Reimagining Cholinergic Therapy for Alzheimer's Disease

Ezio Giacobini; A. Claudio Cuello; Abraham Fisher


Brain. 2022;145(7):2250-2275. 

In This Article

Abstract and Introduction


Currently, enhancement of cholinergic neurotransmission via cholinesterase inhibitors represents the main available approach to treat cognitive and behavioural symptoms of the early as well as late stages of Alzheimer's disease. Restoring the cholinergic system has been a primary means of improving cognition in Alzheimer's disease, as four of the six approved therapies are acetylcholinesterase inhibitors.

Memantine is an N-methyl-D-aspartate antagonist with a well-documented clinical effect on behavioural symptoms, which is often added to cholinesterase inhibitors to potentiate their effect and aducanumab, targeting the amyloid pathology, has recently been approved.

The early, progressive and selective degeneration of the cholinergic system together and its close relation to cognitive deficits supports the use of cholinergic therapy for Alzheimer's disease.

This review provides an updated view of the basal forebrain cholinergic system, its relation to cognition and its relevance for therapy of Alzheimer's disease. It deals with the three main aspects that form the basis of the cholinergic-oriented therapy of Alzheimer's disease, its origin, its mechanism of action, its clinical effects, advantages and limits of a cholinergic therapeutic approach. It includes a new and updated overview of the involvement of muscarinic receptors in Alzheimer's disease as well as the recent development of new and highly selective M1 muscarinic receptor agonists with disease-modifying potential. It also addresses the discovery of a novel nerve growth factor metabolic pathway responsible for the trophic maintenance of the basal forebrain system and its deregulation 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.

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


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

Progressive loss of memory, particularly of episodic memory, starts early in Alzheimer's disease together with neurodegeneration of cholinergic neurons of the basal forebrain. Short-term memory is impaired in later 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 hallmark of Alzheimer's disease. The correlation of severity of dementia with disruption of several cortical cholinergic markers, including reduced choline-acetyltransferase (ChAT) and choline uptake, reduction of acetylcholine (ACh) synthesis and levels and decrease of nicotinic receptors (nAChR) subtypes suggest a close link between cholinergic 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 the loss of noradrenergic innervation exacerbates Alzheimer's disease pathogenesis and progression, although the precise role of noradrenergic components in Alzheimer's disease remains unresolved.[4–6]

Atrophy of the cholinergic basal forebrain progresses against a background of age-related decrease as observed from the normal adult age into the early stages of Alzheimer's disease.[7] The dysfunction of cholinergic circuits and signalling contributes to cognitive decline associated with several neurodegenerative diseases besides Alzheimer's disease, such as Parkinson's and Lewy body disease.[8] Figure 2 illustrates the main neuronal pathways from the nucleus basalis of Meynert (NbM) and septal nucleus supplying cholinergic synapses to the cerebral cortex and hippocampus, differentiated from the diffuse cholinergic projections from the tegmental-pontine nucleus[9,10] and the notorious large local circuit cholinergic neurons of the caudate-putamen.

The early and selective degeneration of the cholinergic system together with its close relation to cognitive deficits supports the use of cholinergic drugs in the therapy of Alzheimer's disease. Currently, enhancement of cholinergic neurotransmission represents the only available approach to treat cognitive and behavioural symptoms of early as well as late stages of Alzheimer's disease. Consequently, restoring the cholinergic system has been and remains a primary means of improving cognition in Alzheimer's disease.