Reinventing cholinergic therapy for Alzheimer’s disease


Summary and introduction


Currently, enhancement of cholinergic neurotransmission via cholinesterase inhibitors represents the main approach available to treat the cognitive and behavioral symptoms of early and late stages of Alzheimer’s disease. Restoring the cholinergic system has been one of the main ways to improve cognition in Alzheimer’s disease, as four of the six approved therapies are acetylcholinesterase inhibitors.

Memantine is a NOT-methyl-D-aspartate antagonist with a well-documented clinical effect on behavioral symptoms, which is often added to cholinesterase inhibitors to potentiate their effect and aducanumab, targeting amyloid pathology, has recently been approved.

Early, progressive, and selective degeneration of the cholinergic system as well as its close relationship to cognitive deficits support the use of cholinergic therapy for Alzheimer’s disease.

This review provides an updated view of the basal forebrain cholinergic system, its relationship to cognition, and its relevance for the treatment of Alzheimer’s disease. It deals with the three main aspects on which the cholinergic-oriented therapy of Alzheimer’s disease is based, its origin, its mechanism of action, its clinical effects, the advantages and the limits of a cholinergic therapeutic approach. It includes new and updated insight into the involvement of muscarinic receptors in Alzheimer’s disease as well as the recent development of novel, highly selective muscarinic M1 receptor agonists with disease-modifying potential. It also discusses the discovery of a novel nerve growth factor metabolic pathway responsible for the trophic maintenance of the basal system of the forebrain and its dysregulation in Alzheimer’s disease. It discusses new clinical studies and provides evidence for the long-term efficacy of cholinesterase inhibitor therapy suggesting a disease-modifying effect of these drugs.

Classic symptomatic cholinergic therapy based on cholinesterase inhibitors is judiciously discussed for its maximum efficacy and best clinical application. The review proposes new cholinergic therapy alternatives that should be developed to amplify its clinical effect and complement the disease-modifying effect of new treatments to slow or arrest disease progression.


The pathology of Alzheimer’s disease is characterized by cognitive deficits and dementia, synaptic loss, degeneration of cholinergic neurons, and the formation of amyloid plaques containing amyloid-β peptide and neurofibrillary tangles composed of hyperphosphorylated tau proteins, normally expressed in axons as microtubule-associated proteins. tau proteins.[1]

Progressive memory loss, especially episodic memory, begins early in Alzheimer’s disease along with neurodegeneration of basal forebrain cholinergic neurons. Short-term memory is impaired in the advanced stages of the disease. A close relationship between progressive cholinergic degeneration and cognitive impairment is supported by the clinical efficacy of pharmacotherapy specifically targeting the cholinergic system.[2,3] Early and selective degeneration of cholinergic neurons is a fundamental feature of Alzheimer’s disease. The correlation between dementia severity and disruption of several cortical cholinergic markers, including reduced choline acetyltransferase (ChAT) and choline uptake, reduced acetylcholine synthesis and levels ( ACh) and decreased nicotinic receptor (nAChR) subtypes suggest a strong link between cholinergic receptor loss of function and cognitive decline in Alzheimer’s disease.[2]

Noradrenergic degeneration is also present in Alzheimer’s disease, particularly localized in the locus coeruleus indicating that loss of noradrenergic innervation exacerbates the pathogenesis and progression of Alzheimer’s disease, although the precise role of noradrenergic components in the Alzheimer’s disease remains unresolved.[4–6]

Cholinergic basal forebrain atrophy progresses against a background of age-related decline, as seen from normal adulthood through the early stages of Alzheimer’s disease.[7] Dysfunction of cholinergic circuits and signaling contribute to cognitive decline associated with several neurodegenerative diseases in addition to Alzheimer’s disease, such as Parkinson’s disease and Lewy body disease.[8] Figure 2 illustrates the major neural pathways originating from Meynert’s basal nucleus (NbM) and septal nucleus supplying cholinergic synapses in the cerebral cortex and hippocampus, differentiated from diffuse cholinergic projections from the tegmento-pontine nucleus[9,10] and the famous local large circuit cholinergic neurons of the caudate putamen.

The early and selective degeneration of the cholinergic system as well as its close relationship with cognitive deficits supports the use of cholinergic drugs in the treatment of Alzheimer’s disease. Currently, enhancing cholinergic neurotransmission represents the only approach available to treat the cognitive and behavioral symptoms of early and late stages of Alzheimer’s disease. Therefore, restoration of the cholinergic system has been and remains a primary means of improving cognition in Alzheimer’s disease.


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