Effect of age on response to rivastigmine or donepezil in patients with Alzheimer's disease

Background: Younger Alzheimer's disease ( AD) patients appear to differ genetically and neuropathologically from older AD patients, and may experience a more aggressive disease course compared with older patients. A randomised trial investigated the efficacy and tolerability of rivastigmine, an inhibitor of acetylcholinesterase ( AChE) and butyrylcholinesterase ( BuChE), and donepezil, an AChE- selective inhibitor, in patients with AD over a 2- year period. This retrospective analysis investigated whether younger and older patients showed differential tolerability and efficacy responses to cholinesterase inhibitor treatment. Methods: For the current analysis, patients were divided according to age at baseline: those aged < 75 years and those aged >= 75 years. Efficacy measures were the Severe Impairment Battery ( SIB), Neuropsychiatric Inventory ( NPI), Global Deterioration Scale ( GDS), Mini- Mental State Examination ( MMSE) and the AD Cooperative Study Activities of Daily Living scale ( ADCS- ADL). Changes in efficacy parameters and adverse event frequencies were calculated for rivastigmine and donepeziltreated patients in both age groups. Exploratory analyses were also conducted on SIB, ADCS- ADL and NPI in patients who consented to pharmacogenetic testing at baseline. Genotyping sof the apolipoprotein E ( APOE) epsilon 4 allele and the BuChE K- variant was conducted using the TaqMan assay. Main efficacy analyses were based on an intent- to- treat last observation carried forward ( ITT- LOCF) population. Results: Of the 994 patients who received the study drug, 362 ( 36.4%) were younger than 75 years and 632 ( 63.6%) were aged 75 years or over. Rivastigmine provided significant benefits in younger patients compared with donepezil on the NPI- 10, NPI- 12, NPI- D, GDS and ADCS- ADL ( all p < 0.05, ITT- LOCF). With the exception of the NPI- D in favour of donepezil ( p < 0.05, ITT- LOCF), no significant treatment differences were observed in older patients. Younger patients with two wild- type BuChE alleles had a significantly greater response to rivastigmine than donepezil on the ADCS- ADL ( p < 0.01, ITT- LOCF) and SIB ( p < 0.05, ITT- LOCF). The most common adverse events were nausea and vomiting and these were more frequent in rivastigmine- treated patients. Conclusion: In this sub group analysis, patients younger than 75 years of age showed greater treatment responses to rivastigmine than donepezil. Analysis of response by BuChE genotype suggests that this differential effect may be due to the inhibition of BuChE, in addition to AChE, by rivastigmine.