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

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.