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Abstract 


Background

The noradrenergic locus coeruleus (LC) accumulates pathology early in Alzheimer's disease (AD), with LC dysfunction contributing to symptoms and disease progression. We investigated LC and substantia nigra (SN) integrity in healthy controls and AD participants.

Methods

Ninety-three AD participants and 29 controls underwent neuromelanin magnetic resonance imaging. LC and SN contrast, reflecting nucleus integrity, related to cognitive and neuropsychiatric symptoms, as well as cognitive decline and atrophy rates.

Results

LC - but not SN - integrity was reduced in AD versus controls (b = -0.39, p = 0.001) and within AD was associated with global cognition (b = 8.53, p = 0.04) and neuropsychiatric symptoms, accounting for SN. An AD subgroup with reduced SN integrity had worse cognition. LC integrity predicted plasma phosphorylated tau protein 217 (b = -0.30, p = 0.03). Lower LC and SN integrities were both related to faster cognitive decline (LC: b = -4.74, p = 0.048; SN: b = -2.27, p = 0.03), accounting for one another.

Discussion

Catecholaminergic nucleus integrity plays an important role in AD. Both systems are relevant to cognitive performance and decline. LC, in particular, relates closely to symptoms, pathology, and rate of progression.

Highlights

In symptomatic AD, LC integrity reflects cortical AD pathology, measured by pTau217. LC integrity predicts cognitive function in AD, independent of cortical atrophy. LC and SN integrity independently relate to attentional performance. Symptoms of anxiety, depression, and apathy are associated with lower LC integrity. LC and SN relate to cognitive decline rate and left LC predicts atrophy rate.

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    Funding 


    Funders who supported this work.

    Alzheimer's Society (1)

    • Grant ID: 608 AS‐CTF‐22‐013

    Alzheimer's Research UK

      Alzheimer's Society (3)

      • Grant ID: 608

      • Grant ID: 10

      • Grant ID: 608 AS-CTF-22-013

      Alzheimer’s Research UK

        Dementias Platform UK

          LifeArc

            Medical Research Council (1)

            • Grant ID: MR/W016095/1

            NIHR Imperial Biomedical Research Centre

              National Institute for Health Research (NIHR) (1)

              • Grant ID: NIHR302971

              National Institute for Health and Care Research (1)

              • Grant ID: NIHR302971

              National Institute for Health and Care Research (NIHR) Advanced Fellow (1)

              • Grant ID: NIHR302971

              the UK DRI (1)

              • Grant ID: UKDRI-7202

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