the associations between cross-sectional patterns of LC activity with age, sex, tau, and beta-amylo... ## Key facts - **NIH application ID:** 10879129 - **Project number:** 5R21AG081681-02 - **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL - **Principal Investigator:** Prokopis Christou Prokopiou - **Activity code:** R21 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $249,550 - **Award type:** 5 - **Project period:** 2023-07-01 → 2026-03-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10879129 ## Citation > US National Institutes of Health, RePORTER application 10879129, Contribution of locus coeruleus activity patterns on tau deposition in Alzheimer's disease (5R21AG081681-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10879129. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*