Cholinergic Dysfunction in Neurodegenerative Diseases

Cholinergic neurotransmission, driven by acetylcholine release from basal forebrain and brainstem nuclei, underpins cognitive processes including attention, memory consolidation and sensory integration. In neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease dementia and dementia with Lewy bodies, selective loss of cholinergic neurons in the nucleus basalis of Meynert and the pedunculopontine nucleus leads to reduced cortical acetylcholine, contributing to hallmark symptoms of cognitive decline, impaired gait and visual disturbances. Structural imaging reveals early atrophy of cholinergic nuclei and white matter tracts, while functional studies demonstrate altered synaptic transmission and receptor down-regulation. Degeneration follows a caudorostral gradient in the basal forebrain, with posterior regions often affected first, and extends to subcortical targets that modulate motor control. Cholinergic dysfunction interacts with amyloid and tau pathology in Alzheimer’s disease and α-synuclein aggregates in Lewy body disorders, exacerbating synaptic disconnection and network failure. Therapeutic approaches have focused on cholinesterase inhibitors to enhance residual acetylcholine levels and on muscarinic or nicotinic receptor agonists to restore receptor function. Emerging strategies aim to protect cholinergic neurons through neurotrophic factors, modulate neuroinflammation and employ deep-brain stimulation of brainstem cholinergic centres. Understanding the patterns of cholinergic loss and compensatory plasticity provides a framework for early diagnosis, risk stratification and tailored interventions that address both cognitive and motor domains.

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Cholinergic Dysfunction in Neurodegenerative Diseases publication trend

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Technical terms

Basal forebrain: A collection of cholinergic nuclei, including the nucleus basalis of Meynert, that project widely to the cortex and hippocampus and regulate cognitive function.

Pedunculopontine nucleus (PPN): A brainstem cholinergic region projecting to thalamus and spinal cord, involved in gait and arousal, often degenerated in Lewy body disorders.

Free water imaging: An advanced diffusion-tensor technique that separates extracellular free water fraction from tissue signal, sensitive to microstructural degeneration.

Cholinesterase inhibitors: Drugs that prevent the breakdown of acetylcholine at synapses, thereby enhancing cholinergic transmission in degenerating brain regions.

Nicotinic and muscarinic receptors: Subtypes of acetylcholine receptors; nicotinic are ionotropic and fast-acting, muscarinic are metabotropic and modulate slower synaptic responses.

References

1. Drug development targeting degeneration of the basal forebrain cholinergic system: its time has come. Molecular Neurodegeneration (2023).
2. Free water imaging of the cholinergic system in dementia with Lewy bodies and Alzheimer's disease. Alzheimer's & Dementia (2023).
3. Associations of cholinergic system integrity with cognitive decline in GBA1 and LRRK2 mutation carriers. npj Parkinson's Disease (2024).