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Alzheimer’s disease pathology: pathways between central norepinephrine activity, memory, and neuropsychiatric symptoms

Molecular Psychiatry volume 26, pages 897–906 (2021)Cite this article

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Abstract

The locus coeruleus (LC) supplies norepinephrine to the brain, is one of the first sites of tau deposition in Alzheimer’s disease (AD) and modulates a variety of behaviors and cognitive functions. Transgenic mouse models showed that norepinephrine dysregulation after LC lesions exacerbates inflammatory responses, blood–brain barrier leakage (BBB), and cognitive deficits. Here, we investigated relationships between central norepinephrine metabolism, tau and beta-amyloid (Aβ), inflammation, BBB-dysfunction, neuropsychiatric problems, and memory in-vivo in a memory clinic population (total n = 111, 60 subjective cognitive decline, 36 mild cognitively impaired, and 19 AD dementia). Cerebrospinal fluid (CSF) and blood samples were collected and analyzed for 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), CSF/plasma albumin ratio (Q-alb), Aβ, phosphorylated tau, and interleukins. The verbal word learning task and the neuropsychiatric inventory assessed memory functioning and neuropsychiatric symptoms. Structural equation models tested the relationships between all fluid markers, cognition and behavior, corrected for age, education, sex, and clinical dementia rating score. Our results showed that neuropsychiatric symptoms show strong links to both MHPG and p-tau, whereas memory deficits are linked to MHPG via a combination of p-tau and inflammation-driven amyloidosis (30–35% indirect effect contribution). These results suggest that the LC-norepinephrine may be pivotal to understand links between AD pathology and behavioral and cognitive deficits in AD.

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Supplementary information is available at MP’s website. Data used in the current study is available from the corresponding author on reasonable request and in accordance with the EU legislation on the general data protection regulation.

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Acknowledgements

This work is supported by a standard grant of Alzheimer Nederland [#15007]. We are grateful to Linda Pagen M.Sc and Ron Mengelers for their assistance in obtaining the clinical data.

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  1. These authors contributed equally: Heidi I.L. Jacobs, Joost M. Riphagen

Authors and Affiliations

  1. Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA

    Heidi I. L. Jacobs

  2. Faculty of Health, Medicine and Life Sciences, School for Mental Health and Neuroscience, Alzheimer Centre Limburg, Maastricht University, Maastricht, The Netherlands

    Heidi I. L. Jacobs, Joost M. Riphagen, Inez H. G. B. Ramakers & Frans R. J. Verhey

  3. Faculty of Psychology and Neuroscience, Department of Cognitive Neuroscience, Maastricht University, PO BOX 616, 6200 MD, Maastricht, The Netherlands

    Heidi I. L. Jacobs

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Jacobs, H.I.L., Riphagen, J.M., Ramakers, I.H.G.B. et al. Alzheimer’s disease pathology: pathways between central norepinephrine activity, memory, and neuropsychiatric symptoms. Mol Psychiatry 26, 897–906 (2021). https://doi.org/10.1038/s41380-019-0437-x

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