Alzheimer's disease is one of the most common causes of mental deterioration in elderly people, accounting for around 50%-60% of the overall cases of dementia among persons over 65 years of age. The past two decades have witnessed a considerable research effort directed towards discovering the cause of Alzheimer's disease with the ultimate hope of developing safe and effective pharmacological treatments. This article examines the existing scientific applicability of the original cholinergic hypothesis of Alzheimer's disease by describing the biochemical and histopathological changes of neurotransmitter markers that occur in the brains of patients with Alzheimer's disease both at postmortem and neurosurgical cerebral biopsy and the behavioural consequences of cholinomimetic drugs and cholinergic lesions. Such studies have resulted in the discovery of an association between a decline in learning and memory, and a deficit in excitatory amino acid (EAA) neurotransmission, together with important roles for the cholinergic system in attentional processing and as a modulator of EAA neurotransmission. Accordingly, although there is presently no "cure" for Alzheimer's disease, a large number of potential therapeutic interventions have emerged that are designed to correct loss of presynaptic cholinergic function. A few of these compounds have confirmed efficacy in delaying the deterioration of symptoms of Alzheimer's disease, a valuable treatment target considering the progressive nature of the disease. Indeed, three compounds have received European approval for the treatment of the cognitive symptoms of Alzheimer's disease, first tacrine and more recently, donepezil and rivastigmine, all of which are cholinesterase inhibitors.

https://jnnp.bmj.com/content/jnnp/66/2/137.full.pdf

The cholinergic hypothesis of Alzheimer’s disease: a review of progress

background Mild cognitive impairment is a transitional state between the cognitive changes of normal aging and early Alzheimer’s disease. methods In a double-blind study, we evaluated subjects with the amnestic subtype of mild cognitive impairment. Subjects were randomly assigned to receive 2000 IU of vitamin E daily, 10 mg of donepezil daily, or placebo for three years. The primary outcome was clinically possible or probable Alzheimer’s disease; secondary outcomes were cognition and function. results A total of 769 subjects were enrolled, and possible or probable Alzheimer’s disease developed in 212. The overall rate of progression from mild cognitive impairment to Alzheimer’s disease was 16 percent per year. As compared with the placebo group, there were no significant differences in the probability of progression to Alzheimer’s disease in the vitamin E group (hazard ratio, 1.02; 95 percent confidence interval, 0.74 to 1.41; P=0.91) or the donepezil group (hazard ratio, 0.80; 95 percent confidence interval, 0.57 to 1.13; P=0.42) during the three years of treatment. Prespecified analyses of the treatment effects at 6-month intervals showed that as compared with the placebo group, the donepezil group had a reduced likelihood of progression to Alzheimer’s disease during the first 12 months of the study (P=0.04), a finding supported by the secondary outcome measures. Among carriers of one or more apolipoprotein E e 4 alleles, the benefit of donepezil was evident throughout the three-year follow-up. There were no significant differences in the rate of progression to Alzheimer’s disease between the vitamin E and placebo groups at any point, either among all patients or among apolipoprotein E e 4 carriers. conclusions Vitamin E had no benefit in patients with mild cognitive impairment. Although donepezil therapy was associated with a lower rate of progression to Alzheimer’s disease during the first 12 months of treatment, the rate of progression to Alzheimer’s disease after three years was not lower among patients treated with donepezil than among those given placebo.

https://www.nejm.org/doi/pdf/10.1056/NEJMoa050151

Vitamin E and Donepezil for the Treatment of Mild Cognitive Impairment

Article abstract—Objective: To update the 1994 practice parameter for the diagnosis of dementia in the elderly. Background: The AAN previously published a practice parameter on dementia in 1994. New research and clinical developments warrant an update of some aspects of diagnosis. Methods: Studies published in English from 1985 through 1999 were identified that addressed four questions: 1) Are the current criteria for the diagnosis of dementia reliable? 2) Are the current diagnostic criteria able to establish a diagnosis for the prevalent dementias in the elderly? 3) Do laboratory tests improve the accuracy of the clinical diagnosis of dementing illness? 4) What comorbidities should be evaluated in elderly patients undergoing an initial assessment for dementia? Recommendations: Based on evidence in the literature, the following recommendations are made. 1) The DSM-III-R definition of dementia is reliable and should be used (Guideline). 2) The National Institute of Neurologic, Communicative Disorders and Stroke‐AD and Related Disorders Association (NINCDS-ADRDA) or the Diagnostic and Statistical Manual, 3rd edition, revised (DSM-IIIR) diagnostic criteria for AD and clinical criteria for Creutzfeldt‐Jakob disease (CJD) have sufficient reliability and validity and should be used (Guideline). Diagnostic criteria for vascular dementia, dementia with Lewy bodies, and frontotemporal dementia may be of use in clinical practice (Option) but have imperfect reliability and validity. 3) Structural neuroimaging with either a noncontrast CT or MR scan in the initial evaluation of patients with dementia is appropriate. Because of insufficient data on validity, no other imaging procedure is recommended (Guideline). There are currently no genetic markers recommended for routine diagnostic purposes (Guideline). The CSF 14-3-3 protein is useful for confirming or rejecting the diagnosis of CJD (Guideline). 4) Screening for depression, B12 deficiency, and hypothyroidism should be performed (Guideline). Screening for syphilis in patients with dementia is not justified unless clinical suspicion for neurosyphilis is present (Guideline). Conclusions: Diagnostic criteria for dementia have improved since the 1994 practice parameter. Further research is needed to improve clinical definitions of dementia and its subtypes, as well as to determine the utility of various instruments of neuroimaging, biomarkers, and genetic testing in increasing diagnostic accuracy.

https://n.neurology.org/content/neurology/56/9/1143.full.pdf

Practice parameter: Diagnosis of dementia (an evidence-based review) Report of the Quality Standards Subcommittee of the American Academy of Neurology

ContextAlcohol dependence treatment may include medications, behavioral therapies, or both. It is unknown how combining these treatments may impact their effectiveness, especially in the context of primary care and other nonspecialty settings.ObjectivesTo evaluate the efficacy of medication, behavioral therapies, and their combinations for treatment of alcohol dependence and to evaluate placebo effect on overall outcome.Design, Setting, and ParticipantsRandomized controlled trial conducted January 2001-January 2004 among 1383 recently alcohol-abstinent volunteers (median age, 44 years) from 11 US academic sites with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnoses of primary alcohol dependence.InterventionsEight groups of patients received medical management with 16 weeks of naltrexone (100 mg/d) or acamprosate (3 g/d), both, and/or both placebos, with or without a combined behavioral intervention (CBI). A ninth group received CBI only (no pills). Patients were also evaluated for up to 1 year after treatment.Main Outcome MeasuresPercent days abstinent from alcohol and time to first heavy drinking day.ResultsAll groups showed substantial reduction in drinking. During treatment, patients receiving naltrexone plus medical management (n = 302), CBI plus medical management and placebos (n = 305), or both naltrexone and CBI plus medical management (n = 309) had higher percent days abstinent (80.6, 79.2, and 77.1, respectively) than the 75.1 in those receiving placebos and medical management only (n = 305), a significant naltrexone × behavioral intervention interaction (P = .009). Naltrexone also reduced risk of a heavy drinking day (hazard ratio, 0.72; 97.5% CI, 0.53-0.98; P = .02) over time, most evident in those receiving medical management but not CBI. Acamprosate showed no significant effect on drinking vs placebo, either by itself or with any combination of naltrexone, CBI, or both. During treatment, those receiving CBI without pills or medical management (n = 157) had lower percent days abstinent (66.6) than those receiving placebo plus medical management alone (n = 153) or placebo plus medical management and CBI (n = 156) (73.8 and 79.8, respectively; P<.001). One year after treatment, these between-group effects were similar but no longer significant.ConclusionsPatients receiving medical management with naltrexone, CBI, or both fared better on drinking outcomes, whereas acamprosate showed no evidence of efficacy, with or without CBI. No combination produced better efficacy than naltrexone or CBI alone in the presence of medical management. Placebo pills and meeting with a health care professional had a positive effect above that of CBI during treatment. Naltrexone with medical management could be delivered in health care settings, thus serving alcohol-dependent patients who might otherwise not receive treatment.Trial Registrationclinicaltrials.gov Identifier: NCT00006206

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Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence: The COMBINE Study: A Randomized Controlled Trial

Structural imaging based on magnetic resonance is an integral part of the clinical assessment of patients with suspected Alzheimer dementia. Prospective data on the natural history of change in structural markers from preclinical to overt stages of Alzheimer disease are radically changing how the disease is conceptualized, and will influence its future diagnosis and treatment. Atrophy of medial temporal structures is now considered to be a valid diagnostic marker at the mild cognitive impairment stage. Structural imaging is also included in diagnostic criteria for the most prevalent non-Alzheimer dementias, reflecting its value in differential diagnosis. In addition, rates of whole-brain and hippocampal atrophy are sensitive markers of neurodegeneration, and are increasingly used as outcome measures in trials of potentially disease-modifying therapies. Large multicenter studies are currently investigating the value of other imaging and nonimaging markers as adjuncts to clinical assessment in diagnosis and monitoring of progression. The utility of structural imaging and other markers will be increased by standardization of acquisition and analysis methods, and by development of robust algorithms for automated assessment.

http://users.loni.usc.edu/~thompson/PDF/FrisoniNRN-09.pdf

The clinical use of structural MRI in Alzheimer disease

The efficacy and safety of donepezil as a treatment for patients with mild to moderate Alzheimer's disease (AD) was investigated in a multicenter, double-blind study. Patients were randomly assigned to treatment with placebo (n = 162), 5 mg/d donepezil (n = 154), or 10 mg/d donepezil (n = 157) for 24 weeks followed by a 6-week, single-blind placebo washout. The primary efficacy measures were the cognitive portion of the Alzheimer's Disease Assessment Scale (ADAS-cog) and the Clinician's Interview Based Assessment of Change-Plus (CIBIC plus), with the Mini-Mental State Examination (MMSE), Clinical Dementia Rating Scale-Sum of the Boxes (CDR-SB), and patient rated Quality of Life (QoL) used as secondary measures. Cognitive function, as measured by the ADAS-cog, was significantly improved in the 5- and 10-mg/d donepezil groups as compared with the placebo group at weeks 12, 18, and 24. Clinician's global ratings on the CIBIC plus also improved in both the 5- and 10-mg/d donepezil groups relative to placebo. At the end of the 6-week placebo washout phase, ADAS-cog scores and CIBIC plus ratings were not significantly different for the three groups. Significant treatment benefits were also observed consistently in both the 5- and 10-mg/d groups on the MMSE and the CDR-SB, but there was no consistent effect on the patient-rated QoL. Cholinergic side effects (primarily diarrhea, nausea, and vomiting) were reported more often in the 10-mg/d group than either the 5-mg/d or placebo groups. Side effects were transient and generally mild in severity. These data indicate that donepezil is a well-tolerated drug that improves cognition and global function in patients with mild to moderate AD.

A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease

Methods: This was a 12-week, double-blind, placebocontrolled, parallel-group trial with a 3-week single-blind washout. Outpatients at 23 centers in the United States were randomized 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-totreat (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#.008); and 1.0 and 1.3 units for Mini-Mental State Examination (P#.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 ADAScog (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 treatmentemergent clinically 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. Arch Intern Med. 1998;158:1021-1031

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Donepezil Improves Cognition and Global Function in Alzheimer Disease A 15-Week, Double-blind, Placebo-Controlled Study

This study evaluated the efficacy and safety of donepezil in patients with mild to moderately severe Alzheimer's disease, and examined the relationships between plasma donepezil concentration, red blood cell acetylcholinesterase (AChE) activity and clinical response. The trial was of a multicenter, double-blind, parallel-group design and patients were randomised to once-daily treatment with either donepezil (1, 3 or 5 mg) or placebo. The 12-week double-blind phase was followed by a 2-week single-blind placebo washout. 161 patients (55-85 years of age) entered the study and 141 completed treatment. Patients treated with donepezil showed dose-related improvements in the Alzheimer's Disease Assessment Scale-cognitive subscale score (ADAS-cog) and in MMSF scores. The improvements in ADAS-cog were statistically significantly greater with donepezil 5 mg/day than with placebo. There was a 50% reduction in the percentage of patients showing clinical decline with donepezil at 5 mg/day (11%) relative to placebo (20%). In addition, a statistically significant correlation between plasma concentrations of donepezil and AChE inhibition was demonstrated. A plateau of inhibition (76-84%) was reached at plasma donepezil concentrations > 50 ng/ml. The correlation between plasma drug concentrations and ADAS-cog (p = 0.014), MMSE (p = 0.023) and patient quality of life scores, assessed by the patient (p = 0.037) were also statistically significant, as was the correlation between AChE inhibition and change in ADAS-cog (p = 0.008). The incidence of treatment-emergent adverse events with all three dosages of donepezil (64-68%) was comparable to that observed with placebo (65%). Donepezil had no clinically significant effect on vital signs, haematology or clinical biochemistry tests. Importantly, donepezil was not associated with any hepatotoxicity, as observed with acridine-based cholinesterase inhibitors.

The efficacy and safety of donepezil in patients with Alzheimer's disease: Results of a US multicentre, randomized, double-blind, placebo-controlled trial

Objective: To examine the effects of donepezil compared with placebo on the preservation of function in patients with AD over a 1-year period. Methods: This was a prospective, 54-week, double-blind, placebo-controlled, survival to endpoint study. Patients were required to have at entry: a diagnosis of probable AD (National Institute of Neurological and Communicative Disorders and Stroke criteria); Mini-Mental State Examination score of 12 to 20; Clinical Dementia Rating of 1 or 2; modified Hachinski ischemia score ≤4; and capability of performing 8 of 10 instrumental activities of daily living and 5 of 6 basic activities of daily living. Patients (n = 431) were randomized to placebo or donepezil (5 mg/day for 28 days, 10 mg/day thereafter). Outcome measures were the AD Functional Assessment and Change Scale, the Mini-Mental State Examination, and Clinical Dementia Rating scale. At each visit, investigators determined whether predefined criteria for clinically evident decline in functional status had been met. Patients who met the endpoint criteria were discontinued per protocol. Results: Donepezil extended the median time to clinically evident functional decline by 5 months versus placebo. The probability of patients treated with donepezil remaining in the study with no clinically evident functional loss was 51% at 48 weeks, compared with 35% for placebo. The Kaplan–Meier survival curves for the two treatment groups were different ( p = 0.002, log-rank test). Conclusions: Patients with AD continue to show detectable disease progression over time, but treatment with donepezil for 1 year was associated with a 38% reduction in the risk of functional decline compared with placebo.

A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients

Long-term efficacy and safety of donepezil in the treatment of Alzheimer's disease: an interim analysis of the results of a US multicentre open label extension study

Sharon L. Rogers

Papers

A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease

Donepezil Improves Cognition and Global Function in Alzheimer Disease A 15-Week, Double-blind, Placebo-Controlled Study

The efficacy and safety of donepezil in patients with Alzheimer's disease: Results of a US multicentre, randomized, double-blind, placebo-controlled trial

A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients

Long-term efficacy and safety of donepezil in the treatment of Alzheimer's disease: an interim analysis of the results of a US multicentre open label extension study