Current and future treatments in Alzheimer’s disease

Four drugs (donepezil, memantine, galantamine, rivastigmine) are approved on the market and belong to two families: anticholinesterase inhibitors and anti-glutaminergics.

“Four drugs (donepezil, memantine, galantamine, rivastigmine) are approved on the market and belong to two families: anticholinesterase inhibitors and anti-glutaminergics.”

Non-pharmacological therapies, in addition to drug treatments, represent an alternative for treating neurodegenerative diseases.

“Non-pharmacological therapies, in addition to drug treatments, represent an alternative to the treatment of neurodegenerative diseases [156].”

The predominant route of elimination for donepezil and galantamine is hepatic metabolism, whereas for rivastigmine it is both hepatic and intestinal metabolism.

“The predominant route of elimination for donepezil and galantamine is reported to be hepatic metabolism, whereas those for rivastigmine is both hepatic and intestinal metabolism.”

Rivastigmine forms a covalent carbamoyl-AChE complex after reacting with the crucial active site serine, preventing it from catalyzing the synthesis of acetylcholine.

“The “pseudo irreversible” acetylcholinesterase activity of rivastigmine refers to the fact that it forms a covalent carbamoyl-AChE complex after reacting with the crucial active site serine, preventing it from catalyzing the synthesis of acetylcholine.”

Donepezil and galantamine block acetylcholinesterase specifically and reversibly, but rivastigmine is a pseudo-irreversible acetylcholinesterase and butyrylcholinesterase inhibitor.

“Donepezil and galantamine are known to block acetylcholinesterase specifically and reversibly, but rivastigmine is a “pseudo-irreversible” acetylcholinesterase and butyrylcholinesterase inhibitor.”

Anti-amyloid therapy acts by two major mechanisms: either by reducing Aβ42 production and Aβ-plaque burden or by promoting Aβ clearance.

“To circumvent the said condition, anti-amyloid therapy acts by two major mechanisms either by reducing of Aβ42 production and Aβ-plaque burden or by promoting Aβ clearance (Atri 2019).”

Galantamine has a t1/2 of 6 to 8 hours, donepezil has a 70-hour elimination half-life, and rivastigmine has a short elimination half-life but a prolonged duration of effect.

“Galantamine has a t1/2 of 6 to 8 h, while donepezil has a 70-hour elimination half-life. Rivastigmine has a short elimination half-life, but it has a prolonged duration of effect (Atri 2019).”

All three acetylcholinesterase inhibitor drugs delay neurodegeneration and stabilise cognition when used in patients with mild to severe Alzheimer's disease symptoms, as shown in clinical trials.

“All three drugs delay neurodegeneration and stabilise cognition when used in patients with mild to severe AD symptoms, as shown in clinical trials.”

Between 5 and 20% of patients treated with acetylcholinesterase inhibitors show adverse effects mainly associated with the digestive, cardiac, and pulmonary systems.

“reports indicate that between 5 and 20% of patients show adverse effects mainly associated with the digestive, cardiac and pulmonary systems”

Memantine is normally well-tolerated without the gastrointestinal adverse effects presented by acetylcholinesterase inhibitors, but some patients manifest dizziness, constipation, headache, cough, and drowsiness.

“It is normally well-tolerated without the adverse effects presented by the AChEI at the gastrointestinal level, which are the most severe; however, some patients have manifested negative effects such as dizziness, constipation, headache, cough, and drowsiness [33,35,36].”

Memantine monotherapy has shown beneficial effects in the short and long term in patients with moderate to severe Alzheimer's disease, improving quality of life, cognition, and behavioral and psychological symptoms.

“Monotherapy has shown beneficial effects in the short and long term in patients with moderate to severe AD, improving their quality of life, cognition, and behavioral and psychological symptoms of neurodegenerative diseases [33,34]”

Additional pathogenic mechanisms possibly overlapping with Aβ plaques and NFT formation include inflammation, oxidative damage, iron deregulation, cholesterol metabolism, blood-brain barrier dysfunction, or α-synuclein toxicity.

“A number of additional pathogenic mechanisms have been described, possibly overlapping with Aβ plaques and NFT formation or induced by them, including inflammation, oxidative damage, iron deregulation, and cholesterol metabolism blood-brain barrier (BBB) dysfunction or α-synuclein toxicity.9-13”

The acetylcholinesterase inhibitors donepezil, galantamine, rivastigmine, and the NMDA antagonist memantine are the only FDA-approved Alzheimer disease medications.

“The AChEIs donepezil, galantamine, rivastigmine, and the NMDA antagonist memantine are the only FDA-approved AD medications.10”

All three acetylcholinesterase inhibitors have proved treatment benefits in delaying decline, stabilizing, or even improving cognition and activities of daily living in randomized placebo-controlled trials up to 52 weeks duration.

“All 3 AChEIs have proved their treatment benefits in delaying decline, stabilizing, or even improving cognition and activities of daily living in randomized placebo-controlled trials up to 52 weeks duration.10,18”

Donepezil and galantamine selectively and reversibly inhibit acetylcholinesterase, whereas rivastigmine is a pseudo-irreversible inhibitor of acetylcholinesterase and butyrylcholinesterase.

“Donepezil and galantamine inhibit selectively and reversibly the acetylcholinesterase, whereas rivastigmine is a “pseudo-irreversible” inhibitor of acetylcholinesterase and butyrylcholinesterase.”

Pharmacokinetic characteristics differ among acetylcholinesterase inhibitors: donepezil and galantamine are primarily eliminated by hepatic metabolism, whereas rivastigmine is eliminated by liver and intestine metabolism.

“Pharmacokinetic characteristics differ among AChEIs: the primary route of elimination for donepezil and galantamine is hepatic metabolism, whereas for rivastigmine is liver and intestine metabolism.”

Longer term open-label extension studies support longer term treatment benefits of acetylcholinesterase inhibitors.

“Longer term open-label extension studies support also longer term treatment benefits.10”

Disease-modifying treatments are suggested to be effective to delay or halt disease progression expressed clinically with long-lasting benefits in cognition over many months to years.

“The DMTs are suggested to be effective to delay or halt disease progression that would be expressed clinically with long-lasting benefits in cognition over many months to years.”

The drug pipeline for Alzheimer disease is still full of agents with mechanisms of action that target either disease modification or symptoms.

“Nevertheless, drug pipeline for AD is still full of agents with mechanisms of action (MOA) that target either disease modification or symptoms.4,10”

More than 200 research projects in the last decade have failed or have been abandoned.

“As a matter of fact, more than 200 research projects in the last decade have failed or have been abandoned.10”

Symptomatic agents are supposed to show symptomatic benefits over weeks to many months in cognition improvement or behavioral and psychological symptoms of dementia elimination.

“Symptomatic agents are supposed to show symptomatic benefits over weeks to many months in cognition improvement or BPSD elimination.10”

Anti-amyloid disease-modifying treatments have focused on three major mechanisms of action: reduction of Aβ42 production, reduction of Aβ-plaque burden, and promotion of Aβ clearance.

“Consequently, anti-amyloid DMTs have focused on 3 major MOAs: (1) reduction of Aβ42 production (γ-secretase inhibitors, β-secretase inhibitors, α-secretase potentiation), (2) reduction of Aβ-plaque burden (aggregation inhibitors, drugs interfering with metals), and (3) promotion of Aβ clearance (active or passive immunotherapy).10”

The phase 3 lanabecestat trial was discontinued due to lack of efficacy, whereas verubecestat and atabecestat trials were ceased due to ineffectiveness and safety reasons (rash, falls, liver toxicity, and neuropsychiatric symptoms).

“The phase 3 lanabecestat trial was discontinued due to lack of efficacy, whereas verubecestat and atabecestat trials were ceased due to ineffectiveness, as well as safety reasons (rash, falls, liver toxicity, and neuropsychiatric symptoms).10,32-34”

The design of monoclonal antibody studies became more specific and targeted: amyloid-related imaging abnormalities were associated with dose of antibodies and APOε4 genotyping, higher dosing necessity was recognized, and accurate measures for specific targets, such as reduction of Aβ plaque burden on amyloid PET, were required.

“Furthermore, the design of the studies became more specific and targeted: the characteristics of amyloid-related imaging abnormalities were associated with the dose of antibodies and APOε4 genotyping, higher dosing necessity was recognized, and accurate measures for specific targets, such as reduction of Aβ plaque burden on amyloid PET, were required.10”