Apolipoprotein E ε4 Allele Differentiates the Clinical Response to Donepezil in Alzheimer’s Disease

Abstract

The existence of an association between apolipoprotein E (APOE) and Alzheimer’s disease (AD) has been reported in several studies. The possession of an ApoE ε4 allele is now considered a genetic risk factor for sporadic AD. There has been a growing agreement about the role exerted by the ApoE ε4 allele on the neuropsychological profile and the rate of cognitive decline in AD patients. However, a more controversial issue remains about a possible influence of the APOE genotype on acetylcholinesterase inhibitor therapy response in AD patients. In order to address this issue, 81 patients diagnosed as having probable AD were evaluated by a complete neuropsychological test battery at the time of diagnosis (baseline) and after 12–16 months (retest). Patients were divided into two subgroups: (1) treated with donepezil at a dose of 5 mg once a day (n = 41) and (2) untreated (n = 40). Donepezil therapy was started after baseline evaluation. The APOE genotype was determined according to standardized procedures. We evaluated the possible effect of the APOE genotype on the neuropsychological tasks in relation to donepezil therapy. The statistical analysis of the results showed a global worsening of cognitive performances for all AD patients at the retest. Differences in the clinical outcome were analysed in the four subgroups of AD patients for each neuropsychological task. ApoE ε4 carriers/treated patients had improved or unchanged scores at retest evaluation for the following tasks: visual and verbal memory, visual attention and inductive reasoning and Mini Mental State Examination. These results indicate an effect of donepezil on specific cognitive domains (attention and memory) in the ApoE ε4 carriers with AD. This might suggest an early identification of AD patients carrying at least one ε4 allele as responders to donepezil therapy.

Proteomics Identification of Proteins in Human Cortex Using Multidimensional Separations and MALDI Tandem Mass Spectrometer

“…The APOE*4 2 allele is genetically associated with the common late onset familial and sporadic forms of AD (34). The mechanism by which APOE*4 participates in AD pathogenesis is not known.…”

Effect of apolipoprotein E and butyrylcholinesterase genotypes on cognitive response to cholinesterase inhibitor treatment at different stages of Alzheimer's disease

“…In another study of donepezil treatment in AD, a beneficial late effect (12 months) on cognition was found in the APOE e4 carriers. 19 In a study of Korean subjects with AD, a beneficial late response (48 weeks) to donepezil, as measured by the ADAS-Cog subscale, was found in APOE e4 carriers. 20 Other reports in the literature have not found APOE e4 genotype to influence cognitive response to ChEI therapy.…”

“…However, our finding of an improved response to ChEI treatment with APOE e4 carriage is plausible and consistent with other subsequent treatment studies. [16][17][18][19][20] APOE e4 carriers have higher levels of acetylcholinesterase, 65 and the cholinergic deficit is less marked in AD, potentially leading to better response to treatment than in non-APOE e4 carriers.…”

“…15 However, other researchers have reported that the presence of APOE e4 is associated with improved outcome with ChEI therapy. [16][17][18][19][20] Several studies did not find that APOE genotype influenced treatment response. [21][22][23][24][25][26][27][28] Gender, either alone or in interaction with APOE genotype, was not found to influence response to ChEIs.…”

Association of the Choline Acetyltransferase Gene with Responsiveness to Acetylcholinesterase Inhibitors in Alzheimer’s Disease

“…One promising approach is pharmacogenomics [6]. Several preliminary pharmacogenomic studies [7,8] have reported that the clinical response to donepezil is highest in carriers of the APOE epsilon4 allele, although a recent large study obtained a negative result [9]. also aimed to assess in our Asian (Korean) population the replicability of previous reports in Caucasians [10,11].…”