Pharmacogenetic considerations when prescribing cholinesterase inhibitors for the treatment of Alzheimer’s disease

ABSTRACT

Introduction

Cholinergic dysfunction, demonstrated in the late 1970s and early 1980s, led to the introduction of acetylcholinesterase inhibitors (AChEIs) in 1993 (Tacrine) to enhance cholinergic neurotransmission as the first line of treatment against Alzheimer’s disease (AD). The new generation of AChEIs, represented by Donepezil (1996), Galantamine (2001) and Rivastigmine (2002), is the only treatment for AD to date, together with Memantine (2003). AChEIs are not devoid of side-effects and their cost-effectiveness is limited. An option to optimize the correct use of AChEIs is the implementation of pharmacogenetics (PGx) in the clinical practice.

Areas covered

(i) The cholinergic system in AD, (ii) principles of AD PGx, (iii) PGx of Donepezil, Galantamine, Rivastigmine, Huperzine and other treatments, and (iv) practical recommendations.

Expert opinion

The most relevant genes influencing AChEI efficacy and safety are APOE and CYPs. APOE-4 carriers are the worst responders to AChEIs. With the exception of Rivastigmine (UGT2B7, BCHE-K), the other AChEIs are primarily metabolized via CYP2D6, CYP3A4, and UGT enzymes, with involvement of ABC transporters and cholinergic genes (CHAT, ACHE, BCHE, SLC5A7, SLC18A3, CHRNA7) in most ethnic groups. Defective variants may affect the clinical response to AChEIs. PGx geno-phenotyping is highly recommended prior to treatment.

KEYWORDS:

• Alzheimer’s disease
• acetylcholinesterase inhibitors
• apoe
• cyps
• cholinergic neurotransmission
• donepezil
• galantamine
• huperzine
• rivastigmine
• pharmacogenetics

Article highlights

• The identification of a selective cholinergic dysfunction in the basal forebrain and cortical neuronal loss led to the introduction of acetylcholinesterase inhibitors (AChEIs) as the first therapeutic option to restore cholinergic neurotransmission, improve memory function and slow cognitive decline in AD.

• Key elements of the cholinergic neurotransmission important in AD include acetylcholine (ACh) precursors, enzymes responsible for the synthesis (cholineacetyltransferase, CHAT, EC 2.3.1.6, 10q11.23) and hydrolysis of ACh (acetylcholinesterase, ACHE, EC 3.1.1.7, 7q22.1; butyrylcholinesterase, BCHE, EC 3.1.1.8, 3q26.1), choline transporter (CHT, SLC5A7, 2q12.3), vesicular ACh transporter (VAChT, SLC18A3, 10q11.23), and cholinergic receptors (nicotinic, muscarinic).

• AChEIs used in AD: Tacrine (1993; discontinued due to hepatotoxicity), Huperzine A (1994), Donepezil (1996), Galantamine (2001), and Rivastigmine (2002).

• The co-administration of several drugs (6-12 drugs/day) for the treatment of comorbidities in dementia (>80%) and the intrinsic toxicity of AChEIs, with limited cost-effectiveness (<30%), causes DDIs and ADRs which can be mitigated by the implementation of AChEI Pharmacogenetics (PGx).

• The genes involved in the PGx of AChEIs in AD include pathogenic, mechanistic, metabolic, transporter and pleiotropic genes and their products, together with genes encoding key components of cholinergic neurotransmission.

• Donepezil is a major substrate of CYP2D6, CYP3A4, ACHE and UGTs, inhibits ACHE and BCHE, and is transported by ABCB1. BCHE-K* and CHRNA7 variants also affect donepezil efficacy and safety.

• Galantamine is a major substrate of CYP2D6, CYP3A4, ABCB1 and UGT1A1, and an inhibitor of ACHE and BCHE. APOE, APP, ACHE, BCHE, CHRNA4, CHRNA7 and CHRNB2 variants may also modify the effects of galantamine.

• Rivastigmine metabolism is mediated by esterases in the liver and in the intestine, and APOE, APP, CHAT, ACHE, BCHE, CHRNA4, CHRNB2 and MAPT variants may affect rivastigmine pharmacokinetics and pharmacodynamics, with special relevance in UGT2B7-PMs. CYP enzymes are not involved in the metabolism of rivastigmine.

• Huperzine A metabolism is mediated primarily by CYP1A2, with a secondary contribution of CYP3A1/2 and negligible involvement of CYP2C11 and 2E1. In humans, huperzine A is excreted unchanged by kidney rather than metabolized by liver, with no apparent involvement of CYP enzymes.

• Tacrine is a major substrate of CYP1A2 and CYP3A4, and a minor substrate of CYP2D6, GSTM1, GSTT1; is an inhibitor of ACHE, BCHE, and CYP1A2; and is transported by SCN1A and ABCB4. Other genes that may influence tacrine efficacy and safety are APOE, CES1, LEPR, MTHFR, CHRNA4 and CHRNB2. Tacrine-related hepatotoxicity has been attributed to GSTM1 and GSTT1 variants.

• As a general rule, intermediate metabolizers (IMs) and ultra-rapid metabolizers (UMs) require AChEI dose adjustment.

• AChEIs should not be prescribed to poor metabolizers (PMs).

• APOE-4 carriers are the worst responders to AChEIs and other conventional treatments.

• The implementation of AChEIs PGx may reduce unwanted effects and unnecessary costs in over 30-40% of the cases.

This box summarizes key points contained in the article.

Acknowledgments

The author would like to thank his collaborators at the International Center of Neuroscience and Genomic Medicine EuroEspes, Corunna, Spain, for technical assistance.

Declaration of interest

The author is president and stockholder of EuroEspes (Biomedical Research Center), EuroEspes Biotechnology (Ebiotec), IABRA and EuroEspes Publishing Co. The author have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This article was funded by EuroEspes Biomedical Research Center and IABRA (International Agency for Brain Research and Aging), Corunna, Spain.