Neurotransmitters and Neuromodulators in Dementia

doi:10.1017/9781108985055.005

Chapter 5 - Neurotransmitters and Neuromodulators in Dementia

from Section 1 - Introductory Chapters on Dementia

Published online by Cambridge University Press: 17 November 2025

Neus Falgàs Martínez ,

Caroline Lew ,

Alejandra Sánchez López ,

Cathrine Petersen and

Lea T. Grinberg

Edited by

Bruce L. Miller and

Bradley F. Boeve

Show author details

Bruce L. Miller: Affiliation:
University of California, San Francisco
Bradley F. Boeve: Affiliation:
Mayo Clinic, Minnesota

Book contents

Get access

Summary

The brain neuromodulatory systems consist of small regions in the brainstem, pontine nucleus, and basal forebrain that regulate cognitive behavior by releasing neurotransmitters. Ascending projections from the brainstem and basal forebrain regions spread these neurotransmitters to broad areas of the central nervous system within the frontal cortex, anterior cingulate, or hippocampus, signaling a range of neural pathways. The modulator effect executed in these brain areas, together with the interplay between the systems, is crucial for regulating and adjusting many cognitive and behavioral functions. Neurodegenerative disease processes frequently affect the normal functioning of these modulator circuitries, directly leading to or contributing to the appearance of cognitive and neuropsychiatric symptoms. Even though these neuromodulatory systems’ impairment and imbalance happen early, further efforts to understand better their neurobiological basis are warranted . Hence, this chapter aims to review the role of the neuromodulatory systems in behavior and cognition and how their dysfunction shapes the neurodegenerative dementia phenotype.

Keywords

neuromodulation neurotransmitter noradrenaline serotonin dopamine acetylcholine locus coeruleus dorsal raphe neuropsychiatric symptoms cognition neurodegeneration

Information

Type: Chapter
Information: The Behavioral Neurology of Dementia , pp. 75 - 86

DOI: https://doi.org/10.1017/9781108985055.005 [Opens in a new window]

Publisher: Cambridge University Press

Print publication year: 2025

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Book purchase

Temporarily unavailable

References

Theofilas, P, Dunlop, S, Heinsen, H, Grinberg, LT. Turning on the light within: subcortical nuclei of the isodentritic core and their role in Alzheimer’s disease pathogenesis. J Alzheimers Dis. 2015 May 7;46(1):17–34.10.3233/JAD-142682CrossRef Google Scholar PubMed

Gut, NK, Mena-Segovia, J. Dichotomy between motor and cognitive functions of midbrain cholinergic neurons. Neurobiol Dis. 2019 Aug 1;128:59–66.10.1016/j.nbd.2018.09.008CrossRef Google Scholar PubMed

Zhou, F-M, Wilson, CJ, Dani, JA. Cholinergic interneuron characteristics and nicotinic properties in the striatum. J Neurobiol. 2002 Dec;53(4):590–605.10.1002/neu.10150CrossRef Google Scholar PubMed

Eser, RA, Ehrenberg, AJ, Petersen, C, et al. Selective vulnerability of brainstem nuclei in distinct tauopathies: a postmortem study. J Neuropathol Exp Neurol. 2018;77(2):149–161.10.1093/jnen/nlx113CrossRef Google Scholar PubMed

Hampel, H, Mesulam, M-M, Cuello, AC, et al. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain. 2018 Jul 1;141(7):1917–1933.10.1093/brain/awy132CrossRef Google Scholar PubMed

Oswal, A, Gratwicke, J, Akram, H, et al. Cortical connectivity of the nucleus basalis of Meynert in Parkinson’s disease and Lewy body dementias. Brain J Neurol. 2020 Dec 26;144(3):781–788.10.1093/brain/awaa411CrossRef Google Scholar

Barrett, MJ, Cloud, LJ, Shah, H, Holloway, KL. Therapeutic approaches to cholinergic deficiency in Lewy body diseases. Expert Rev Neurother. 2020 Jan 2;20(1):41–53.10.1080/14737175.2020.1676152CrossRef Google Scholar PubMed

Lim, YY, Maruff, P, Schindler, R, et al. Disruption of cholinergic neurotransmission exacerbates Aβ-related cognitive impairment in preclinical Alzheimer’s disease. Neurobiol Aging. 2015 Oct;36(10):2709–2715.10.1016/j.neurobiolaging.2015.07.009CrossRef Google Scholar PubMed

Birks, JS, Harvey, RJ. Donepezil for dementia due to Alzheimer’s disease. Cochrane Database Syst Rev. 2018;(6):CD001190.Google Scholar PubMed

Dubois, B, Chupin, M, Hampel, H, et al. Donepezil decreases annual rate of hippocampal atrophy in suspected prodromal Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc. 2015 Sep;11(9):1041–1049.10.1016/j.jalz.2014.10.003CrossRef Google Scholar PubMed

Ranjbar-Slamloo, Y, Fazlali, Z. Dopamine and noradrenaline in the brain; overlapping or dissociate functions? Front Mol Neurosci. 2020 Jan 21;12:334.10.3389/fnmol.2019.00334CrossRef Google Scholar PubMed

Berridge, CW, Schmeichel, BE, España, RA. Noradrenergic modulation of wakefulness/arousal. Sleep Med Rev. 2012 Apr;16(2):187–197.10.1016/j.smrv.2011.12.003CrossRef Google Scholar PubMed

Braak, H, Braak, E. Neurofibrillary changes confined to the entorhinal region and an abundance of cortical amyloid in cases of presenile and senile dementia. Acta Neuropathol (Berl). 1990;80(5):479–486.10.1007/BF00294607CrossRef Google Scholar

Stratmann, K, Heinsen, H, Korf, H-W, et al. Precortical phase of Alzheimer’s disease (AD)-related tau cytoskeletal pathology. Brain Pathol Zurich Switz. 2016 May;26(3):371–386.10.1111/bpa.12289CrossRef Google Scholar PubMed

Tomlinson, BE, Irving, D, Blessed, G. Cell loss in the locus coeruleus in senile dementia of Alzheimer type. J Neurol Sci. 1981 Mar;49(3):419–428.10.1016/0022-510X(81)90031-9CrossRef Google Scholar PubMed

Parvizi, J. Corticocentric myopia: old bias in new cognitive sciences. Trends Cogn Sci. 2009 Aug;13(8):354–359.10.1016/j.tics.2009.04.008CrossRef Google Scholar PubMed

Braak, H, Del Tredici, K. The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol (Berl). 2011;121(2):171–181.10.1007/s00401-010-0789-4CrossRef Google Scholar PubMed

Oh, J, Eser, RA, Ehrenberg, AJ, et al. Profound degeneration of wake-promoting neurons in Alzheimer’s disease. Alzheimers Dement. 2019;(July):1–11.Google Scholar

Grudzien, A, Shaw, P, Weintraub, S, et al. Locus coeruleus neurofibrillary degeneration in aging, mild cognitive impairment and early Alzheimer’s disease. Neurobiol Aging. 2007;28(3):327–335.10.1016/j.neurobiolaging.2006.02.007CrossRef Google Scholar PubMed

Ehrenberg, AJ, Nguy, AK, Theofilas, P, et al. Quantifying the accretion of hyperphosphorylated tau in the locus coeruleus and dorsal raphe nucleus: the pathological building blocks of early Alzheimer’s disease. Neuropathol Appl Neurobiol. 2017;43(5):393–408.10.1111/nan.12387CrossRef Google Scholar PubMed

Theofilas, P, Ehrenberg, AJ, Dunlop, S, et al. Locus coeruleus volume and cell population changes during Alzheimer’s disease progression: a stereological study in human postmortem brains with potential implication for early-stage biomarker discovery. Alzheimers Dement. 2017;13(3):236–246.10.1016/j.jalz.2016.06.2362CrossRef Google Scholar

Elobeid, A, Soininen, H, Alafuzoff, I. Hyperphosphorylated tau in young and middle-aged subjects. Acta Neuropathol (Berl). 2012;123(1):97–104.10.1007/s00401-011-0906-zCrossRef Google Scholar

Jacobs, HIL, Riphagen, JM, Ramakers, IHGB, Verhey, FRJ. Alzheimer’s disease pathology: pathways between central norepinephrine activity, memory, and neuropsychiatric symptoms. Mol Psychiatry. 2019 May 28;26(3):897–906.10.1038/s41380-019-0437-xCrossRef Google Scholar PubMed

Pillet, L-E, Taccola, C, Cotoni, J, et al. Correlation between cognition and plasma noradrenaline level in Alzheimer’s disease: a potential new blood marker of disease evolution. Transl Psychiatry. 2020 Jul 3;10(1):213.10.1038/s41398-020-0841-7CrossRef Google Scholar PubMed

Ehrenberg, AJ, Suemoto, CK, França Resende, E de P, et al. Neuropathologic correlates of psychiatric symptoms in Alzheimer’s disease. J Alzheimers Dis. 2018 Oct 16;66(1):115–126.10.3233/JAD-180688CrossRef Google Scholar PubMed

Matchett, BJ, Grinberg, LT, Theofilas, P, Murray, ME. The mechanistic link between selective vulnerability of the locus coeruleus and neurodegeneration in Alzheimer’s disease. Acta Neuropathol (Berl). 2021 Jan 11;141(5):631–650.10.1007/s00401-020-02248-1CrossRef Google Scholar PubMed

Weinshenker, D. Long road to ruin: noradrenergic dysfunction in neurodegenerative disease. Trends Neurosci. 2018 Apr;41(4):211–223.10.1016/j.tins.2018.01.010CrossRef Google Scholar PubMed

Betts, MJ, Kirilina, E, Otaduy, MCG, et al. Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases. Brain J Neurol. 2019 Sep 1;142(9):2558–2571.10.1093/brain/awz193CrossRef Google Scholar PubMed

Kelberman, M, Keilholz, S, Weinshenker, D. What’s that (blue) spot on my MRI? Multimodal neuroimaging of the locus coeruleus in neurodegenerative disease. Front Neurosci. 2020;14:583421.10.3389/fnins.2020.583421CrossRef Google Scholar PubMed

Gatchel, JR, Donovan, NJ, Locascio, JJ, et al. depressive symptoms and tau accumulation in the inferior temporal lobe and entorhinal cortex in cognitively normal older adults: a pilot study. J Alzheimers Dis. 2017;59(3):975–985.10.3233/JAD-170001CrossRef Google Scholar PubMed

Falgàs, N, Walsh, CM, Neylan, TC, Grinberg, LT. Deepen into sleep and wake patterns across Alzheimer’s disease phenotypes. Alzheimers Dement. 2021 Aug;17(8):1403–1406.10.1002/alz.12304CrossRef Google Scholar PubMed

Murphy, DL, Fox, MA, Timpano, KR, et al. How the serotonin story is being rewritten by new gene-based discoveries principally related to SLC6A4, the serotonin transporter gene, which functions to influence all cellular serotonin systems. Neuropharmacology. 2008 Nov;55(6):932–960.10.1016/j.neuropharm.2008.08.034CrossRef Google Scholar PubMed

Hornung, J-P. The neuronatomy of the serotonergic system. In Müller, CP, Jacobs, BL, eds. Handbook of Behavioral Neuroscience, vol. 21 [Internet]. Elsevier, 2010 [cited 2021 Feb 17]; pp. 51–64. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1569733910700710 Google Scholar

Grinberg, LT, Rüb, U, Ferretti, REL, et al. The dorsal raphe nucleus shows phospho-tau neurofibrillary changes before the transentorhinal region in Alzheimer’s disease. A precocious onset? Neuropathol Appl Neurobiol. 2009 Aug;35(4):406–416.10.1111/j.1365-2990.2008.00997.xCrossRef Google Scholar PubMed

Rüb, U, Del Tredici, K, Schultz, C, et al. The evolution of Alzheimer’s disease-related cytoskeletal pathology in the human raphe nuclei. Neuropathol Appl Neurobiol. 2000;26(6):553–567.10.1046/j.0305-1846.2000.00291.xCrossRef Google Scholar PubMed

Grinberg, LT, Rueb, U, Heinsen, H. Brainstem: neglected locus in neurodegenerative diseases. Front Neurol. 2011;2:42.10.3389/fneur.2011.00042CrossRef Google Scholar PubMed

Theofilas, P, Ehrenberg, AJ, Nguy, A, et al. Probing the correlation of neuronal loss, neurofibrillary tangles, and cell death markers across the Alzheimer’s disease Braak stages: a quantitative study in humans. Neurobiol Aging. 2018 Jan;61:1–12.10.1016/j.neurobiolaging.2017.09.007CrossRef Google Scholar PubMed

Lai, MKP, Tsang, SWY, Francis, PT, et al. Postmortem serotoninergic correlates of cognitive decline in Alzheimer’s disease. Neuroreport. 2002 Jul 2;13(9):1175–1178.10.1097/00001756-200207020-00021CrossRef Google Scholar PubMed

Geldenhuys, WJ, Van der Schyf, CJ. Role of serotonin in Alzheimer’s disease: a new therapeutic target? CNS Drugs. 2011 Sep 1;25(9):765–781.10.2165/11590190-000000000-00000CrossRef Google Scholar PubMed

Klein, MO, Battagello, DS, Cardoso, AR, et al. Dopamine: functions, signaling, and association with neurological diseases. Cell Mol Neurobiol. 2019 Jan;39(1):31–59.10.1007/s10571-018-0632-3CrossRef Google Scholar

McRitchie, DA, Cartwright, HR, Halliday, GM. Specific A10 dopaminergic nuclei in the midbrain degenerate in Parkinson’s disease. Exp Neurol. 1997 Mar;144(1):202–213.10.1006/exnr.1997.6418CrossRef Google Scholar PubMed

Djang, DSW, Janssen, MJR, Bohnen, N, et al. SNM practice guideline for dopamine transporter imaging with 123i-ioflupane SPECT 1.0. J Nucl Med. 2012 Jan 1;53(1):154–163.10.2967/jnumed.111.100784CrossRef Google Scholar PubMed

Gomperts, SN, Marquie, M, Locascio, JJ, et al. PET radioligands reveal the basis of dementia in Parkinson disease and dementia with Lewy bodies. Neurodegener Dis. 2016;16(1–2):118–124.10.1159/000441421CrossRef Google Scholar PubMed

Armstrong, MJ, Okun, MS. Diagnosis and treatment of Parkinson disease: a review. JAMA. 2020 Feb 11;323(6):548–560.10.1001/jama.2019.22360CrossRef Google Scholar PubMed

McKeith, IG, Boeve, BF, Dickson, DW, et al. Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium. Neurology. 2017 Jul 4;89(1):88–100.10.1212/WNL.0000000000004058CrossRef Google Scholar PubMed

Chieffi, S, Carotenuto, M, Monda, V, et al. Orexin system: the key for a healthy life. Front Physiol. 2017 May 31;8:357.10.3389/fphys.2017.00357CrossRef Google Scholar PubMed

Willie, JT, Chemelli, RM, Sinton, CM, Yanagisawa, M. To eat or to sleep? Orexin in the regulation of feeding and wakefulness. Annu Rev Neurosci. 2001 Mar;24(1):429–458.10.1146/annurev.neuro.24.1.429CrossRef Google Scholar PubMed

Liguori, C. Orexin and Alzheimer’s disease. Curr Top Behav Neurosci. 2017;33: 305–322.10.1007/7854_2016_50CrossRef Google Scholar PubMed

Naddafi, F, Mirshafiey, A. The neglected role of histamine in Alzheimer’s disease. Am J Alzheimers Dis Dementiasr. 2013 Jun 1;28(4):327–336.10.1177/1533317513488925CrossRef Google Scholar PubMed

Oh, J, Petersen, C, Walsh, CM, et al. The role of co-neurotransmitters in sleep and wake regulation. Mol Psychiatry. 2019 Sep;24(9):1284–1295.10.1038/s41380-018-0291-2CrossRef Google Scholar PubMed

Counts, SE, Perez, SE, Ginsberg, SD, Mufson, EJ. Neuroprotective role for galanin in Alzheimer’s disease. In Hökfelt, T, ed. Galanin (Experientia Supplementum; vol. 102) [Internet]. Basel: Springer Basel, 2010 [cited 2021 Mar 10]; pp. 143–162. Available from: http://link.springer.com/10.1007/978-3-0346-0228-0_1110.1007/978-3-0346-0228-0_11CrossRef Google Scholar PubMed

Falgàs, N, Peña-González, M, Val-Guardiola, A, Pérez-Millan, A, Guillén, N, Sarto, J, Esteller, D, Bosch, B, Fernández-Villullas, G, Tort-Merino, A, Mayà, G, Augé, JM, Iranzo, A, Balasa, M, Lladó, A, Morales-Ruiz, M, Bargalló, N, Muñoz-Moreno, E, Grinberg, LT, Sánchez-Valle R. Locus coeruleus integrity and neuropsychiatric symptoms in a cohort of early- and late-onset Alzheimer’s disease. Alzheimers Dement. 2024 Sep;20(9):6351–6364. doi: 10.1002/alz.14131. Epub 2024 Jul 25. PMID: 39051173; PMCID: PMC11497680.CrossRef Google Scholar

Oh, JY, Walsh, CM, Ranasinghe, K, Mladinov, M, Pereira, FL, Petersen, C, Falgàs, N, Yack, L, Lamore, T, Nasar, R, Lew, C, Li, S, Metzler, T, Coppola, Q, Pandher, N, Le, M, Heuer, HW, Heinsen, H, Spina, S, Seeley, WW, Kramer, J, Rabinovici, GD, Boxer, AL, Miller, BL, Vossel, K, Neylan, TC, Grinberg, LT. Subcortical Neuronal Correlates of Sleep in Neurodegenerative Diseases. JAMA Neurol. 2022 May 1;79(5):498–508. doi: 10.1001/jamaneurol.2022.0429. PMID: 35377391; PMCID: PMC8981071.CrossRef Google Scholar PubMed

Accessibility standard: WCAG 2.1 AA

Why this information is here

This section outlines the accessibility features of this content - including support for screen readers, full keyboard navigation and high-contrast display options. This may not be relevant for you.

Accessibility Information

The PDF of this book complies with version 2.1 of the Web Content Accessibility Guidelines (WCAG), covering newer accessibility requirements and improved user experiences and achieves the intermediate (AA) level of WCAG compliance, covering a wider range of accessibility requirements.

Content Navigation

Table of contents navigation
Allows you to navigate directly to chapters, sections, or non‐text items through a linked table of contents, reducing the need for extensive scrolling.

Index navigation
Provides an interactive index, letting you go straight to where a term or subject appears in the text without manual searching.

Reading Order & Textual Equivalents

Single logical reading order
You will encounter all content (including footnotes, captions, etc.) in a clear, sequential flow, making it easier to follow with assistive tools like screen readers.

Short alternative textual descriptions
You get concise descriptions (for images, charts, or media clips), ensuring you do not miss crucial information when visual or audio elements are not accessible.

Visual Accessibility

Use of colour is not sole means of conveying information
You will still understand key ideas or prompts without relying solely on colour, which is especially helpful if you have colour vision deficiencies.

Structural and Technical Features

ARIA roles provided
You gain clarity from ARIA (Accessible Rich Internet Applications) roles and attributes, as they help assistive technologies interpret how each part of the content functions.