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Basic Science and Pathogenesis.

Ronald Marcus1, Scott Vuocolo1, Ian Ramsey1

  • 1Bristol Myers Squibb, Princeton, NJ, USA.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 24, 2025
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Summary
This summary is machine-generated.

New Alzheimer's disease (AD) treatments targeting M1 and M4 muscarinic receptors show promise for improving cognition and psychosis. These receptors modulate neurotransmitter pathways, offering a novel therapeutic approach for AD symptoms.

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Area of Science:

  • Neuroscience
  • Pharmacology

Background:

  • Alzheimer's disease (AD) and related dementias are characterized by cognitive impairment and neuropsychiatric symptoms like psychosis.
  • Current treatments for these symptoms have limitations, necessitating novel therapeutic mechanisms.
  • Previous research indicates that xanomeline, a muscarinic receptor agonist, improved cognition and psychosis in AD patients.

Purpose of the Study:

  • To review preclinical data on muscarinic receptor regulation of neural networks involved in psychosis and cognition.
  • To develop hypotheses on the role of muscarinic receptors in AD-related psychosis and cognitive pathways.

Main Methods:

  • Literature review of preclinical data.
  • Development of hypotheses based on gathered evidence.

Main Results:

  • Muscarinic receptors are highly expressed in brain regions critical for psychosis (striatum, PFC) and learning/memory (hippocampus).
  • Hypothesized mechanisms include M4 autoreceptor activation reducing VTA dopamine circuit excitation and M1 activation dampening cortical excitation.
  • M4 activation in the hippocampus may inhibit glutamate release, while M1 activation in the PFC may normalize the excitation/inhibition balance.

Conclusions:

  • M1 and M4 muscarinic receptors modulate neurotransmitter levels through distinct pathways, impacting psychosis and cognition in AD.
  • The specific brain region localization of these receptors dictates targeted neurotransmitter responses.
  • Muscarinic receptor agonists represent a potential new therapeutic class for managing cognitive and neuropsychiatric symptoms in AD.