At-Home Administration of Gantenerumab by Care Partners to People with Early Alzheimer's Disease: Feasibility, Safety and Pharmacodynamic Impact.

BACKGROUND: Monoclonal antibodies that target amyloid-beta and remove amyloid plaques can slow cognitive and functional decline in early Alzheimer's disease. Gantenerumab is a subcutaneously administered fully-human anti-amyloid-beta monoclonal antibody with highest affinity for aggregated amyloid-beta. Since the phase 3 GRADUATE trials did not meet the primary endpoint (change from baseline to Week 116 in Clinical Dementia Rating scale - Sum of Boxes), development of gantenerumab in sporadic Alzheimer's disease was stopped and all ongoing trials were terminated early due to sponsor decision. Subcutaneous administration at the clinic or at home by care partner would be an important option for other therapies in this class in order to increase flexibility and reduce overall burden. The insights obtained from the experience with gantenerumab home administration by care partner in the phase 2 GRADUATION trial will serve to guide the ongoing efforts with other anti-amyloid-beta antibodies. OBJECTIVES: To evaluate the pharmacodynamic effects on brain amyloid load of once weekly subcutaneous administration of gantenerumab and the safety and feasibility of home administration by care partners. DESIGN: Phase 2, open-label, single arm study. SETTING: Multicenter trial conducted in 33 sites in 8 countries from November 2020 to March 2023. PARTICIPANTS: Participants aged 50 to 90 with early symptomatic Alzheimer's disease (mild cognitive impairment/mild dementia due to Alzheimer's disease), and evidence of amyloid positron emission tomography positivity. INTERVENTION: Participants could receive up to 255 mg gantenerumab once-weekly, administered subcutaneously at site or at home by healthcare professionals or non-healthcare-professional care partners. MEASUREMENTS: The primary endpoint was the change from baseline to Week 52 and to Week 104 in brain amyloid load as measured by PET centiloid levels. The secondary endpoints were responses to the home administration questionnaire, plasma concentrations and safety. RESULTS: The overall number of participants enrolled was 192, with a mean (standard deviation) amyloid PET load at baseline of 101.80 (29.80) centiloids. At the time of early study termination by sponsor, 149 participants had valid Week 52 amyloid PET data (primary endpoint), and 12 participants had an early termination PET within the pre-defined time range of Week 104. The mean change in amyloid PET from baseline to Week 52 and Week 104 was -26.19 centiloids (range: -75.6-15.8; n=149) and -35.48 centiloids (range: -63.2--7.0; n=12), respectively. Responses to the home administration questionnaire at Week 52 (n=148) indicated that the majority of care partners (88-97%) considered administration of study drug at home easy (30.4%) or very easy (57.4%), and convenient (25.7%) or very convenient (70.9%). Care partners felt confident (31.1%) or very confident (62.2%) and satisfied (29.7%) or very satisfied (64.9%) with giving the injection at home. Responses by care partners at Week 36 (n=72), Week 76 (n=126) and Week 104 (n=29) and participant (patient) assessment of convenience and satisfaction at these time points were similar. There were no new safety findings associated with gantenerumab administered subcutaneously once weekly at 255 mg or safety issues associated with at-home injections by non-healthcare professional care partners. CONCLUSIONS: Once-weekly subcutaneous home administration of the anti-amyloid-beta antibody gantenerumab by non-healthcare-professional care partners to participants with early Alzheimer's disease was feasible, safe, well tolerated, and considered as a convenient option by both the care partners and participants with Alzheimer's disease. Although gantenerumab's development has been stopped due to lack of efficacy, this approach has the potential to reduce the frequency of hospital/outpatient clinic visits required for treatment with other anti-amyloid-ß antibodies and can increase flexibility of drug administration for people living with Alzheimer's disease and their families.

Establishing Clinically Meaningful Change on Outcome Assessments Frequently Used in Trials of Mild Cognitive Impairment Due to Alzheimer's Disease.

BACKGROUND: Consensus is lacking on what constitutes a meaningful score change for individual patients on clinical outcome assessments (COAs) that are commonly used in clinical trials of Alzheimer's disease. Such thresholds are one important approach to help contextualize trial results and demonstrate meaningful treatment benefit. OBJECTIVES: To estimate meaningful within-patient change thresholds for the Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog), and the Mini-Mental State Examination (MMSE) among participants with mild cognitive impairment (MCI). DESIGN: Retrospective anchor- and distribution-based analyses of data from the ADC-008 (NCT00000173) study were used to estimate thresholds for meaningful within-patient change on the target measures. SETTING: Analyses were conducted using data from ADC-008 a Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study among participants with the amnestic subtype of MCI, which was conducted by the Alzheimer's Disease Cooperative Study (ADCS) between March 1999 and January 2004 in the United States and Canada. PARTICIPANTS: Analyses were based on 769 eligible participants who completed the baseline assessment from 69 ADCS sites in the United States and Canada. MEASUREMENTS: The target outcome measures for this analysis included the CDR-SB, the ADAS-Cog, and the MMSE. The anchor measures for this analysis included the Global Deterioration Scale and the MCI-Clinical Global Impression of Change. RESULTS: Focusing on the 12-month time point, within-patient increases of 1-2.5 points in the CDR-SB and increases of 2-5 points on the 11-item ADAS-Cog and 13-item ADAS-Cog, on average, reflect minimal-to-moderate levels of deterioration, respectively. CONCLUSIONS: These thresholds may be useful to aid the interpretation of Alzheimer's disease clinical trial data by illustrating meaningful within-patient progression over the course of a clinical trial via supplementary progressor analyses, which may in turn be informative for treatment decisions. Estimates generated via these methods are specifically intended to evaluate within-patient change and are not intended to assess the magnitude and meaningfulness of differences between group-level changes over time.

Chinese Version of the Baylor Profound Mental Status Examination: A Brief Staging Measure for Patients with Severe Alzheimer's Disease.

BACKGROUND: A specialized instrument for assessing the cognition of patients with severe Alzheimer's disease (AD) is needed in China. OBJECTIVES: To validate the Chinese version of the Baylor Profound Mental Status Examination (BPMSE-Ch). DESIGN: The BPMSE is a simplified scale which has proved to be a reliable and valid tool for evaluating patients with moderate to severe AD, it is worthwhile to extend the use of it to Chinese patients with AD. SETTING: Patients were assessed from the Memory Clinic Outpatient. PARTICIPANTS: All participants were diagnosed as having probable AD by assessment. MEASUREMENTS: The BPMSE was translated into Chinese and back translated. The BPMSE-Ch was administered to 102 AD patients with a Mini-Mental State Examination (MMSE) score below 17. We assessed the internal consistency, reliability, and construct validity between the BPMSE-Ch and MMSE, Severe Impairment Battery (SIB), Global Deterioration Scale (GDS-1), Geriatric Depression Scale(GDS-2), Instrumental Activities of Daily Living (IADL), Physical Self-Maintenance Scale (PSMS), Neuropsychiatric Inventory (NPI) and Clinical Dementia Rating (CDR). RESULTS: The BPMSE-Ch showed good internal consistency (α = 0.87); inter-rater and test-retest reliability were both excellent, ranging from 0.91 to 0.99. The construct validity of the measure was also supported by significant correlations with MMSE, SIB. Moreover, as expected, the BMPSE-Ch had a lower floor effect than the MMSE, but a ceiling effect existed for patients with MMSE scores above 11. CONCLUSIONS: The BPMSE-Ch is a reliable and valid tool for evaluating cognitive function in Chinese patients with severe AD.

Olfactory copy number association with age at onset of Alzheimer disease.

OBJECTIVES: Copy number variants (CNVs) have been recognized as a source of genetic variation that contributes to disease phenotypes. Alzheimer disease (AD) has high heritability for occurrence and age at onset (AAO). We performed a cases-only genome-wide CNV association study for age at onset of AD. METHODS: The discovery case series (n = 40 subjects with AD) was evaluated using array comparative genome hybridization (aCGH). A replication case series (n = 507 subjects with AD) was evaluated using Affymetrix array (n = 243) and multiplex ligation-dependent probe amplification (n = 264). Hazard models related onset age to CNV. RESULTS: The discovery sample identified a chromosomal segment on 14q11.2 (19.3-19.5 Mb, NCBI build 36, UCSC hg18 March 2006) as a region of interest (genome-wide adjusted p = 0.032) for association with AAO of AD. This region encompasses a cluster of olfactory receptors. The replication sample confirmed the association (p = 0.035). The association was found for each APOE4 gene dosage (0, 1, and 2). CONCLUSION: High copy number in the olfactory receptor region on 14q11.2 is associated with younger age at onset of AD.

Report of the task force on designing clinical trials in early (predementia) AD.

BACKGROUND: A large number of promising candidate disease-modifying treatments for Alzheimer disease (AD) continue to advance into phase II and phase III testing. However, most completed trials have failed to demonstrate efficacy, and there is growing concern that methodologic difficulties may contribute to these clinical trial failures. The optimal time to intervene with such treatments is probably in the years prior to the onset of dementia, before the neuropathology has progressed to the advanced stage corresponding to clinical dementia. METHOD: An international task force of individuals from academia, industry, nonprofit foundations, and regulatory agencies was convened to discuss optimal trial design in early (predementia) AD. RESULTS: General consensus was reached on key principles involving the scope of the AD diagnosis, the selection of subjects for trials, outcome measures, and analytical methods. CONCLUSION: A consensus has been achieved in support of the testing of candidate treatments in the early (predementia) AD population.

Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe.

BACKGROUND: There is some evidence that statins may have a protective and symptomatic benefit in Alzheimer disease (AD). The LEADe study is a randomized controlled trial (RCT) evaluating the efficacy and safety of atorvastatin in patients with mild to moderate AD. METHODS: This was an international, multicenter, double-blind, randomized, parallel-group study. Subjects had mild to moderate probable AD (Mini-Mental State Examination score 13-25), were aged 50-90 years, and were taking donepezil 10 mg daily for > or 3 months prior to screening. Entry low-density lipoprotein cholesterol levels (LDL-C) were > 95 and < 195 mg/dL. Patients were randomized to atorvastatin 80 mg/day or placebo for 72 weeks followed by a double-blind, 8-week atorvastatin withdrawal phase. Coprimary endpoints were changes in cognition (Alzheimer's Disease Assessment Scale-Cognitive Subscale [ADAS-Cog]) and global function (Alzheimer's Disease Cooperative Study Clinical Global Impression of Change [ADCS-CGIC]) at 72 weeks. RESULTS: A total of 640 patients were randomized in the study. There were no significant differences in the coprimary endpoints of ADAS-cog or ADCS-CGIC or the secondary endpoints. Atorvastatin was generally well-tolerated. CONCLUSIONS: In this large-scale randomized controlled trial evaluating statin therapy as a treatment for mild to moderate Alzheimer disease, atorvastatin was not associated with significant clinical benefit over 72 weeks. This treatment was generally well-tolerated without unexpected adverse events. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that intensive lipid lowering with atorvastatin 80 mg/day in patients with mild to moderate probable Alzheimer disease (aged 50-90), taking donepezil, with low-density lipoprotein cholesterol levels between 95 and 195 mg/dL over 72 weeks does not benefit cognition (as measured by Alzheimer's Disease Assessment Scale-Cognitive Subscale) (p = 0.26) or global function (as measured by Alzheimer's Disease Cooperative Study Clinical Global Impression of Change) (p = 0.73) compared with placebo.

Evolving early (pre-dementia) Alzheimer's disease trials: suit the outcomes to the population and study design.

Assuming that some cases of Alzheimer's disease (AD) could be prevented or delayed, prevention trials will be developed for this neurodegenerative condition. Initially, stakeholders will have to agree about the definition of prevention-true primary prevention, meaning the prevention of AD neuropathological changes; the prevention of clinical signs and symptoms that often augur AD; or preventing the progression of signs and symptoms to full-blown dementia. True primary prevention trials will have to rely completely upon neuroimaging or biomarker outcomes that reflect AD pathology. On the other hand, trials designed to prevent signs and symptoms of dementia will require researchers to agree on the phenomenology that would constitute an unequivocal endpoint: cognitive worsening on one or more measure compared to a normative group; development of Mild cognitive impairment (MCI); or development of Alzheimer's dementia. Prevention trials utilizing any of these outcomes in the general public will be large, will have to utilize low risk public health interventions, and might therefore have only a small impact (treatment effect size), especially if the studies are too short or the study populations are too diverse. An alternative to interventions aimed at the general public would be any attempt to prevent signs and symptoms of dementia in individuals thought to be at an increased risk for clinical dementia. These trials could try to reduce the development of signs and symptoms of dementia in cognitively normal subjects, or they could try to prevent progression from some form of Mild Cognitive Impairment to AD, or they could have the more subtle goal of reducing the accumulation of subclinical deficits in MCI subjects. If the populations for these trials are limited to individuals who have abnormal laboratory and neuroimaging studies associated with AD neuropathology, the results will not generalize to biomarker-negative, at risk individuals, who are likely to constitute the majority of any clinically relevant study population. Outcome measures for each study design will depend upon the characteristics of the study.

Korean version of the Baylor Profound Mental Status Examination: a brief staging measure for patients with severe Alzheimer's disease.

BACKGROUND: The Baylor Profound Mental Status Examination (BPMSE) was modeled to provide a brief patient-derived rating scale for staging and tracking patients with severe stages of Alzheimer's disease (AD). METHODS: The BPMSE was administered to 91 patients with probable AD (Korean version of the MMSE less than 16) according to the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria. The patients were also evaluated using the Korean version of the Severe Impairment Battery (SIB-Ko), Clinical Dementia Rating (CDR), Global Deterioration Scale (GDS), Barthel Activities of Daily Living (B-ADL), the Korean version of the Instrumental Activities of Daily Living (K-IADL), the Korean version of the Neuropsychiatric Inventory (K-NPI) and the Functional Assessment Staging (FAST). RESULTS: There were significant correlations between the BPMSE- Ko and K-MMSE scores (r = 0.66, p < 0.001) and between the BPMSE-Ko and SIB-Ko scores (r = 0.83, p < 0.001). The BPMSE-Ko correlated with the CDR, GDS, B-ADL, K-IADL, K-NPI and FAST scores (p < 0.001). The BPMSE-Ko scores continued to decline even after the K-MMSE reached values near 0. CONCLUSIONS: The BPMSE-Ko is a time efficient and useful tool to measure cognitive function in patients with severe AD.

Donepezil treatment of patients with MCI: a 48-week randomized, placebo-controlled trial.

BACKGROUND: Treatment of mild cognitive impairment (MCI) with cholinesterase inhibitors may improve symptoms. METHODS: In this multicenter, randomized, placebo-controlled trial, subjects with MCI entered a 3-week placebo run-in period followed by 48 weeks of double-blind donepezil (5 mg/day for 6 weeks, then 10 mg/day for 42 weeks) or placebo treatment. Primary efficacy variables included change from baseline in the modified Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-Cog) and Clinical Dementia Rating Scale-sum of boxes (CDR-SB) after 48 weeks of treatment (modified intention-to-treat analysis). Secondary efficacy measures evaluated cognition, behavior, and function. RESULTS: The dual primary efficacy endpoint was not reached. We noted a small, but significant, decrease in modified ADAS-Cog scores in favor of donepezil at study endpoint. Little change from baseline in CDR-SB and secondary variables was observed for either group. Patient Global Assessment scores favored donepezil at all time points except week 12 (p < or = 0.05). Perceived Deficits Questionnaire scores favored donepezil at week 24 (p = 0.05). Clinical Global Impression of Change-MCI scores favored donepezil only at week 6 (p = 0.04). Adverse events were generally mild or moderate. More donepezil-treated subjects (18.4%) discontinued treatment due to adverse events than placebo-treated subjects (8.3%). CONCLUSIONS: Donepezil demonstrated small but significant improvement on the primary measure of cognition but there was no change on the primary measure of global function. Most other measures of global impairment, cognition, and function were not improved, possibly because these measures are insensitive to change in MCI. Responses on subjective measures suggest subjects perceived benefits with donepezil treatment.

Importance of subtle amnestic and nonamnestic deficits in mild cognitive impairment: prognosis and conversion to dementia.

BACKGROUND/AIMS: To evaluate baseline characteristics and conversion to dementia in mild cognitive impairment (MCI) subtypes. METHODS: We prospectively evaluated conversion to dementia in 106 patients with amnestic MCI (A-MCI) as defined by Petersen's operationalized criteria on a paragraph recall task, amnestic-subthreshold MCI (AS-MCI) as defined by impairment on the ADAS-cog delayed word list recall with normal paragraph recall, nonamnestic MCI (NA-MCI) defined by a nonmemory domain, and in 27 patients with subjective memory loss who had no deficit on formal neuropsychological testing. RESULTS: For all MCI subtypes, the 4-year conversion to dementia was 56% (14% annually) and to AD was 46% (11% annually). Conversion to AD in the A-MCI (56%) was similar to the rate in AS-MCI (50%). Conversion to AD in the A-MCI and AS-MCI combined was 56% (14% annually). Conversion to dementia in the NA-MCI was 52% (13% annually) and the majority converted to AD (62%). CONCLUSIONS: All MCI subtypes are at risk of converting to AD if the groups are carefully defined by an abnormal psychometric domain. All subtypes except subjective memory loss converted to AD at higher than expected rates. Both the A-MCI and AS-MCI subtypes had a similarly high rate of conversion to AD. The deficit on a word list recall task may develop before an abnormality on delayed paragraph recall is evident, at least in some subjects.

Realistic expectations for treatment success in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive degenerative disease that warrants active management to delay or slow progression of its symptoms. The symptoms of AD encompass behavior and daily function as well as cognition, so clinicians should take a global view in the assessment of treatment success. Because there is currently no cure for AD, one cannot expect an initial cognitive improvement observed in the first few months of therapy to be sustained indefinitely. However, one should expect that the patient who is treated early and persistently with medication for AD will show less evidence of behavioral, functional, and cognitive deterioration over a period of time than one would expect in the absence of pharmacotherapy. Thus, treatment success includes not only short-term improvement of symptoms but also less decline over the long term. Determination of treatment success therefore also requires awareness of the typical progression of untreated AD. In this article we review the natural history of AD and evidence for the effectiveness of the treatments indicated for AD: donepezil, galantamine, rivastigmine, and memantine.

Influence of premorbid IQ and education on progression of Alzheimer's disease.

BACKGROUND: Lower education is associated with a higher risk of developing Alzheimer's disease (AD). Years of education and measures of general intellectual function (IQ) are highly correlated. It is important to determine whether there is a relationship between education and AD outcomes that is independent of IQ. OBJECTIVE: To test the hypothesis that premorbid IQ is a stronger predictor of cognitive decline, global progression, and overall survival, than education in patients with AD. METHODS: The study included 478 probable AD patients (322 women and 156 men, mean age 74.5 years) followed in a large AD referral center for a mean of 3.2 years. Eligible participants had a baseline estimate of premorbid IQ using the American version of the Nelson Adult Reading Test (AMNART) and at least one follow-up visit with complete neuropsychological assessment. We used random effects linear regression analysis, and Cox proportional hazards analysis to determine whether or not education and/or premorbid IQ were independently associated with cognitive decline, global progression of AD, and survival. RESULTS: When the baseline AMNART score was included in regression models along with education and other demographic variables, AMNART score, but not education, was associated with a higher baseline score and slower rate of decline in MMSE and ADAS-Cog scores, and the Clinical Dementia Rating sum of boxes score. Neither higher premorbid IQ nor higher education was associated with longer survival. CONCLUSIONS: We conclude that a baseline AMNART score is a better predictor of cognitive change in AD than education, but neither variable is associated with survival after diagnosis.

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

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 < or =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.

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

OBJECTIVE: To define and investigate key issues in the management of dementia and to make literature-based treatment recommendations. METHODS: The authors searched the literature for four clinical questions: 1) Does pharmacotherapy for cognitive symptoms improve outcomes in patients with dementia? 2) Does pharmacotherapy for noncognitive symptoms improve outcomes in patients with dementia? 3) Do educational interventions improve outcomes in patients and/or caregivers? 4) Do other nonpharmacologic interventions improve outcomes in patients and/or caregivers? RESULTS: Cholinesterase inhibitors benefit patients with AD (Standard), although the average benefit appears small; vitamin E likely delays the time to clinical worsening (Guideline); selegiline, other antioxidants, anti-inflammatories, and estrogen require further study. Antipsychotics are effective for agitation or psychosis in patients with dementia where environmental manipulation fails (Standard), and antidepressants are effective in depressed patients with dementia (Guideline). Educational programs should be offered to family caregivers to improve caregiver satisfaction and to delay the time to nursing home placement (Guideline). Staff of long-term care facilities should also be educated about AD to minimize the unnecessary use of antipsychotic medications (Guideline). Behavior modification, scheduled toileting, and prompted voiding reduce urinary incontinence (Standard). Functional independence can be increased by graded assistance, skills practice, and positive reinforcement (Guideline).

Chronic donepezil treatment is associated with slowed cognitive decline in Alzheimer's disease.

OBJECTIVE: To compare rates of cognitive decline between probable Alzheimer's disease (AD) patients treated with long-duration cholinesterase inhibitors (ChE-Is) and those who remained untreated. BACKGROUND: ChE-Is, including donepezil and tracrine, have shown beneficial effects on cognition and global functioning in patients with AD. The duration of these benefits is unknown because the longest double-blind placebo-controlled studies reported were only approximately 6 months long. Ethical concerns regarding randomization of patients to placebo for long periods make it difficult to undertake trials of longer duration. METHODS: We identified patients in 4 AD centers who were or were not consistently treated with ChE-Is and who had demographic, psychometric and follow-up data. We compared 205 ChE-I-treated and 218 untreated AD patients on baseline variables hypothesized to differ between these groups, on baseline Mini Mental Status Examination (MMSE) scores and on rates of MMSE change at 1 year. The analysis was performed initially with all ChE-I-treated patients as a single group versus untreated subjects, and then with donepezil versus untreated subjects and tacrine versus untreated subjects. RESULTS: As expected, treated and untreated patients differed with respect to age, education, ethnicity, percentage of community dwelling and exact days of follow-up (ANOVA and chi2) in several comparisons, but did not differ on baseline MMSE score. These baseline variables were highly intercorrelated. MMSE scores declined significantly more slowly after 1 year of ChE-I treatment compared to untreated patients (p = 0.05) after controlling for baseline differences in age, education, ethnicity and percentage of community dwelling. Slowing of decline was significant in the donepezil-treated patients (p = 0.007) but not in the tacrine-treated group (p = 0.33). CONCLUSIONS: This study, utilizing concurrent, nonrandomized controls, suggests that donepezil continues to have efficacy over at least the first year of therapy. Other studies are needed to determine whether the benefits are maintained beyond 1 year.

Cognitive intervention in Alzheimer disease: a randomized placebo-controlled study.

The efficacy of a cognitive intervention consisting of training in face-name associations, spaced retrieval, and cognitive stimulation was tested in a sample of 37 patients (16 men, 21 women) with probable Alzheimer disease (AD). Patients with AD were randomly assigned to receive either the cognitive intervention or a mock (placebo) intervention for 5 weeks. The placebo group then crossed over to receive the intervention. During the intervention, AD patients showed significant improvement in recall of personal information, face-name recall, and performance on the Verbal Series Attention Test. Improvement did not generalize to additional neuropsychologic measures of dementia severity, verbal memory, visual memory, word generation, or motor speed, or to caregiver-assessed patient quality of life. Results suggest that although face-name training, spaced retrieval, and cognitive stimulation may produce small gains in learning personal information and on a measure of attention, improvement does not generalize to overall neuropsychologic functioning or patient quality of life.

Open-label, multicenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer disease.

BACKGROUND: Donepezil hydrochloride is a selective acetylcholinesterase inhibitor approved for the symptomatic treatment of mild to moderately severe Alzheimer disease (AD). Controlled clinical trials of up to 24 weeks have demonstrated that donepezil treatment (5 and 10 mg/d) significantly improves cognition and global function. OBJECTIVE: To investigate the long-term benefits of donepezil treatment in patients with AD. DESIGN: Multicenter, open-label, 144-week extension of 2 US phase 3, double-blind, placebo-controlled clinical trials: a 15-week study (12 weeks of treatment followed by a 3-week placebo washout) and a 30-week study (24 weeks of treatment followed by a 6-week placebo washout). INTERVENTIONS: All patients (N = 763) initially received donepezil, 5 mg/d, for 6 weeks, after which an increase to 10 mg/d was encouraged. MEASURES: Primary efficacy measures were the Alzheimer's Disease Assessment Scale-cognitive subscale and the Clinical Dementia Rating-Sum of the Boxes. RESULTS: After the shorter 3-week placebo washout, donepezil-associated benefits remained above original baseline values for an additional 24 weeks of open-label treatment. Benefits on Alzheimer's Disease Assessment Scale-cognitive subscale scores for patients who received 10 mg/d in the double-blind study were evident compared with the other groups for 108 weeks of open-label treatment. In contrast, donepezil-associated benefits were lost after the 6-week placebo washout, and scores decreased below original baseline values for all patient groups. Although scores improved relative to the new open-label study baseline scores after drug use was restarted, patients remained below original baseline values. The most common adverse events were associated with the nervous and digestive systems and were generally mild and transient; 17% of patient discontinuations were associated with adverse events. CONCLUSIONS: Donepezil is an effective and safe drug for the long-term symptomatic treatment of mild to moderately severe AD for up to 144 weeks (2.8 years), and sustained treatment may confer some advantages.

A method for estimating progression rates in Alzheimer disease.

BACKGROUND: The ability to predict progression of disease in patients with Alzheimer disease (AD) would aid clinicians, improve the validation of biomarkers, and contribute to alternative study designs for AD therapies. OBJECTIVE: To test a calculated rate of initial decline prior to the first physician visit (preprogression rate) for its ability to predict progression during subsequent follow-up. METHODS: We calculated preprogression rates for 298 patients with probable or possible AD (using the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Associations (NINCDS-ADRDA) with a formula using expected Mini-Mental State Examination (MMSE) scores, scores at presentation, and a standardized estimate of duration. The patients are being followed up longitudinally in our Alzheimer Disease Research Center. The time to clinically meaningful deterioration, defined as an MMSE score drop of 5 or more points, was compared for patients stratified as slow, intermediate, and rapid progressors based on the preprogression rate. Cox regression analysis was used to examine the contribution of demographic variables (age, sex, ethnicity, and level of education), initial MMSE scores, estimated symptom duration, and the calculated preprogression rate to the time it took to reach the end point across the groups. RESULTS: Both initial MMSE (hazard ratio, 0.95 (0.002); z = 4.19; P<.001) and the calculated preprogression rate (hazard ratio, 1.06 (0.019); z = 3.16; P =.002) were significant in determining time to clinically meaningful decline during longitudinal follow-up (Cox regression analysis). Slow, intermediate, and rapid progressors (based on preprogression rates) experienced significantly different time intervals to clinically meaningful deterioration, with the slow progressors taking the longest time, the intermediate progressors in the middle, and the rapid progressors reaching the end point first (log rank chi(2)(1) = 9.81, P =.002). CONCLUSION: An easily calculable rate of early disease progression can classify patients as rapid, intermediate, or slow progressors with good predictive value, even at initial presentation.