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

Abstract

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.

Introduction

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.

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Table 1. *In vivo* PET-measured ChE cortical inhibition at clinical doses
Drug	Dose in mg	Duration of treatment	Percentage inhibition	References
Galantamine	16–24	2 months	30–40	Kadir et al. ¹⁴⁹
Donepezil	5	12 weeks	19–24	Bohnen et al. ¹⁵⁰
Donepezil	5–10	5 weeks	27	Kuhl et al. ¹⁵¹
Donepezil	10	3 months	39	Kaasinen et al. ¹⁴⁸
Donepezil	3–5	3 months	39.5	Shinotoh et al. ¹⁵²
Rivastigmine	3–5	3 months	29–39	Kaasinen et al. ¹⁴⁸
Physostigmine	1.5	5 weeks	52	Kaasinen et al. ¹⁴⁸

Table 2. Differences in ADAS-Cog points following ChEI treatment
Drug	Duration	Points	References
Rivastigmine	18 months	2.57	Minthon et al. ¹⁵³
Galantamine	18 months	2.4	Wallin et al. ¹⁵⁴
Donepezil	26 weeks^a	2.67	Birks et al. ¹⁵⁵

^aAverage of five studies.

Table 3. Studies demonstrating long-term efficacy of cholinesterase inhibitors in patients with Alzheimer's disease
Drug	Number of patients	Maximum treatment duration (years)	Assessment criteria	Reference
Donepezil	1600	2	ADAS-Cog	Rogers et al. ¹⁵⁹
Donepezil	286	3	MMSE, GDR, PDS	Winblad et al. ¹⁸²
Tacrine	50	5	MMSE	Wallin et al. ¹⁸³
Rivastigmine	2149	2	ADAS-Cog, MMSE, CIBIC-Plus, GDS	Anand et al. ¹⁸⁴
Rivastigmine	217	2	MMSE, CIBIC, ADAS-Cog	Minthon et al. ¹⁵³
Galantamine	44	3	ADAS-Cog	Rainer et al. ¹⁸⁵
Galantamine	280	3	MMSE, ADAS-Cog, IADL, CDR	Wallin et al. ¹⁵⁴
Donepezil, rivastigmine or galantamine	843	3	MMSE, ADAS-Cog	Wattmo et al. ¹⁷⁸
Donepezil, rivastigmine or galantamine	790	3	MMSE, IADL, PSMS	Wattmo et al. ¹⁷⁸
Donepezil, rivastigmine or galantamine	1021	3	MMSE, ADAS-Cog	Wattmo et al. ¹⁸⁶
Donepezil, rivastigmine or galantamine	129	3	MMSE, CIBIC, ADAS-Cog, IADL ADL CSF P-tau, total tau, Aβ42, PET Aβ and PET-tau	Wattmo et al. ¹⁸⁰
Donepezil, rivastigmine or galantamine	11 562	5	MMSE, death risk	Xu et al. ¹⁸⁷

ADFACS = Alzheimer's disease Functional Assessment and Change Scale; Aβ = amyloid-β; CDR = Clinical Dementia Rating Scale; CIBIC-Plus = Clinicians Interview-Based Impression of Change with Caregiver Input; GBS = Gottfries-Brane-Steen Scale; GDS = Global Deterioration Scale; HA = hippocampal atrophy; IADL = Instrumental Activities of Daily Living; PDS = Progressive Deterioration Scale; PSMS = Physical Self-Maintenance Scale; P-tau = phosphorylated tau.

Table 4. Clinical studies with orthosteric muscarinic agonists and an M1 PAM
Compound	Selectivity	Parkinson's disease studies	Protein kinase studies	Toxicity and safety	Clinical studies	Comments
AF102B (Cevimeline, Evoxac)	Partial M1>M3 agonist	Effective in a multitude of animal models of Alzheimer's disease	T_1/2 5 ± 1 h. Bioavailability in humans >50%	The only significant AEs at 60 mg, tid were cholinergic, e.g. diaphoresis and excessive salivation of Alzheimer's disease patients	AF102B decreased CSF Aβ in Alzheimer's disease patients.AF102B was effective on ADAS-Cog in a pilot single-blind study in Alzheimer's disease. AF102B was effective in a double-blind study in Alzheimer's disease patients.	Repurposed for the treatment of Sjogren's disease. Evoxac is the only orthosteric M1 muscarinic agonist approved by the FDA and Japanese health authorities for the treatment of dry mouth in Sjogren's disease.
Talsaclidine	M1>M3; M3 agonistic effect (in SH-SY5Y cells); Nicotinic ligand with similar affinity to mAChR	No effects in animal models below 1 mg/kg except in a study in monkeys (0.6 mg/kg, po)	T_1/2 3 h. Bioavailability 70%	AEs (e.g. salivation, diaphoresis, nausea) at 6, 12, 24 mg, tid, and 24 mg in young healthy volunteers	Talsaclidine decreased CSF Aβ in Alzheimer's disease patients. No beneficial effects in Alzheimer's disease (12 weeks study, tid); wrong protocol? Some positive effects in severely demented patients.	Talsaclidine increased BACE1 levels. GI AEs; HR increased; not well tolerated.
Xanomeline	M1/M4 agonist; potent agonist at 5-HT1A and 5HT1B and antagonist at 5HT2 receptor subtype	Selectivity for M1 mAChR not manifested in vivo. Allometric scaling from some studies: 6 mg/day in Alzheimer's disease or schizophrenia but see PK	Very unfavourable PK profile with low oral bioavailability: 3–7% in rats and <1% in monkeys and humans. Several metabolites mask the M1 selectivity in vivo. Very low levels in plasma in patients. PET studies (man, rats and monkeys) brain/plasma ratio 0.1	In Alzheimer's disease AEs were: sweating (46% versus 5%); nausea (29% versus 17%); dyspepsia (23% versus 7%); chills (22% versus 1%); chest pain (13% versus 1%); syncope (loss of consciousness) (11% versus 4%); increase in HR and liver function	High dose shows beneficial effects in Alzheimer's disease (75, tid, po). However, 52% of Alzheimer's disease patients discontinued due to GI AEs. Methyl-scopolamine (peripheral muscarinic antagonist) did not prevent xanomeline-induced syncope.	Syncope is a CNS effect mediated by 5HT receptors.
KartXT, xanomeline + trospium	Xanomeline and Trospium (a peripheral antimuscarinic drug)	Clinical studies reported in schizophrenia	Better profile than xanomeline alone	Fewer AEs versus Xanomeline but AE due to trospium. Trospium may not prevent xanomeline-induced syncope	Effective in schizophrenia 115 mg, bid; no reports in Alzheimer's disease patients.	Trospium has peripheral AEs; might leak into the brain of Alzheimer's disease patients with a defective blood–brain barrier causing cognitive defects.
MK-7622	M1 PAM	Questionable qEEG in humans reminiscent of antimuscarinic drugs	Only 0.05% of the drug is free in plasma and this is the amount that can cross the blood–brain barrier	AEs in Alzheimer's disease patients (diarrhoea); convulsions in rodents	Alzheimer's disease on SOC: MK-7622 (45 mg; 12 weeks) did not improve cognition or function in Alzheimer's disease.	Trial stopped due to futility.

Aβ = amyloid-β; AEs = adverse events; GI = gastrointestinal; HR = heart rate; PAM = positive allosteric modulator; PK = protein kinase; SOC = standard of care. References: AF102B;^275,280,281 Fisher, unpublished; talsaclidine;^279,282 Xanomeline;^277,283 KarXT;²⁷⁶ and MK-7622.^278,284

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Reimagining Cholinergic Therapy for Alzheimer's Disease

Abstract and Introduction

Abstract

Introduction

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