***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Background A varying response to cholinesterase inhibitor ( ChEI ) treatment has been reported among patients with Alzheimer 's disease ( AD ) . Whether the individual-specific response , specific ChEI agent or dose affects mortality is unclear . We aim ed to examine the relationship between the 6-month response to ChEI and lifespan . Methods Six hundred and eighty-one deceased patients with a clinical AD diagnosis and a Mini-Mental State Examination ( MMSE ) score of 10 - 26 at the start of ChEI therapy ( baseline ) were included in a prospect i ve , observational , multicentre study in clinical practice . At baseline and after 6 months of treatment , the participants were assessed using the  MMSE , the Alzheimer 's Disease Assessment Scale-cognitive subscale ( ADAS-cog ) , the Clinician 's Interview-Based Impression of Change ( CIBIC ) , the Instrumental Activities of Daily Living ( IADL ) scale , and the Physical Self-Maintenance Scale ( PSMS ) . The individuals ' socio-demographic characteristics , ChEI dose , and date of death were recorded . Responses to ChEI and the association of possible risk factors with survival were analysed using general linear models . Results A longer lifespan ( mean of 0.5 years ) was observed among the improved/unchanged patients , as measured by MMSE or CIBIC score , but not by ADAS-cog score , after 6 months of ChEI therapy . In the multivariate models , increased survival time was independently related to a better 6-month response in MMSE , CIBIC , IADL , and PSMS scores , female sex , no antihypertensive/cardiac or antidiabetic therapy , younger age , lower education , milder disease stage at baseline , and higher ChEI dose . Apolipoprotein E genotype did not affect mortality significantly . The patients who received a higher ChEI dose during the first 6 months had a mean lifespan after baseline that was 15 months longer than that of those who received a lower dose . Conclusions A better short-term response to ChEI might prolong survival in naturalistic AD patients . In individuals who received and tolerated higher ChEI doses , a longer lifespan can be expected OBJECTIVE The only approved pharmacological approach for the symptomatic treatment of Alzheimer 's disease in Japan is the use of a cholinesterase inhibitor , donepezil hydrochloride . Recent in vivo and in vitro studies raise the possibility that cholinesterase inhibitors can slow the progression of Alzheimer 's disease . The purpose of the present study was to determine whether donepezil has a neuroprotective effect in Alzheimer 's disease by using the rate of hippocampal atrophy as a surrogate marker of disease progression . METHOD In a prospect i ve cohort study , 54 patients with Alzheimer 's disease who received donepezil treatment and 93 control patients with Alzheimer 's disease who never received anti-Alzheimer drugs underwent magnetic resonance imaging ( MRI ) twice at a 1-year interval . The annual rate of hippocampal atrophy of each subject was determined by using an MRI-based volumetric technique . Background characteristics , age , sex , disease duration , education , MRI interval , apolipoprotein E ( APOE ) genotype , and baseline Alzheimer 's Disease Assessment Scale score were comparable between the treated and control groups . RESULTS The mean annual rate of hippocampal volume loss among the treated patients ( mean=3.82 % , SD=2.84 % ) was significantly smaller than that among the control patients ( mean=5.04 % , SD=2.54 % ) . Upon analysis of covariance , where those confounding variables ( age , sex , disease duration , education , MRI interval , APOE genotype , and baseline Alzheimer 's Disease Assessment Scale score ) were entered into the model as covariates , the effect of  donepezil treatment on hippocampal atrophy remained significant . CONCLUSIONS Donepezil treatment slows the progression of hippocampal atrophy , suggesting a neuroprotective effect of donepezil in Alzheimer 's disease BACKGROUND Donepezil hydrochloride ( Aricept ) is a selective acetylcholinesterase inhibitor developed for the treatment of Alzheimer disease . This phase 3 study was 1 of 2 pivotal trials undertaken to establish the efficacy and safety of using donepezil in patients with mild to moderately severe Alzheimer disease . OBJECTIVES To further examine the efficacy and safety of using donepezil in the treatment of patients with mild to moderately severe Alzheimer disease . To examine the relationships between plasma donepezil concentrations , inhibition of red blood cell acetylcholinesterase activity , and clinical response . METHODS This was a 12-week , double-blind , placebo-controlled , parallel-group trial with a 3-week single-blind washout . Out patients at 23 centers in the United States were r and omized to receive placebo , 5 mg of donepezil hydrochloride , or 10 mg of donepezil hydrochloride ( 5 mg/d during week 1 then 10 mg/d thereafter ) administered once daily at bedtime . Primary efficacy was measured using the Alzheimer 's Disease Assessment Scale-Cognitive Subscale ( ADAS-cog ) and Clinician 's Interview-Based Impression of Change including caregiver information ( CIBIC plus ) . RESULTS A total of 468 patients entered the study , more than 97 % of whom were included in the intention-to-treat ( end point ) analyses . The use of donepezil produced statistically significant improvements in ADAS-cog , CIBIC plus , and Mini-Mental State Examination scores , relative to placebo . The mean drug-placebo differences , at end point , for the groups receiving 5 mg/d and 10 mg/d of donepezil hydrochloride were , respectively , 2.5 and 3.1 units for ADAS-cog ( P<.001 ) ; 0.3 and 0.4 units for CIBIC plus ( P < or = .008 ) ; and 1.0 and 1.3 units for Mini-Mental State Examination ( P < or = .004 ) . On the CIBIC plus scale , 32 % and 38 % of patients , respectively , treated with 5 mg/d and 10 mg/d of donepezil hydrochloride demonstrated clinical improvement ( a score of 1 , 2 , or 3 ) compared with placebo ( 18 % ) . The mean ( + /-SEM ) donepezil plasma concentrations at study end point were 25.9 + /- 0.7 ng/mL and 50.6 + /- 1.9 ng/mL in the groups receiving dosages of 5 mg/d and 10 mg/d , respectively . Corresponding mean ( + /-SEM ) percentages of inhibition of red blood cell acetylcholinesterase activity were 63.9 % + /- 0.9 % and 74.7 % + /- 1.2 % for these 2 dosages , respectively . There was a statistically significant positive correlation between plasma concentrations of donepezil and acetylcholinesterase inhibition ; the EC50 ( 50 % effect ) was obtained at a concentration of 15.6 ng/mL. A plateau of inhibition ( 80%-90 % ) was reached at plasma donepezil concentrations higher than 50 ng/mL. The correlations between plasma drug concentrations and both ADAS-cog ( P<.001 ) and CIBIC plus ( P = .006 ) were also statistically significant , as were the correlations between red blood cell acetylcholinesterase inhibition and change in ADAS-cog ( P<.001 ) and CIBIC plus ( P = .005 ) . The incidence of treatment-emergent adverse events with both dosages of donepezil ( 68%-78 % ) was comparable with that observed with placebo ( 69 % ) . The use of 10 mg/d of donepezil hydrochloride was associated with transient mild nausea , insomnia , and diarrhea . There were no treatment-emergent clinical ly significant changes in vital signs or clinical laboratory test results . More important , the use of donepezil was not associated with the hepatotoxic effects observed with acridine-based cholinesterase inhibitors . CONCLUSION Donepezil hydrochloride ( 5 and 10 mg ) administered once daily is a well-tolerated and efficacious agent for treating the symptoms of mild to moderately severe Alzheimer disease BACKGROUND Cholinesterase inhibitors produce small improvements in cognitive and global assessment s in Alzheimer 's disease . We aim ed to determine whether donepezil produces worthwhile improvements in disability , dependency , behavioural and psychological symptoms , carers ' psychological wellbeing , or delay in institutionalisation . If so , which patients benefit , from what dose , and for how long ? METHODS 565 community-resident patients with mild to moderate Alzheimer 's disease entered a 12-week run-in period in which they were r and omly allocated donepezil ( 5 mg/day ) or placebo .  486 who completed this period were rer and omised to either donepezil ( 5 or 10 mg/day ) or placebo , with double-blind treatment continuing as long as judged appropriate . Primary endpoints were entry to institutional care and progression of disability , defined by loss of either two of four basic , or six of 11 instrumental , activities on the Bristol activities of daily living scale ( BADLS ) . Outcome assessment s were sought for all patients and analysed by logrank and multilevel models . FINDINGS Cognition averaged 0.8 MMSE ( mini-mental state examination ) points better ( 95 % CI 0.5 - 1.2 ; p<0.0001 ) and functionality 1.0 BADLS points better ( 0.5 - 1.6 ; p<0.0001 ) with donepezil over the first 2 years . No significant benefits were seen with donepezil compared with placebo in institutionalisation ( 42 % vs 44 % at 3 years ; p=0.4 ) or progression of disability ( 58 % vs 59 % at 3 years ; p=0.4 ) . The relative risk of entering institutional care in the donepezil group compared with placebo was 0.97 ( 95 % CI 0.72 - 1.30 ; p=0.8 ) ; the relative risk of progression of disability or entering institutional care was 0.96 ( 95 % CI 0.74 - 1.24 ; p=0.7 ) . Similarly , no significant differences were seen between donepezil and placebo in behavioural and psychological symptoms , carer psychopathology , formal care costs , unpaid caregiver time , adverse events or deaths , or between 5 mg and 10 mg donepezil . INTERPRETATION Donepezil is not cost effective , with benefits below minimally relevant thresholds . More effective treatments than cholinesterase inhibitors are needed for Alzheimer 's disease BACKGROUND Alzheimer disease ( AD ) causes progressive cognitive and functional decline over years . Although cholinesterase inhibitors have demonstrated efficacy in studies lasting 3 to 6 months , little is known about long-term therapy . OBJECTIVE To report the long-term cognitive effects of galantamine hydrobromide given continuously for 36 months in AD patients . PARTICIPANTS Subjects were 194 US patients with mild to moderate AD who had been r and omized to continuous galantamine therapy in either of 2 double-blind placebo-controlled trials . Subjects subsequently received open-label continuous galantamine therapy for up to 36 months . MAIN OUTCOME MEASURES Effects on cognition were analyzed as change from study enrollment baseline in scores on the Alzheimer 's Disease Assessment Scale-11-item cognitive subscale . Cognitive decline in galantamine-treated subjects was compared with that in a clinical ly similar historical control sample of AD patients who had received placebo for 12 months and with the mathematically predicted decline of untreated patients over 36 months . The rate of cognitive decline of patients who completed the entire 36-month trial ( n = 119 ) was compared with that of patients who withdrew for any reason during the long-term open-label extension ( n = 75 ) . An inverted responder analysis was also performed in 36-month completers . RESULTS Patients treated continuously with galantamine for 36 months increased a mean + /- SE of 10.2 + /- 0.9 points on the Alzheimer 's Disease Assessment Scale-11-item cognitive subscale-a substantially smaller cognitive decline ( approximately 50 % ) than that predicted for untreated patients . Patients discontinuing galantamine therapy before 36 months had declined at a similar rate before discontinuation as those completing 36 months of treatment . Almost 80 % of patients who received galantamine continuously for up to 36 months seemed to demonstrate cognitive benefits compared with those predicted for untreated patients . CONCLUSIONS Cognitive decline over 36 months of continuous galantamine treatment was substantially less than the predicted cognitive decline of untreated patients with mild to moderate dementia . Thus , the cognitive benefits of galantamine seemed to be sustained for at least 36 months . These findings suggest that galantamine slows the clinical progression of AD We developed a set of informant-based items describing performance of activities of daily living ( ADL ) by patients with Alzheimer 's disease ( AD ) to identify which ADL are useful for assessment of patients in clinical trials .  Evaluation of ADL is an important outcome measure in AD clinical trials . For 
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Conclusion While cholinesterase inhibitors show a poor risk-benefit relationship as indicated by mild symptom improvement and a higher than placebo all-cause discontinuation , a reduction of mortality was suggested .
Intervention- and patient-related factors modify the effect of cholinesterase inhibitors in patients with Alzheimer 's disease