Other Supporting Document for Cognitive Impairment in Older Adults: Screening
Screening for Cognitive Impairment in Older Adults
A Systematic Review for the U.S. Preventive Services Task Force
Release Date: October 22, 2013
By Jennifer S. Lin, MD, MCR; Elizabeth O'Connor, PhD; Rebecca C. Rossom, MD, MCR; Leslie A. Perdue, MPH; and Elizabeth Eckstrom, MD, MPH
The information in this article is intended to help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services. This article is intended as a reference and not as a substitute for clinical judgment.
This article may be used, in whole or in part, as the basis for the development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.
This article was first published in Annals of Internal Medicine on October 22, 2013 (Ann Intern Med 2013;159:601-612; http://www.annals.org). Select for copyright and source information.
Background: Earlier identification of cognitive impairment may reduce patient and caregiver morbidity.
Purpose: To systematically review the diagnostic accuracy of brief cognitive screening instruments and the benefits and harms of pharmacologic and nonpharmacologic interventions for early cognitive impairment.
Data Sources: MEDLINE, PsycINFO, and the Cochrane Central Register of Controlled Trials through December 2012; systematic reviews; clinical trial registries; and experts.
Study Selection: English-language studies of fair to good quality, primary care–feasible screening instruments, and treatments aimed at persons with mild cognitive impairment or mild to moderate dementia.
Data Extraction: Dual quality assessment and abstraction of relevant study details.
Data Synthesis: The Mini-Mental State Examination (k = 25) is the most thoroughly studied instrument but is not available for use without cost. Publicly available instruments with adequate test performance to detect dementia include the Clock Drawing Test (k = 7), Mini-Cog (k = 4), Memory Impairment Screen (k = 5), Abbreviated Mental Test (k = 4), Short Portable Mental Status Questionnaire (k = 4), Free and Cued Selective Reminding Test (k = 2), 7-Minute Screen (k = 2), and Informant Questionnaire on Cognitive Decline in the Elderly (k = 5). Medications approved by the U.S. Food and Drug Administration for Alzheimer disease (k = 58) and caregiver interventions (k = 59) show a small benefit of uncertain clinical importance for patients and their caregivers. Small benefits are also limited by common adverse effects of acetylcholinesterase inhibitors and limited availability of complex caregiver interventions. Although promising, cognitive stimulation (k = 6) and exercise (k = 10) have limited evidence to support their use in persons with mild to moderate dementia or mild cognitive impairment.
Limitation: Limited studies in persons with dementia other than Alzheimer disease and sparse reporting of important health outcomes.
Conclusion: Brief instruments to screen for cognitive impairment can adequately detect dementia, but there is no empirical evidence that screening improves decision making. Whether interventions for patients or their caregivers have a clinically significant effect in persons with earlier detected cognitive impairment is still unclear.
Primary Funding Source: Agency for Healthcare Research and Quality.
Dementia, a decline in cognitive function severe enough to affect social or occupational functioning 1, can be due to Alzheimer disease (AD), vascular dementia, frontotemporal dementia, dementia with Lewy bodies, Parkinson disease with dementia, dementia of mixed cause, or many rarer causes 2. Although the exact prevalence is unknown, researchers estimate that dementia affects between 2.4 million and 5.5 million Americans 2–4. Mild cognitive impairment (MCI) differs from dementia in that it is not severe enough to interfere with independence in daily life (for example, instrumental activities of daily living (IADLs)); however, it may be useful for predicting dementia.
Primary care clinicians may not recognize cognitive impairment when using routine history and physical examination 3, 5 in as many as 76% of patients with dementia or probable dementia 6–8, and most of these patients are not diagnosed until they are at moderate to severe stages of the disease 9. Early identification of cognitive impairment would ideally allow patients and their families to receive care at an earlier stage in the disease process, which could lead to improved prognosis and decreased morbidity. Health, psychological, and social benefits from early recognition of dementia through education and improved decision making may make screening valuable even if early treatment cannot alter the natural history of dementia by preventing or slowing the rate of cognitive decline 10.
In 2003, the U.S. Preventive Services Task Force (USPSTF) concluded that there was insufficient evidence to recommend for or against routine screening for dementia in older adults (I statement) 11. We conducted this systematic review to support the USPSTF in updating its prior recommendation. The current review addresses the benefits, harms, and diagnostic accuracy of brief screening instruments to detect cognitive impairment in community-dwelling older adults and the benefits and harms of the commonly used treatment and management options for older adults with MCI or early dementia and their caregivers.
Our review included 5 key questions. First, does screening for cognitive impairment in community-dwelling older adults in primary care–relevant settings improve decision-making, patient, family or caregiver, or societal outcomes? Second, what is the test performance of screening instruments to detect cognitive impairment in elderly, community-dwelling primary care patients? Third, what are the harms of screening for cognitive impairment? Fourth, do interventions for MCI or mild to moderate dementia in older adults improve decision-making, patient, family or caregiver, or societal outcomes? Fifth, what are the harms of interventions for cognitive impairment?
Detailed methods, including the analytic framework, search strategies, flow diagrams of the search and selection processes, detailed inclusion criteria, quality assessment, excluded studies, and description of data analyses are publicly available in our full evidence report at www.uspreventiveservicestaskforce.org.
Data Sources and Searches
We first searched for systematic reviews published since 2001 by using MEDLINE; the Cochrane Database of Systematic Reviews; the Database of Abstracts of Reviews of Effects; and publications from the Institute of Medicine, the Agency for Healthcare Research and Quality (AHRQ), and the National Institute for Health and Care Excellence. We used the most relevant existing systematic reviews—1 on screening for dementia3 and 11 on treatment of dementia and MCI12–22—to identify primary studies for inclusion and to develop comprehensive search strategies for each question. We searched MEDLINE, PsycINFO, and the Cochrane Central Register of Controlled Trials from the end search dates of existing reviews until 10 December 2012. We supplemented our searches with expert suggestions, reference lists of systematic reviews, and trial registry platforms for ongoing trials.
Two investigators independently reviewed 16,179 abstracts and 1190 articles (Figure 1) against the specified inclusion criteria (Appendix Table 1). We resolved discrepancies through consensus and consultation with a third investigator. We included fair- to good-quality English-language studies of community-dwelling adults that were most applicable to primary care in the United States. For screening questions, we included studies that evaluated any brief screening instrument that could be delivered by a clinician in primary care in 10 minutes or less or self-administered in 20 minutes or less. Screening instruments could be administered to the patient or an informant. For treatment questions, we included the major pharmacologic and nonpharmacologic interventions intended for use in older adults with MCI or mild to moderate dementia, excluding Parkinson dementia, to approximate persons with “screen-detected” cognitive impairment. We considered any decision-making, patient, or caregiver health outcome. For harms of screening, we considered any study design reporting harms, including psychological harms and those due to labeling or poor adherence to diagnostic follow-up. For harms of treatment, we focused primarily on serious harms that resulted in unexpected medical care, illness, or death for interventions that showed any evidence of benefit.
Data Extraction and Quality Assessment
One investigator extracted data, and a second investigator checked the extraction. Two reviewers independently appraised all articles by using the USPSTF's design-specific quality criteria28. We supplemented these criteria with the National Institute for Health and Care Excellence methodology checklists29, AMSTAR (A Measurement Tool to Assess Systematic Reviews) for systematic reviews30, the Newcastle-Ottawa Scale for observational studies31, and QUADAS (Quality Assessment of Diagnostic Accuracy Studies) for studies of diagnostic accuracy32. Fair-quality (as opposed to good-quality) studies did not meet at least 1 criterion but had no important limitations that would invalidate the results. The most common limitations in studies excluded because of poor quality were verification bias in diagnostic studies and greater than 40% attrition or inability to assess for criteria due to limited reporting in trials.
Data Synthesis and Analysis
For diagnostic accuracy studies on screening for MCI or dementia, our primary outcomes of interest were sensitivity and specificity at a given cut point for the instrument, by instrument type (according to length of administration) and separated by detection of dementia, MCI, or both. We synthesized and reported the results for the most commonly used cut points, when applicable. We conducted quantitative syntheses of sensitivity and specificity if sufficient data were presented in more than 2 similar studies based on populations, scoring or cut points, and outcomes. We ran a bivariate model using the “metandi” procedure in Stata 11.2 (StataCorp, College Station, Texas), which models sensitivity and specificity simultaneously, thus accounting for the correlation between these variables33.
For treatment trials, we grouped interventions into 4 broad categories: U.S. Food and Drug Administration (FDA)–approved medications to treat AD, other medications or dietary supplements, nonpharmacologic interventions for caregiver–patient dyads, and nonpharmacologic interventions meant primarily for the patient. We synthesized results within each category and examined results and the association of key study characteristics with results and effect sizes on commonly reported outcomes. Characteristics included age, sex, severity of cognitive impairment of the patient, caregiver hours, setting, country, intervention components, dosing frequency or intensity, length of follow-up, and study quality. Commonly reported outcomes included measures of cognition, global functioning, and physical functioning. For assessment of global cognitive function, the most commonly used measures in our included studies were the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog)34 and the Mini-Mental State Examination (MMSE). Assessment of global function was not commonly reported except in trials evaluating FDA-approved medications for AD, which used the Clinician Interview-Based Impression of Change Plus Caregiver Input (CIBIC-plus)35 Global physical functioning was measured by various instruments that captured the patient's ability to complete basic ADLs36 or IADLs37. The most commonly reported caregiver outcomes were caregiver burden, usually measured with the Zarit Caregiver Burden Interview (38), and caregiver depression, usually measured with the Center for Epidemiologic Studies Depression Scale39.
We conducted quantitative analyses on important patient outcomes reported in most trials. We analyzed a standardized effect size (Hedge g) based on the differences in change between groups from baseline to follow-up using standard formulas40–42. For global cognitive measures, a change of 4 points or more on the ADAS-cog over 6 months was considered a clinically important improvement in mild to moderate dementia43. For standardized effect sizes, standardized mean differences of 0.2 to less than 0.5 were considered small, those 0.5 to less than 0.8 were considered medium, and those 0.8 or greater were considered large 44. We used meta-regressions and visual inspection of forest plots to explore heterogeneity of effect sizes. We assessed the presence of statistical heterogeneity among the studies by using standard chi-square tests and estimated the magnitude of heterogeneity using the I2 statistic45. Publication bias was assessed using tests to examine for bias due to small-study effects46, 47. We used Stata 11.2 for all statistical analyses.
Role of the Funding Source
The study was funded by AHRQ under a contract to support the work of the USPSTF. Members of the USPSTF and the AHRQ medical officer assisted in the development of the scope of this review.
We found no trials that directly assessed whether screening for cognitive impairment in primary care could affect decision-making, patient or caregiver, or societal outcomes (key question 1) (Figure 1). No studies directly addressed the adverse psychological effects of screening or adverse effects from false-positive or false-negative test results (key question 3). We found only 1 fair-quality study showing that approximately half of older adults with positive screening test results for cognitive impairment declined to complete a formal diagnostic work-up for dementia48, 49. Included evidence, therefore, focused on the diagnostic accuracy of screening instruments (key question 2) and the benefits and harms of different treatment and management options in older adults with early cognitive impairment (key questions 4 and 5). Detailed results are publicly available in our full evidence report at www.uspreventiveservicestaskforce.org.
Test Performance of Brief Cognitive Screening Instruments (Key Question 2)
We identified 55 fair- to good-quality diagnostic accuracy studies of brief screening instruments (29 administered in ≤5 minutes, 19 administered in 6 to 10 minutes, and 5 self-administered) conducted in primary care–relevant populations50–88. Forty-six studies provided the test performance for detection of dementia. These studies covered a broad range of older adults selected from the community or primary care practices. Almost all studies had a majority of female participants, but the studies varied in mean age (range, 69 to 95 years) and prevalence of dementia (range, 1.2% to 47.1%). Among trials that reported education level, included adults usually had at least some high school education.
Only 12 brief instruments have been studied more than once in well-designed diagnostic accuracy studies that evaluated their ability to detect dementia in primary care–relevant populations: the MMSE (k = 25; n = 12,348), the Clock Drawing Test (CDT) (k = 7; n = 2509), verbal or category fluency tests (k = 6; n = 2083), the short or full Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) (k = 5; n = 1251), the Memory Impairment Screen (MIS) (MIS: k = 4; n = 1671; MIS by telephone: k = 1; n = 300), Mini-Cog (k = 4; n = 1570), the Abbreviated Mental Test (AMT) (k = 4; n = 824), the Short Portable Mental Status Questionnaire (SPMSQ) (k = 4; n = 1057), the Mental Status Questionnaire (k = 2; n = 522), the Free and Cued Selective Reminding Test (FCSRT) (k = 2; n = 734), the 7-Minute Screen (7MS) (k = 2; n = 553), and the Telephone Interview for Cognitive Status (TICS) (k = 2; n = 677) (Appendix Table 2). Only 4 studies were of good quality; the rest were of fair quality and had various risks of bias, the most common being partial verification, unclear independence of application or interpretation of screening test and reference standard, selection bias with stratified sampling or sampling of volunteers only, and unclear spectrum of patients due to poor reporting of how study population was derived or percentage of or reasons for attrition. The most common reference standards were criteria from the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III), the DSM-IV, or the National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association, and formal diagnosis was based on a combination of history, examination, neuropsychological testing, and expert consensus.
The best-studied instrument was the MMSE. Pooled estimates across 14 studies (n = 10,185) resulted in sensitivity of 88.3% (95% CI, 81.3% to 92.9%) and specificity of 86.2% (CI, 81.8% to 89.7%) for the most commonly reported cut points of 23/24 or 24/25. The CDT, Mini-Cog, MIS, SPMSQ, AMT, FCSRT, 7MS, TICS, and IQCODE can also have acceptable test performance; however, less evidence supported the use of each of these instruments and had limited reproducibility in primary care–relevant populations and unknown optimum cut points for each instrument. The CDT had a wider range of sensitivity and specificity (67% to 97.9% and 69% to 94.2%, respectively), and the optimum cut point is unclear from the body of literature we examined. The Mini-Cog probably has better sensitivity than the CDT alone (76% to 100%) but with a possible tradeoff of lower specificity (54% to 85.2%). Although the MIS can have relatively good test performance in screening for dementia (sensitivity, 43% to 86%; specificity, 93% to 97%), the sensitivities in the 2 good-quality studies (n = 948) were low (about 40%). Likewise, the AMT can have relatively good test performance in screening for dementia (sensitivity, 42% to 100%; specificity, 83% to 95.4%), but 1 fair-quality study (n = 289) had low sensitivity (42%) and no studies were done in the United States. The SPMSQ, FCSRT, 7MS, and TICS also have reasonable test performance, but this is based on a limited number of studies. The verbal fluency tests had worse performance than other instruments regardless of cut point. The IQCODE, a self-administered informant-based screening tool, had a sensitivity of 75% to 87.6% and a specificity of 65% to 91.1%. The 6-Item Screener, Visual Association Test, General Practitioner Assessment of Cognition, ADL/IADL, Benton Orientation Test, Delayed Recall Test, and Short Concord Informant Dementia Scale all had greater than 80% sensitivity and specificity to detect dementia in a single study, but their test performance has not been reproduced in other primary care–relevant populations.
We found 27 studies designed to assess the diagnostic accuracy of 22 screening instruments to detect MCI in primary care–relevant populations56–58, 67–69, 73, 74, 78, 83, 86–101. Only 6 instruments were examined in more than 1 study: the MMSE (k = 15; n = 5758), IQCODE (k = 4; n = 975), CDT (k = 4; n = 4191), Mini-Cog (k = 3; n = 1092), TICS (k = 3; n = 568), and Montreal Cognitive Assessment (k = 2; n = 251). Overall, the sensitivity to detect MCI for each of these instruments, except for the IQCODE, was lower than that to detect dementia (data not shown). Results for screening instruments to detect MCI are available in our full evidence report.
Benefits and Harms of Treatment in Early Cognitive Impairment (Key Questions 4 and 5)
We identified 1 systematic review from 2008 and 118 trials that addressed the benefit of the treatment or management of mild to moderate dementia, MCI, or both (Appendix Table 3).
To evaluate adverse effects of treatments with evidence of benefit, we examined the systematic review, 40 trials, and 6 open-label extensions of medication trials that reported harms and 13 observational trials designed to assess medication harms. Most trials (90%) were of fair quality. Common limitations included differences in baseline characteristics, high attrition (>20%), evidence of attrition bias, nonblinded assessment of outcomes, completers-only analyses, and limited reporting to evaluate trial conduct. Medication trials were either exclusively or partially industry-funded.
One well-conducted systematic review of FDA-approved medications for the treatment of AD included 39 randomized, controlled trials of acetylcholinesterase inhibitors (AChEIs) in persons with MCI or mild to moderate dementia14. We identified an additional 9 randomized, controlled trials published since this systematic review. Overall, on the basis of 48 fair- to good-quality trials (n = 18,390) (donepezil: k = 24; n = 7552; galantamine: k = 12; n = 6008; rivastigmine: k = 12; n = 4829), AChEIs can improve cognitive function and global functioning in the short term (Appendix Table 3)102–149. However, the pooled magnitude of these changes is small, with a change of approximately 1 to 3 points on the ADAS-cog (Figure 2). The pooled estimate of benefit for rivastigmine is not reliable given the large statistical heterogeneity. Most available evidence comes from trials in persons with moderate AD with 6 months of follow-up. The average effect of these changes may not be clinically meaningful as defined using commonly accepted values. Only 4 trials (n = 1960) were conducted in persons with MCI102, 115, 119, 131. Measures of global functioning were reported in 30 trials (donepezil, k = 14; galantamine, k = 7; rivastigmine, k = 9). Acetylcholinesterase inhibitors seem to consistently slow the rate of decline of global functioning by a fraction of a point in persons with AD in the short term, as measured by the CIBIC-plus. Only 1 galantamine trial reporting global functioning was conducted in persons with MCI131. Outcome measures of global physical function were reported in only half of the trials and showed mixed results. Therefore, whether AChEIs can improve physical functioning is unclear given the inconsistent and sparsely reported findings. Six included trials and 7 open-label extension studies of included trials examined outcomes beyond 6 months. These studies generally found persistent statistically significant benefits of unknown clinical importance for commonly reported outcomes, consistent with the 6-month trial outcomes. Two trials evaluating donepezil in persons with MCI did not show any differences in conversion to AD at about 3 years. Withdrawal or discontinuation is more common with AChEIs than with placebo (Figure 3)102, 103, 105–107, 109, 111, 112, 114, 116–130, 132–136, 138–142, 144–147, 149–159, 273–287. Discontinuation rates were 14% for donepezil and rivastigmine and 17% for galantamine. However, total serious adverse events did not seem to differ for these medications across trials with limited duration of follow-up (data not shown). Three small trials reporting zero adverse events are not reflected in these estimates111, 112, 123. Estimates of total serious adverse events were higher in observational studies than in randomized trials. The definitions of serious adverse events were not commonly described in the included studies. Observational studies suggest that bradycardia and adverse events related to it (for example, fall or syncope) were increased with AChEIs. Memantine is currently FDA-approved for use in moderate to severe AD but has also been evaluated in persons with mild to moderate dementia or MCI. On the basis of 10 fair- to good-quality trials (n = 3015), memantine had a benefit similar to that seen with AChEIs on global cognitive functioning in persons with moderate dementia: a change of approximately 1 to 2 points on the ADAS-cog at 6 months (Appendix Table 3, Figure 2)150–159. Only 1 trial had longer-term follow-up, and it showed no differences in cognitive functioning between the memantine and placebo groups at 52 weeks. The effect of memantine on global functioning and physical functioning was inconsistent. Only 1 trial was done in persons with MCI, and it did not report outcome measures of global cognitive or physical function. From trial data, the percentage of persons stopping memantine therapy due to adverse effects was similar to that of placebo (Figure 3).
Twenty-six fair- to good-quality trials (n = 5325) evaluated other medications or dietary supplements160–185, including low-dose aspirin (k = 2; n = 459), 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (simvastatin and atorvastatin) (k = 4; n = 1153), nonsteroidal anti-inflammatory drugs (ibuprofen, naproxen, indomethacin, and celecoxib) (k = 4; n = 959), gonadal steroids (estrogen with or without progesterone and testosterone) (k = 5; n = 295), and dietary supplements (multivitamins, B vitamins, vitamin E with or without vitamin C, and ω-3 fatty acids) (k = 12; n = 2608) (Appendix Table 3). None of the trials found a benefit for any of the medications or supplements on cognitive or physical function in persons with mild to moderate dementia or MCI.
We identified 59 trials (n = 8932) representing a wide variety of interventions that targeted the caregiver or the caregiver–patient dyad with the primary aim of improving caregiver outcomes or skills41, 42, 186–241. Most of the trials (k = 52; n = 8103) evaluated interventions with some type of psychoeducational component (that is, one that provided information about dementia or caregiving and sought to increase caregiver skills) (Appendix Table 3). Other trials evaluated interventions that provided little or no dementia education or caregiver skill development but instead involved peer support only (k = 4; n = 644)191, 235–237, physical activity for caregivers (k = 3; n = 293)238–240, or an assessment and treatment plan development (k = 1; n = 50)234.
Most of the psychoeducational trials reported at least caregiver burden (k = 29; n = 4598) or caregiver depression (k = 34; n = 5423) outcomes. Although there were substantial clinical differences among interventions evaluated and significant statistical heterogeneity among these trials, overall there was a generally consistent finding of small benefit on caregiver burden and caregiver depression outcomes in persons caring for patients with moderate dementia. Pooled analyses of 24 trials (n = 2679) showed a small but statistically significant effect (standardized mean difference, −0.23 [CI, −0.35 to −0.12]; I2 = 52.7%) on caregiver burden (Figure 4). Most studies reported 0- to 5-point group differences on the 88-item Zarit Caregiver Burden Interview. Likewise, pooled analyses of 30 trials (n = 3537) showed a small but statistically significant effect (standardized mean difference, −0.21 [CI, −0.30 to −0.13]; I2 = 34.1%) on caregiver depression (Figure 5). Most trials reported an approximate 2- to 5-point difference between groups on the 60-point Center for Epidemiologic Studies Depression Scale. The clinical meaning of these changes in caregiver burden and depression was, on average, probably small at best. Our ability to interpret the clinical importance and consistency of findings for other self-reported caregiver outcomes (for example, global stress or distress, anxiety, health-related quality of life [HRQL], or self-reported health status) and institutionalization was limited by sparse reporting of these outcomes. Only 1 of the included trials mentioned harms, and it found no adverse events in either group.
Nonpharmacologic Interventions Aimed at the Patient
We identified 32 trials (n = 5662) that evaluated nonpharmacologic interventions that targeted the patient rather than the caregiver or patient–caregiver dyad104, 242–272. These included cognitive training, rehabilitation, or stimulation with or without motor skills training (k = 15; n = 1128); exercise interventions (k = 10; n = 1033); multidisciplinary care interventions involving assessment and care coordination (k = 5; n = 1766); and education-only intervention (k = 2; n = 741) (Appendix Table 3). Although findings were inconsistent across 15 cognitive intervention trials, cognitive stimulation with or without cognitive training (k = 6; n = 513) seemed to improve global cognitive function at 6 to 12 months for persons with MCI or dementia (Appendix Table 3). A meta-analysis of these trials showed a moderate standardized effect size for global cognitive functioning favoring the intervention (−0.59 [CI, −0.93 to −0.25]; I2 = 52.7%). The 3 trials that included cognitive stimulation reported a wide range of differences in means, with a range of approximately 0 to 13 points on the ADAS-cog between the intervention and control groups104, 243, 296. The 2 trials that used the MMSE differed by approximately 1 point between groups244, 250. However, the limited number of trials, the clinical and statistical heterogeneity, and the wide CIs (ranging from not clinically meaningful to a large effect) limited our ability to determine the consistency of this benefit. Other important outcomes (for example, physical function, HRQL, and symptoms) were sparsely reported. None of the included trials reported harms. We did not identify any additional studies that explicitly evaluated harms of cognitive interventions.
Ten mostly fair-quality exercise trials showed no consistent benefit on cognitive outcomes and no benefit on patient depression outcomes (Appendix Table 3). Other self-reported outcomes (for example, physical function and HRQL) and institutionalization were not commonly reported. Two trials of a multicomponent self-guided exercise intervention (n = 220) in persons with MCI found a small benefit in global cognitive function (approximately 1 point on the MMSE or ADAS-cog) at 12 to 18 months258, 261. Although there was evidence of a benefit in a few of the better-conducted trials, we were unable to determine whether there is a clinically important benefit for exercise interventions on reported outcomes because of the limited number of trials and clinical heterogeneity of the populations, exercise interventions, and reported outcomes. We found no evidence of increased total or serious adverse effects due to exercise interventions among trial participants258–260, 264.
Five trials evaluating different multidisciplinary care interventions found no benefit in cognitive or physical function, HRQL, or institutionalization. Two trials evaluating educational interventions aimed at residential care staff or clinicians caring for persons with dementia showed no benefits in reported outcomes.
Despite a large body of well-conducted diagnostic accuracy studies, only a handful of instruments have been studied in more than 1 study applicable to primary care. Although the MMSE is the best-studied instrument, it has the longest administration time and is not available for public use without cost. Other publicly available instruments that have been studied in primary care–relevant populations can have adequate test performance, including the CDT, Mini-Cog, MIS, AMT, SPMSQ, FCSRT, 7MS, and IQCODE. However, the AMT, SPMSQ, FCSRT, and 7MS have limited evidence, and each has been studied only once in English. Although other instruments seem to have adequate test performance (such as the 6-Item Screener, Visual Association Test, General Practitioner Assessment of Cognition, ADL/IADL, Benton Orientation Test, Delayed Recall Test, and Short Concord Informant Dementia Scale), each of them has been studied only once in primary care–relevant populations. Our review of the diagnostic accuracy of screening for dementia includes twice the number of studies in existing reviews but is generally consistent with the findings of others3, 69, 297, 298.
We found no studies to substantiate or refute concerns about harms of screening. Although screening and the subsequent diagnostic work-up for abnormal results are noninvasive, false-positive results could represent a harm if patients or clinicians do not follow through with subsequent diagnostic testing and falsely assign a diagnosis of dementia. If false-positive results are a concern, instruments or cut points with high specificity should be given preference. Potential harms from false-negative results, if they are of concern, can be minimized with repeated screening.
Although screening for cognitive impairment can identify persons with dementia, there is no empirical evidence on whether interventions affect clinician, patient, or family decision making. Caregiver interventions and FDA-approved medications for AD show a small benefit for patients and caregivers, although the clinical importance of this benefit is unclear, especially in persons with screen-detected cognitive impairment or those with MCI or mild dementia. Acetylcholinesterase inhibitors and memantine can improve global cognitive function, and AChEIs can improve short-term global function for patients with moderate AD. The average effects of changes in cognitive functioning observed in trials are small, and the clinical importance of population benefits is probably negligible when commonly accepted thresholds are used. This small benefit of AChEIs must be balanced by the common adverse effects. Because of resource limitations, we did not search the FDA Web site or contact industry for unpublished data. A review of trial registry data suggested that 2 trials in persons with MCI (ClinicalTrials.gov, NCT00236574 and NCT00236431) were stopped early because of interim analyses suggesting increased mortality in persons receiving galantamine compared with those receiving placebo. Our review's findings are consistent with those of other similar systematic reviews and guidelines14, 299, 300.
Likewise, complex interventions aimed at caregivers and dyads can reduce caregiver burden and depression, but the average effects in these trials were small. Only half of the trials of caregiver interventions were conducted in the United States, and availability of these complex interventions in the United States is limited. Our review is generally consistent with existing systematic reviews except for slight differences in the magnitude of effect on caregiver outcomes due to differences in included trials and definitions of outcomes301–305.
Other interventions (for example, cognitive stimulation or exercise) have limited evidence to support use in persons with MCI or mild to moderate dementia. Although our review's findings are promising, the certainty and magnitude of effect of cognitive stimulation in persons with mild to moderate dementia or MCI are still unclear. Findings from existing systematic reviews evaluating cognitive interventions were generally consistent with those of our review306–308, although 1 comprehensive Cochrane review that included persons with any stage of dementia and institutionalized individuals found more consistent and precise findings of benefit on cognitive function306. Although no consistent benefit was observed for exercise interventions, 3 of the better-conducted trials suggested a benefit in global cognitive function or physical functioning and HRQL, consistent with another existing systematic review's findings in noninstitutionalized older adults with dementia309.
Because of this narrow scope, our review does not address several important aspects of screening test performance, including the psychometric properties of testing other than sensitivity and specificity, the validation of screening instruments in different languages, the optimum cut points in scoring the included instruments, the differential ability of instruments to detect different types of dementia, the comparative performance of screening instruments, and the ability to improve diagnostic performance by combining screening instruments. Our review of treatments focuses only on the benefits and harms in a subset of persons with mild to moderate dementia or MCI and does not address the comparative effectiveness of different types of interventions or the minimum necessary components for the effectiveness of complex interventions.
Expert consensus guidelines state that early detection of cognitive decline may be beneficial because clinicians can optimize medical management, offer relief based on better understanding of symptoms, maximize decision-making autonomy and planning for the future, and offer appropriate access to services that will ultimately improve patient outcomes and reduce future costs310. Although this is a logical argument, there is little or no empirical evidence to support it. How and whether clinician decision making and patient and family decision making are affected by earlier identification of cognitive impairment or earlier management of patients with dementia and their caregivers are important aspects of management of this rapidly growing health care problem. Important patient outcomes, such as global functioning, HRQL, global physical functioning, emergent or unexpected health care utilization, and institutionalizations, are inconsistently reported but crucial to understanding the true balance of benefits and harms for patients and caregivers, especially in light of small, clinically uncertain benefits seen on continuous measures of cognitive function or caregiver burden.
On the basis of empirical evidence, how best to apply brief cognitive assessment tools to aid in the identification of dementia (population-based screening vs. more targeted approaches suggested by Medicare's Annual Wellness Visit) is still unclear. To operationalize the Annual Wellness Visit's mandate to assess for cognitive impairment, experts have suggested a stepwise approach to identifying persons to whom a brief cognitive instrument should be applied. Research comparing which criteria (for example, age, comorbid conditions, or functional status) should lead primary care clinicians to perform cognitive assessment is much needed. Additional evaluation of brief instruments in more representative populations is needed after initial validation studies to establish reproducibility and to understand population and scoring differences that may lead to important variation in test performance. The harms of screening are poorly studied. Some have argued that these harms are minimal, whereas others contend that the harms of screening and mislabeling persons with dementia are real given the variation in practice of diagnostic confirmation of disease. If broader adoption of screening for cognitive impairment is implemented, it would be wise to better understand these tradeoffs.
Clinical research around defining, diagnosing, and treating cognitive impairment before the loss of independence with IADLs is rapidly evolving. Experts in this field are working to refine diagnostic criteria and to standardize the identification of persons with MCI or “mild neurocognitive disorder,” as it is called in the DSM-V. Future research should focus on improved criteria and subtypes of MCI with demonstrated prognostic and predictive value. Criteria with established predictive value should then be operationalized in a standardized fashion in research studies.
Although it is clear that brief instruments to screen for cognitive impairment can adequately detect dementia, there is no empirical evidence that screening for or early diagnosis of cognitive impairment improves decision-making or important patient, caregiver, or societal outcomes. Despite a large body of evidence spanning decades of research, it is still unclear whether FDA-approved medications, caregiver interventions, cognitive interventions, or exercise interventions in persons with earlier detected cognitive impairment have a clinically significant effect. How best to identify persons with cognitive impairment and understanding how and whether early identification affects important decision making is much needed to address this common, growing, and costly health condition.
Copyright and Source Information
Source: This article was first published in Annals of Internal Medicine on October 22, 2013 (Ann Intern Med 2013;159:601-612).
Acknowledgment: The authors thank Matthew Thompson, MD, MPH, DPhil, for his assistance with the introduction to the full evidence report; Mary Ganguli, MD, MPH, for her expert advice on MCI; Patricia G. Archbold, DNSc, RN, and Barbara J. Stewart, PhD, for their advice on caregiver interventions and outcome measures; Brittany Burda, MPH, for her assistance on data abstraction and preparation of this manuscript; Clara Soh, MPA, and Carin Olson, MD, for their assistance in data abstraction; Daphne Plaut, MLS, for creating and conducting the literature searches; Kevin Lutz, MFA, for his editorial assistance; AHRQ staff; members of the USPSTF; and Soo Borson, MD, Katie Maslow, MSW, Riley McCarten, MD, Parminder Raina, PhD, Raj Shah, MD, Joseph Chin, MD, MS, Kurt Greenlund, PhD, and Susan Cooley, PhD, for their feedback on an early version of the evidence report.
Financial Support: This review was conducted by the Kaiser Permanente Research Affiliates Evidence-based Practice Center under contract to AHRQ, Rockville, Maryland (contract HHS-290-2007-10057-I). AHRQ staff provided oversight for the project and assisted in external review of the companion draft evidence synthesis.
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-1466.
Requests for Single Reprints: Reprints are available from the USPSTF Web site (www.uspreventiveservicestaskforce.org).
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
2. Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR, Ofstedal MB, et al. Prevalence of dementia in the United States: the aging, demographics, and memory study. Neuroepidemiology. 2007;29:125-32. [PMID: 17975326]
3. Holsinger T, Deveau J, Boustani M, Williams JW Jr. Does this patient have dementia? JAMA. 2007;297:2391-404. [PMID: 17551132]
4. Querfurth HW, LaFerla FM. Alzheimer's disease. N Engl J Med. 2010;362:329-44. [PMID: 20107219]
5. Ganguli M, Rodriguez E, Mulsant B, Richards S, Pandav R, Bilt JV, et al. Detection and management of cognitive impairment in primary care: The Steel Valley Seniors Survey. J Am Geriatr Soc. 2004;52:1668-75. [PMID: 15450043]
6. Valcour VG, Masaki KH, Curb JD, Blanchette PL. The detection of dementia in the primary care setting. Arch Intern Med. 2000;160:2964-8. [PMID: 11041904]
7. Olafsdóttir M, Skoog I, Marcusson J. Detection of dementia in primary care: the Linköping study. Dement Geriatr Cogn Disord. 2000;11:223-9. [PMID: 10867449]
8. Chodosh J, Petitti DB, Elliott M, Hays RD, Crooks VC, Reuben DB, et al. Physician recognition of cognitive impairment: evaluating the need for improvement. J Am Geriatr Soc. 2004;52:1051-9. [PMID: 15209641]
9. Mitchell AJ. The clinical significance of subjective memory complaints in the diagnosis of mild cognitive impairment and dementia: a meta-analysis. Int J Geriatr Psychiatry. 2008;23:1191-202. [PMID: 18500688]
10. Plassman BL, Williams JW Jr, Burke JR, Holsinger T, Benjamin S. Systematic review: factors associated with risk for and possible prevention of cognitive decline in later life. Ann Intern Med. 2010;153:182-93. [PMID: 20547887]
11. U.S. Preventive Services Task Force. Screening for dementia: recommendations and rationale. Am J Nurs. 2003;103:87, 89, 91, 93, 95. [PMID: 14501480]
12. McGuinness B, O'Hare J, Craig D, Bullock R, Malouf R, Passmore P. Statins for the treatment of dementia. Cochrane Database Syst Rev. 2010:CD007514. [PMID: 20687089]
13. Williams PS, Rands G, Orrel M, Spector A. Aspirin for vascular dementia. Cochrane Database Syst Rev. 2000:CD001296. [PMID: 11034710]
14. Raina P, Santaguida P, Ismaila A, Patterson C, Cowan D, Levine M, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med. 2008;148:379-97. [PMID: 18316756]
15. Malouf R, Grimley Evans J. The effect of vitamin B6 on cognition. Cochrane Database Syst Rev. 2003:CD004393. [PMID: 14584010]
16. Malouf R, Areosa Sastre A. Vitamin B12 for cognition. Cochrane Database Syst Rev. 2003:CD004326. [PMID: 12918012]
17. Malouf R, Grimley Evans J. Folic acid with or without vitamin B12 for the prevention and treatment of healthy elderly and demented people. Cochrane Database Syst Rev. 2008:CD004514. [PMID: 18843658]
18. Balk E, Chung M, Raman G, Tatsioni A, Chew P, Ip S, et al. B vitamins and berries and age-related neurodegenerative disorders. Evid Rep Technol Assess (Full Rep). 2006:1-161. [PMID: 17628125]
19. Jia X, McNeill G, Avenell A. Does taking vitamin, mineral and fatty acid supplements prevent cognitive decline? A systematic review of randomized controlled trials. J Hum Nutr Diet. 2008;21:317-36. [PMID: 18721399]
20. Issa AM, Mojica WA, Morton SC, Traina S, Newberry SJ, Hilton LG, et al. The efficacy of omega-3 fatty acids on cognitive function in aging and dementia: a systematic review. Dement Geriatr Cogn Disord. 2006;21:88-96. [PMID: 16340205]
21. van Uffelen JG, Chin A Paw MJ, Hopman-Rock M, van Mechelen W. The effects of exercise on cognition in older adults with and without cognitive decline: a systematic review. Clin J Sport Med. 2008;18:486-500. [PMID: 19001882]
22. Forbes D, Forbes S, Morgan DG, Markle-Reid M, Wood J, Culum I. Physical activity programs for persons with dementia. Cochrane Database Syst Rev. 2008:CD006489. [PMID: 18646158]
23. Ransohoff DF, Feinstein AR. Problems of spectrum and bias in evaluating the efficacy of diagnostic tests. N Engl J Med. 1978;299:926-30. [PMID: 692598]
24. Lijmer JG, Mol BW, Heisterkamp S, Bonsel GJ, Prins MH, van der Meulen JH, et al. Empirical evidence of design-related bias in studies of diagnostic tests. JAMA. 1999;282:1061-6. [PMID: 10493205]
25. Whiting P, Rutjes AW, Reitsma JB, Glas AS, Bossuyt PM, Kleijnen J. Sources of variation and bias in studies of diagnostic accuracy: a systematic review. Ann Intern Med. 2004;140:189-202. [PMID: 14757617]
26. Rutjes AW, Reitsma JB, Di Nisio M, Smidt N, van Rijn JC, Bossuyt PM. Evidence of bias and variation in diagnostic accuracy studies. CMAJ. 2006;174:469-76. [PMID: 16477057]
27. Leeflang MM, Bossuyt PM, Irwig L. Diagnostic test accuracy may vary with prevalence: implications for evidence-based diagnosis. J Clin Epidemiol. 2009;62:5-12. [PMID: 18778913]
28. U.S. Preventive Services Task Force. Procedure Manual. AHRQ Publication No. 08-05118-EF. Rockville, MD: U.S. Preventive Services Task Force; 2008. Accessed at www.uspreventiveservicestaskforce.org/uspstf08/methods/procmanual.htm on 22 January 2010.
29. National Institute for Health and Clinical Excellence. The Guidelines Manual. London: National Institute for Health and Clinical Excellence; 2006.
30. Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol. 2007;7:10. [PMID: 17302989]
31. Wells GA, Shea B, O'Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Meta-Analyses. Ottawa, Ontario, Canada: Ottawa Hospital Research Institute; 2013. Accessed at www.ohri.ca/programs/clinical_epidemiology/oxford.asp on 1 April 2013.
32. Whiting P, Rutjes AW, Reitsma JB, Bossuyt PM, Kleijnen J. The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews. BMC Med Res Methodol. 2003;3:25. [PMID: 14606960]
33. Bradburn MJ, Deeks JJ, Altman DG. Metan—a command for meta-analysis in Stata. In: Sterne JAC, ed. Meta-Analysis in Stata: An Updated Collection From the Stata Journal. College Station, TX: Stata Press; 1998:3-28.
34. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. Am J Psychiatry. 1984;141:1356-64. [PMID: 6496779]
35. Schneider LS, Olin JT, Doody RS, Clark CM, Morris JC, Reisberg B, et al. Validity and reliability of the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord. 1997;11Suppl2:S22-32. [PMID: 9236949]
36. Katz S, Downs TD, Cash HR, Grotz RC. Progress in development of the index of ADL. Gerontologist. 1970;10:20-30. [PMID: 5420677]
37. Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist. 1969;9:179-86. [PMID: 5349366]
38. Zarit SH, Reever KE, Bach-Peterson J. Relatives of the impaired elderly: correlates of feelings of burden. Gerontologist. 1980;20:649-55. [PMID: 7203086]
39. Radloff LS. The CES-D Scale: A self-report depression scale for research in the general population. Appl Psychol Meas. 1977;1:385-401.
40. Borenstein M, Hedges LV, Higgins JPT, Rothstein HR. Introduction to Meta-Analysis. 1st ed. West Sussex, United Kingdom: J Wiley; 2009.
41. Teri L, McCurry SM, Logsdon R, Gibbons LE. Training community consultants to help family members improve dementia care: a randomized controlled trial. Gerontologist. 2005;45:802-11. [PMID: 16326662]
42. Hepburn KW, Lewis M, Narayan S, Center B, Tornatore J, Bremer KL, et al. Partners in caregiving: a psychoeducation program affecting dementia family caregivers' distress and caregiving outlook. Clin Gerontol. 2005;29:53-69.
43. Qaseem A, Snow V, Cross JT Jr, Forciea MA, Hopkins R Jr, Shekelle P, et al; American College of Physicians/American Academy of Family Physicians Panel on Dementia. Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2008;148:370-8. [PMID: 18316755]
44. Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Hillsdale, NJ: Lawrence Earlbaum Associates; 1988.
45. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539-58. [PMID: 12111919]
46. Sterne JAC, Harbord RM. Funnel plots in meta-analysis. In: Sterne JAC, ed. Meta-Analysis in Stata: An Updated Collection From the Stata Journal. College Station, TX: Stata Press; 2009:109-23.
47. Steichen TJ. Nonparametric trim and fill analysis of publication bias in meta-analysis. In: Sterne JAC, ed. Meta-Analysis in Stata: An Updated Collection From the Stata Journal. College Station, TX: Stata Press; 2009:165-77.
48. Boustani M, Callahan CM, Unverzagt FW, Austrom MG, Perkins AJ, Fultz BA, et al. Implementing a screening and diagnosis program for dementia in primary care. J Gen Intern Med. 2005;20:572-7. [PMID: 16050849]
49. Boustani M, Perkins AJ, Fox C, Unverzagt F, Austrom MG, Fultz B, et al. Who refuses the diagnostic assessment for dementia in primary care? Int J Geriatr Psychiatry. 2006;21:556-63. [PMID: 16783796]
50. Fuchs A, Wiese B, Altiner A, Wollny A, Pentzek M. Cued recall and other cognitive tasks to facilitate dementia recognition in primary care. J Am Geriatr Soc. 2012;60:130-5. [PMID: 22150245]
51. Kirby M, Denihan A, Bruce I, Coakley D, Lawlor BA. The clock drawing test in primary care: sensitivity in dementia detection and specificity against normal and depressed elderly. Int J Geriatr Psychiatry. 2001;16:935-40. [PMID: 11607936]
52. Ball LJ, Ogden A, Mandi D, Birge SJ. The validation of a mailed health survey for screening of dementia of the Alzheimer's type. J Am Geriatr Soc. 2001;49:798-802. [PMID: 11454121]
53. del Ser T, Sánchez-Sánchez F, García de Yébenes MJ, Otero A, Munoz DG. Validation of the seven-minute screen neurocognitive battery for the diagnosis of dementia in a Spanish population-based sample. Dement Geriatr Cogn Disord. 2006;22:454-64. [PMID: 16988506]
54. Grober E, Hall C, McGinn M, Nicholls T, Stanford S, Ehrlich A, et al. Neuropsychological strategies for detecting early dementia. J Int Neuropsychol Soc. 2008;14:130-42. [PMID: 18078539]
55. Wolf-Klein GP, Silverstone FA, Levy AP, Brod MS. Screening for Alzheimer's disease by clock drawing. J Am Geriatr Soc. 1989;37:730-4. [PMID: 2754158]
56. Holsinger T, Plassman BL, Stechuchak KM, Burke JR, Coffman CJ, Williams JW Jr. Screening for cognitive impairment: comparing the performance of four instruments in primary care. J Am Geriatr Soc. 2012;60:1027-36. [PMID: 22646750]
57. Kaufer DI, Williams CS, Braaten AJ, Gill K, Zimmerman S, Sloane PD. Cognitive screening for dementia and mild cognitive impairment in assisted living: comparison of 3 tests. J Am Med Dir Assoc. 2008;9:586-93. [PMID: 19083293]
58. Borson S, Scanlan JM, Watanabe J, Tu SP, Lessig M. Improving identification of cognitive impairment in primary care. Int J Geriatr Psychiatry. 2006;21:349-55. [PMID: 16534774]
59. Lipton RB, Katz MJ, Kuslansky G, Sliwinski MJ, Stewart WF, Verghese J, et al. Screening for dementia by telephone using the Memory Impairment Screen. J Am Geriatr Soc. 2003;51:1382-90. [PMID: 14511157]
60. Buschke H, Kuslansky G, Katz M, Stewart WF, Sliwinski MJ, Eckholdt HM, et al. Screening for dementia with the Memory Impairment Screen. Neurology. 1999;52:231-8. [PMID: 9932936]
61. Kuslansky G, Buschke H, Katz M, Sliwinski M, Lipton RB. Screening for Alzheimer's disease: the Memory Impairment Screen versus the conventional three-word memory test. J Am Geriatr Soc. 2002;50:1086-91. [PMID: 12110070]
62. Fillenbaum G, Heyman A, Williams K, Prosnitz B, Burchett B. Sensitivity and specificity of standardized screens of cognitive impairment and dementia among elderly black and white community residents. J Clin Epidemiol. 1990;43:651-60. [PMID: 2370572]
63. Hooijer C, Dinkgreve M, Jonker C, Lindeboom J, Kay DWK. Short screening tests for dementia in the elderly population. I: a comparison between AMTS, MMSE, MSQ and SPMSQ. Int J Geriatr Psychiatry. 1992;7:559-71.
64. Erkinjuntti T, Sulkava R, Wikström J, Autio L. Short Portable Mental Status Questionnaire as a screening test for dementia and delirium among the elderly. J Am Geriatr Soc. 1987;35:412-6. [PMID: 3571790]
65. Heun R, Papassotiropoulos A, Jennssen F. The validity of psychometric instruments for detection of dementia in the elderly general population. Int J Geriatr Psychiatry. 1998;13:368-80. [PMID: 9658272]
66. Brodaty H, Pond D, Kemp NM, Luscombe G, Harding L, Berman K, et al. The GPCOG: a new screening test for dementia designed for general practice. J Am Geriatr Soc. 2002;50:530-4. [PMID: 11943052]
67. Callahan CM, Unverzagt FW, Hui SL, Perkins AJ, Hendrie HC. Six-item screener to identify cognitive impairment among potential subjects for clinical research. Med Care. 2002;40:771-81. [PMID: 12218768]
68. Cruz-Orduña I, Bellón JM, Torrero P, Aparicio E, Sanz A, Mula N, et al. Detecting MCI and dementia in primary care: efficiency of the MMS, the FAQ and the IQCODE. Fam Pract. 2012;29:401-6. [PMID: 22121012]
69. Cullen B, Fahy S, Cunningham CJ, Coen RF, Bruce I, Greene E, et al. Screening for dementia in an Irish community sample using MMSE: a comparison of norm-adjusted versus fixed cut-points. Int J Geriatr Psychiatry. 2005;20:371-6. [PMID: 15799072]
70. Fong TG, Jones RN, Rudolph JL, Yang FM, Tommet D, Habtemariam D, et al. Development and validation of a brief cognitive assessment tool: the sweet 16. Arch Intern Med. 2011;171:432-7. [PMID: 21059967]
71. Gagnon M, Letenneur L, Dartigues JF, Commenges D, Orgogozo JM, Barberger-Gateau P, et al. Validity of the Mini-Mental State Examination as a screening instrument for cognitive impairment and dementia in French elderly community residents. Neuroepidemiology. 1990;9:143-50. [PMID: 2402325]
72. Grut M, Fratiglioni L, Viitanen M, Winblad B. Accuracy of the Mini-Mental Status Examination as a screening test for dementia in a Swedish elderly population. Acta Neurol Scand. 1993;87:312-7. [PMID: 8503262]
73. Jeong SK, Cho KH, Kim JM. The usefulness of the Korean version of modified Mini-Mental State Examination (K-mMMSE) for dementia screening in community dwelling elderly people. BMC Public Health. 2004;4:31. [PMID: 15283869]
74. Jorm AF, Broe GA, Creasy H, Sulway MR, Dent O, Fairley MJ, et al. Further data on the validity of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Int J Geriatr Psychiatry. 1996;11:131-9.
75. Kahle-Wrobleski K, Corrada MM, Li B, Kawas CH. Sensitivity and specificity of the Mini-Mental State Examination for identifying dementia in the oldest-old: the 90+ study. J Am Geriatr Soc. 2007;55:284-9. [PMID: 17302668]
76. Kay DW, Henderson AS, Scott R, Wilson J, Rickwood D, Grayson DA. Dementia and depression among the elderly living in the Hobart community: the effect of the diagnostic criteria on the prevalence rates. Psychol Med. 1985;15:771-88. [PMID: 4080881]
77. Lavery LL, Lu SY, Chang CC, Saxton J, Ganguli M. Cognitive assessment of older primary care patients with and without memory complaints. J Gen Intern Med. 2007;22:949-54. [PMID: 17453265]
78. McDowell I, Kristjansson B, Hill GB, Hébert R. Community screening for dementia: the Mini Mental State Exam (MMSE) and Modified Mini-Mental State Exam (3MS) compared. J Clin Epidemiol. 1997;50:377-83. [PMID: 9179095]
79. Morales JM, Bermejo F, Romero M, Del-Ser T. Screening of dementia in community-dwelling elderly through informant report. Int J Geriatr Psychiatry. 1997;12:808-16. [PMID: 9283925]
80. Rait G, Morley M, Burns A, Baldwin R, Chew-Graham C, St Leger AS. Screening for cognitive impairment in older African-Caribbeans. Psychol Med. 2000;30:957-63. [PMID: 11037103]
81. Rait G, Burns A, Baldwin R, Morley M, Chew-Graham C, St Leger AS. Validating screening instruments for cognitive impairment in older South Asians in the United Kingdom. Int J Geriatr Psychiatry. 2000;15:54-62. [PMID: 10637405]
82. Reischies FM, Geiselmann B. Age-related cognitive decline and vision impairment affecting the detection of dementia syndrome in old age. Br J Psychiatry. 1997;171:449-51. [PMID: 9463604]
83. Scharre DW, Chang SI, Murden RA, Lamb J, Beversdorf DQ, Kataki M, et al. Self-Administered Gerocognitive Examination (SAGE): a brief cognitive assessment instrument for mild cognitive impairment (MCI) and early dementia. Alzheimer Dis Assoc Disord. 2010;24:64-71. [PMID: 20220323]
84. Waite LM, Broe GA, Casey B, Bennett HP, Jorm AF, Creasey H, et al. Screening for dementia using an informant interview. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. 1998;5:194-202.
85. Solomon PR, Brush M, Calvo V, Adams F, DeVeaux RD, Pendlebury WW, et al. Identifying dementia in the primary care practice. Int Psychogeriatr. 2000;12:483-93. [PMID: 11263715]
86. Manly JJ, Schupf N, Stern Y, Brickman AM, Tang MX, Mayeux R. Telephone-based identification of mild cognitive impairment and dementia in a multicultural cohort. Arch Neurol. 2011;68:607-14. [PMID: 21555635]
87. Tokuhara KG, Valcour VG, Masaki KH, Blanchette PL. Utility of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) for dementia in a Japanese-American population. Hawaii Med J. 2006;65:72-5. [PMID: 16724448]
88. Lam LC, Tam CW, Lui VW, Chan WC, Chan SS, Chiu HF, et al. Screening of mild cognitive impairment in Chinese older adults—a multistage validation of the Chinese abbreviated mild cognitive impairment test. Neuroepidemiology. 2008;30:6-12. [PMID: 18204291]
89. Donnelly K, Donnelly JP, Cory E. Primary care screening for cognitive impairment in elderly veterans. Am J Alzheimers Dis Other Demen. 2008;23:218-26. [PMID: 18375531]
90. Ehreke L, Luppa M, Luck T, Wiese B, Weyerer S, Eifflaender-Gorfer S, et al; AgeCoDe group. Is the clock drawing test appropriate for screening for mild cognitive impairment? Results of the German study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe). Dement Geriatr Cogn Disord. 2009;28:365-72. [PMID: 19887799]
91. Ehreke L, Luck T, Luppa M, König HH, Villringer A, Riedel-Heller SG. Clock drawing test - screening utility for mild cognitive impairment according to different scoring systems: results of the Leipzig Longitudinal Study of the Aged (LEILA 75+). Int Psychogeriatr. 2011;23:1592-601. [PMID: 21813037]
92. Lee KS, Kim EA, Hong CH, Lee DW, Oh BH, Cheong HK. Clock drawing test in mild cognitive impairment: quantitative analysis of four scoring methods and qualitative analysis. Dement Geriatr Cogn Disord. 2008;26:483-9. [PMID: 18987468]
93. Cook SE, Marsiske M, McCoy KJ. The use of the Modified Telephone Interview for Cognitive Status (TICS-M) in the detection of amnestic mild cognitive impairment. J Geriatr Psychiatry Neurol. 2009;22:103-9. [PMID: 19417219]
94. Vercambre MN, Cuvelier H, Gayon YA, Hardy-Léger I, Berr C, Trivalle C, et al. Validation study of a French version of the Modified Telephone Interview for Cognitive Status (F-TICS-m) in elderly women. Int J Geriatr Psychiatry. 2010;25:1142-9. [PMID: 20054838]
95. Rideaux T, Beaudreau SA, Fernandez S, O'Hara R. Utility of the abbreviated Fuld Object Memory Evaluation and MMSE for detection of dementia and cognitive impairment not dementia in diverse ethnic groups. J Alzheimers Dis. 2012;31:371-86. [PMID: 22555374]
96. Saxton J, Morrow L, Eschman A, Archer G, Luther J, Zuccolotto A. Computer assessment of mild cognitive impairment. Postgrad Med. 2009;121:177-85. [PMID: 19332976]
97. Tariq SH, Tumosa N, Chibnall JT, Perry MH 3rd, Morley JE. Comparison of the Saint Louis University mental status examination and the Mini-Mental State Examination for detecting dementia and mild neurocognitive disorder—a pilot study. Am J Geriatr Psychiatry. 2006;14:900-10. [PMID: 17068312]
98. Lee JY, Lee DW, Cho SJ, Na DL, Jeon HJ, Kim SK, et al. Brief screening for mild cognitive impairment in elderly outpatient clinic: validation of the Korean version of the Montreal Cognitive Assessment. J Geriatr Psychiatry Neurol. 2008;21:104-10. [PMID: 18474719]
99. Markwick A, Zamboni G, de Jager CA. Profiles of cognitive subtest impairment in the Montreal Cognitive Assessment (MoCA) in a research cohort with normal Mini-Mental State Examination (MMSE) scores. J Clin Exp Neuropsychol. 2012;34:750-7. [PMID: 22468719]
100. Ayalon L. The IQCODE versus a single-item informant measure to discriminate between cognitively intact individuals and individuals with dementia or cognitive impairment. J Geriatr Psychiatry Neurol. 2011;24:168-73. [PMID: 21856971]
101. Li M, Ng TP, Kua EH, Ko SM. Brief informant screening test for mild cognitive impairment and early Alzheimer's disease. Dement Geriatr Cogn Disord. 2006;21:392-402. [PMID: 16645272]
102. Doody RS, Ferris SH, Salloway S, Sun Y, Goldman R, Watkins WE, et al. Donepezil treatment of patients with MCI: a 48-week randomized, placebo-controlled trial. Neurology. 2009;72:1555-61. [PMID: 19176895]
103. Mori E, Ikeda M, Kosaka K; Donepezil-DLB Study Investigators. Donepezil for dementia with Lewy bodies: a randomized, placebo-controlled trial. Ann Neurol. 2012;72:41-52. [PMID: 22829268]
104. Requena C, López Ibor MI, Maestú F, Campo P, López Ibor JJ, Ortiz T. Effects of cholinergic drugs and cognitive training on dementia. Dement Geriatr Cogn Disord. 2004;18:50-4. [PMID: 15084794]
105. Black S, Román GC, Geldmacher DS, Salloway S, Hecker J, Burns A, et al; Donepezil 307 Vascular Dementia Study Group. Efficacy and tolerability of donepezil in vascular dementia: positive results of a 24-week, multicenter, international, randomized, placebo-controlled clinical trial. Stroke. 2003;34:2323-30. [PMID: 12970516]
106. Burns A, Rossor M, Hecker J, Gauthier S, Petit H, Möller HJ, et al. The effects of donepezil in Alzheimer's disease—results from a multinational trial. Dement Geriatr Cogn Disord. 1999;10:237-44. [PMID: 10325453]
107. Courtney C, Farrell D, Gray R, Hills R, Lynch L, Sellwood E, et al; AD2000 Collaborative Group. Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial. Lancet. 2004;363:2105-15. [PMID: 15220031]
108. dos Santos Moraes W, Poyares DR, Guilleminault C, Ramos LR, Bertolucci PH, Tufik S. The effect of donepezil on sleep and REM sleep EEG in patients with Alzheimer disease: a double-blind placebo-controlled study. Sleep. 2006;29:199-205. [PMID: 16494088]
109. Feldman H, Gauthier S, Hecker J, Vellas B, Subbiah P, Whalen E; Donepezil MSAD Study Investigators Group. A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer's disease. Neurology. 2001;57:613-20. [PMID: 11524468]
110. Holmes C, Wilkinson D, Dean C, Vethanayagam S, Olivieri S, Langley A, et al. The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease. Neurology. 2004;63:214-9. [PMID: 15277611]
111. Kemp PM, Holmes C, Hoffmann S, Wilkinson S, Zivanovic M, Thom J, et al. A randomised placebo controlled study to assess the effects of cholinergic treatment on muscarinic receptors in Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2003;74:1567-70. [PMID: 14617718]
112. Krishnan KR, Charles HC, Doraiswamy PM, Mintzer J, Weisler R, Yu X, et al. Randomized, placebo-controlled trial of the effects of donepezil on neuronal markers and hippocampal volumes in Alzheimer's disease. Am J Psychiatry. 2003;160:2003-11. [PMID: 14594748]
113. Mazza M, Capuano A, Bria P, Mazza S. Ginkgo biloba and donepezil: a comparison in the treatment of Alzheimer's dementia in a randomized placebo-controlled double-blind study. Eur J Neurol. 2006;13:981-5. [PMID: 16930364]
114. Mohs RC, Doody RS, Morris JC, Ieni JR, Rogers SL, Perdomo CA, et al; “312” Study Group. A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients. Neurology. 2001;57:481-8. [PMID: 11502917]
115. Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, et al; Alzheimer's Disease Cooperative Study Group. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. 2005;352:2379-88. [PMID: 15829527]
116. Rogers SL, Friedhoff LT. The efficacy and safety of donepezil in patients with Alzheimer's disease: results of a US multicentre, randomized, double-blind, placebo-controlled trial. The Donepezil Study Group. Dementia. 1996;7:293-303. [PMID: 8915035]
117. Rogers SL, Doody RS, Mohs RC, Friedhoff LT. Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. Arch Intern Med. 1998;158:1021-31. [PMID: 9588436]
118. Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Donepezil Study Group. Neurology. 1998;50:136-45. [PMID: 9443470]
119. Salloway S, Ferris S, Kluger A, Goldman R, Griesing T, Kumar D, et al; Donepezil 401 Study Group. Efficacy of donepezil in mild cognitive impairment: a randomized placebo-controlled trial. Neurology. 2004;63:651-7. [PMID: 15326237]
120. Seltzer B, Zolnouni P, Nunez M, Goldman R, Kumar D, Ieni J, et al; Donepezil “402” Study Group. Efficacy of donepezil in early-stage Alzheimer disease: a randomized placebo-controlled trial. Arch Neurol. 2004;61:1852-6. [PMID: 15596605]
121. Tariot PN, Cummings JL, Katz IR, Mintzer J, Perdomo CA, Schwam EM, et al. A randomized, double-blind, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzheimer's disease in the nursing home setting. J Am Geriatr Soc. 2001;49:1590-9. [PMID: 11843990]
122. Thomas A, Iacono D, Bonanni L, D'Andreamatteo G, Onofrj M. Donepezil, rivastigmine, and vitamin E in Alzheimer disease: a combined P300 event-related potentials/neuropsychologic evaluation over 6 months. Clin Neuropharmacol. 2001;24:31-42. [PMID: 11290880]
123. Tune L, Tiseo PJ, Ieni J, Perdomo C, Pratt RD, Votaw JR, et al. Donepezil HCl (E2020) maintains functional brain activity in patients with Alzheimer disease: results of a 24-week, double-blind, placebo-controlled study. Am J Geriatr Psychiatry. 2003;11:169-77. [PMID: 12611746]
124. Wilkinson D, Doody R, Helme R, Taubman K, Mintzer J, Kertesz A, et al; Donepezil 308 Study Group. Donepezil in vascular dementia: a randomized, placebo-controlled study. Neurology. 2003;61:479-86. [PMID: 12939421]
125. Winblad B, Engedal K, Soininen H, Verhey F, Waldemar G, Wimo A, et al; Donepezil Nordic Study Group. A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology. 2001;57:489-95. [PMID: 11502918]
126. Auchus AP, Brashear HR, Salloway S, Korczyn AD, De Deyn PP, Gassmann-Mayer C; GAL-INT-26 Study Group. Galantamine treatment of vascular dementia: a randomized trial. Neurology. 2007;69:448-58. [PMID: 17664404]
127. Rockwood K, Fay S, Song X, MacKnight C, Gorman M; Video-Imaging Synthesis of Treating Alzheimer's Disease (VISTA) Investigators. Attainment of treatment goals by people with Alzheimer's disease receiving galantamine: a randomized controlled trial. CMAJ. 2006;174:1099-105. [PMID: 16554498]
128. Brodaty H, Corey-Bloom J, Potocnik FC, Truyen L, Gold M, Damaraju CR. Galantamine prolonged-release formulation in the treatment of mild to moderate Alzheimer's disease. Dement Geriatr Cogn Disord. 2005;20:120-32. [PMID: 15990426]
129. Bullock R, Erkinjuntti T, Lilienfeld S; GAL-INT-6 Study Group. Management of patients with Alzheimer's disease plus cerebrovascular disease: 12-month treatment with galantamine. Dement Geriatr Cogn Disord. 2004;17:29-34. [PMID: 14560062]
130. Erkinjuntti T, Kurz A, Gauthier S, Bullock R, Lilienfeld S, Damaraju CV. Efficacy of galantamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: a randomised trial. Lancet. 2002;359:1283-90. [PMID: 11965273]
131. Koontz J, Baskys A. Effects of galantamine on working memory and global functioning in patients with mild cognitive impairment: a double-blind placebo-controlled study. Am J Alzheimers Dis Other Demen. 2005;20:295-302. [PMID: 16273995]
132. Raskind MA, Peskind ER, Wessel T, Yuan W. Galantamine in AD: A 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group. Neurology. 2000;54:2261-8. [PMID: 10881250]
133. Rockwood K, Mintzer J, Truyen L, Wessel T, Wilkinson D. Effects of a flexible galantamine dose in Alzheimer's disease: a randomised, controlled trial. J Neurol Neurosurg Psychiatry. 2001;71:589-95. [PMID: 11606667]
134. Tariot PN, Solomon PR, Morris JC, Kershaw P, Lilienfeld S, Ding C. A 5-month, randomized, placebo-controlled trial of galantamine in AD. The Galantamine USA-10 Study Group. Neurology. 2000;54:2269-76. [PMID: 10881251]
135. Wilcock GK, Lilienfeld S, Gaens E. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer's disease: multicentre randomised controlled trial. Galantamine International-1 Study Group. BMJ. 2000;321:1445-9. [PMID: 11110737]
136. Wilkinson D, Murray J. Galantamine: a randomized, double-blind, dose comparison in patients with Alzheimer's disease. Int J Geriatr Psychiatry. 2001;16:852-7. [PMID: 11571763]
137. Wilkinson DG, Howe I. Switching from donepezil to galantamine: a double-blind study of two wash-out periods [Letter]. Int J Geriatr Psychiatry. 2005;20:489-91. [PMID: 15852437]
138. Ballard C, Sauter M, Scheltens P, He Y, Barkhof F, van Straaten EC, et al. Efficacy, safety and tolerability of rivastigmine capsules in patients with probable vascular dementia: the VantagE study. Curr Med Res Opin. 2008;24:2561-74. [PMID: 18674411]
139. Feldman HH, Lane R; Study 304 Group. Rivastigmine: a placebo controlled trial of twice daily and three times daily regimens in patients with Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2007;78:1056-63. [PMID: 17353259]
140. Mok V, Wong A, Ho S, Leung T, Lam WW, Wong KS. Rivastigmine in Chinese patients with subcortical vascular dementia. Neuropsychiatr Dis Treat. 2007;3:943-8. [PMID: 19300631]
141. Winblad B, Cummings J, Andreasen N, Grossberg G, Onofrj M, Sadowsky C, et al. A six-month double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer's disease—rivastigmine patch versus capsule. Int J Geriatr Psychiatry. 2007;22:456-67. [PMID: 17380489]
142. Agid Y, Dubois B, Anand R, Gharabawi G. Efficacy and tolerability of rivastigmine in patients with dementia of the Alzheimer type. Curr Ther Res Clin Exp. 1998;59:837-45.
143. Ballard C, Margallo-Lana M, Juszczak E, Douglas S, Swann A, Thomas A, et al. Quetiapine and rivastigmine and cognitive decline in Alzheimer's disease: randomised double blind placebo controlled trial. BMJ. 2005;330:874. [PMID: 15722369]
144. Corey-Bloom J, Anand R, Veach J. A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer's disease. Int J Ger Psychopharm. 1998;1:55-65.
145. Forette F, Anand R, Gharabawi G. A phase II study in patients with Alzheimer's disease to assess the preliminary efficacy and maximum tolerated dose of rivastigmine (Exelon). Eur J Neurol. 1999;6:423-9. [PMID: 10362894]
146. Karaman Y, Erdogan F, Köseoglu E, Turan T, Ersoy AO. A 12-month study of the efficacy of rivastigmine in patients with advanced moderate Alzheimer's disease. Dement Geriatr Cogn Disord. 2005;19:51-6. [PMID: 15383747]
147. McKeith I, Del Ser T, Spano P, Emre M, Wesnes K, Anand R, et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study. Lancet. 2000;356:2031-6. [PMID: 11145488]
148. Potkin SG, Anand R, Fleming K, Alva G, Keator D, Carreon D, et al. Brain metabolic and clinical effects of rivastigmine in Alzheimer's disease. Int J Neuropsychopharmacol. 2001;4:223-30. [PMID: 11602028]
149. Rösler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P, et al. Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial. BMJ. 1999;318:633-8. [PMID: 10066203]
150. Bakchine S, Loft H. Memantine treatment in patients with mild to moderate Alzheimer's disease: results of a randomised, double-blind, placebo-controlled 6-month study. J Alzheimers Dis. 2008;13:97-107. [PMID: 18334761]
151. Ferris S, Schneider L, Farmer M, Kay G, Crook T. A double-blind, placebo-controlled trial of memantine in age-associated memory impairment (memantine in AAMI). Int J Geriatr Psychiatry. 2007;22:448-55. [PMID: 17117395]
152. Porsteinsson AP, Grossberg GT, Mintzer J, Olin JT; Memantine MEM-MD-12 Study Group. Memantine treatment in patients with mild to moderate Alzheimer's disease already receiving a cholinesterase inhibitor: a randomized, double-blind, placebo-controlled trial. Curr Alzheimer Res. 2008;5:83-9. [PMID: 18288936]
153. Saxton J, Hofbauer RK, Woodward M, Gilchrist NL, Potocnik F, Hsu HA, et al. Memantine and functional communication in Alzheimer's disease: results of a 12-week, international, randomized clinical trial. J Alzheimers Dis. 2012;28:109-18. [PMID: 21955815]
154. Wilkinson D, Fox NC, Barkhof F, Phul R, Lemming O, Scheltens P. Memantine and brain atrophy in Alzheimer's disease: a 1-year randomized controlled trial. J Alzheimers Dis. 2012;29:459-69. [PMID: 22269160]
155. Orgogozo JM, Rigaud AS, Stöffler A, Möbius HJ, Forette F. Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300). Stroke. 2002;33:1834-9. [PMID: 12105362]
156. Peskind ER, Potkin SG, Pomara N, Ott BR, Graham SM, Olin JT, et al. Memantine treatment in mild to moderate Alzheimer disease: a 24-week randomized, controlled trial. Am J Geriatr Psychiatry. 2006;14:704-15. [PMID: 16861375]
157. Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ; Memantine Study Group. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med. 2003;348:1333-41. [PMID: 12672860]
158. Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I; Memantine Study Group. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA. 2004;291:317-24. [PMID: 14734594]
159. Wilcock G, Möbius HJ, Stöffler A; MMM 500 group. A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia (MMM500). Int Clin Psychopharmacol. 2002;17:297-305. [PMID: 12409683]
160. Bentham P, Gray R, Sellwood E, Hills R, Crome P, Raftery J; AD2000 Collaborative Group. Aspirin in Alzheimer's disease (AD2000): a randomised open-label trial. Lancet Neurol. 2008;7:41-9. [PMID: 18068522]
161. Clarke R, Harrison G, Richards S; Vital Trial Collaborative Group. Effect of vitamins and aspirin on markers of platelet activation, oxidative stress and homocysteine in people at high risk of dementia. J Intern Med. 2003;254:67-75. [PMID: 12823643]
162. Feldman HH, Doody RS, Kivipelto M, Sparks DL, Waters DD, Jones RW, et al; LEADe Investigators. Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology. 2010;74:956-64. [PMID: 20200346]
163. Sano M, Bell KL, Galasko D, Galvin JE, Thomas RG, van Dyck CH, et al. A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. Neurology. 2011;77:556-63. [PMID: 21795660]
164. Simons M, Schwärzler F, Lütjohann D, von Bergmann K, Beyreuther K, Dichgans J, et al. Treatment with simvastatin in normocholesterolemic patients with Alzheimer's disease: a 26-week randomized, placebo-controlled, double-blind trial. Ann Neurol. 2002;52:346-50. [PMID: 12205648]
165. Sparks DL, Sabbagh MN, Connor DJ, Lopez J, Launer LJ, Browne P, et al. Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results. Arch Neurol. 2005;62:753-7. [PMID: 15883262]
166. Pasqualetti P, Bonomini C, Dal Forno G, Paulon L, Sinforiani E, Marra C, et al. A randomized controlled study on effects of ibuprofen on cognitive progression of Alzheimer's disease. Aging Clin Exp Res. 2009;21:102-10. [PMID: 19448381]
167. Aisen PS, Schafer KA, Grundman M, Pfeiffer E, Sano M, Davis KL, et al; Alzheimer's Disease Cooperative Study. Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA. 2003;289:2819-26. [PMID: 12783912]
168. de Jong D, Jansen R, Hoefnagels W, Jellesma-Eggenkamp M, Verbeek M, Borm G, et al. No effect of one-year treatment with indomethacin on Alzheimer's disease progression: a randomized controlled trial. PLoS One. 2008;3:e1475. [PMID: 18213383]
169. Soininen H, West C, Robbins J, Niculescu L. Long-term efficacy and safety of celecoxib in Alzheimer's disease. Dement Geriatr Cogn Disord. 2007;23:8-21. [PMID: 17068392]
170. Henderson VW, Paganini-Hill A, Miller BL, Elble RJ, Reyes PF, Shoupe D, et al. Estrogen for Alzheimer's disease in women: randomized, double-blind, placebo-controlled trial. Neurology. 2000;54:295-301. [PMID: 10668686]
171. Lu PH, Masterman DA, Mulnard R, Cotman C, Miller B, Yaffe K, et al. Effects of testosterone on cognition and mood in male patients with mild Alzheimer disease and healthy elderly men. Arch Neurol. 2006;63:177-85. [PMID: 16344336]
172. Mulnard RA, Cotman CW, Kawas C, van Dyck CH, Sano M, Doody R, et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer's Disease Cooperative Study. JAMA. 2000;283:1007-15. [PMID: 10697060]
173. Valen-Sendstad A, Engedal K, Stray-Pedersen B, Strobel C, Barnett L, Meyer N, et al; ADACT Study Group. Effects of hormone therapy on depressive symptoms and cognitive functions in women with Alzheimer disease: a 12 month randomized, double-blind, placebo-controlled study of low-dose estradiol and norethisterone. Am J Geriatr Psychiatry. 2010;18:11-20. [PMID: 20094015]
174. Wang PN, Liao SQ, Liu RS, Liu CY, Chao HT, Lu SR, et al. Effects of estrogen on cognition, mood, and cerebral blood flow in AD: a controlled study. Neurology. 2000;54:2061-6. [PMID: 10851363]
175. Aisen PS, Schneider LS, Sano M, Diaz-Arrastia R, van Dyck CH, Weiner MF, et al; Alzheimer Disease Cooperative Study. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA. 2008;300:1774-83. [PMID: 18854539]
176. Connelly PJ, Prentice NP, Cousland G, Bonham J. A randomised double-blind placebo-controlled trial of folic acid supplementation of cholinesterase inhibitors in Alzheimer's disease. Int J Geriatr Psychiatry. 2008;23:155-60. [PMID: 17600848]
177. de Jager CA, Oulhaj A, Jacoby R, Refsum H, Smith AD. Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial. Int J Geriatr Psychiatry. 2012;27:592-600. [PMID: 21780182]
178. Freund-Levi Y, Eriksdotter-Jönhagen M, Cederholm T, Basun H, Faxén-Irving G, Garlind A, et al. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch Neurol. 2006;63:1402-8. [PMID: 17030655]
179. Kwok T, Lee J, Law CB, Pan PC, Yung CY, Choi KC, et al. A randomized placebo controlled trial of homocysteine lowering to reduce cognitive decline in older demented people. Clin Nutr. 2011;30:297-302. [PMID: 21216507]
180. Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N Engl J Med. 1997;336:1216-22. [PMID: 9110909]
181. Sinn N, Milte CM, Street SJ, Buckley JD, Coates AM, Petkov J, et al. Effects of ω-3 fatty acids, EPA v. DHA, on depressive symptoms, quality of life, memory and executive function in older adults with mild cognitive impairment: a 6-month randomised controlled trial. Br J Nutr. 2012;107:1682-93. [PMID: 21929835]
182. Quinn JF, Raman R, Thomas RG, Yurko-Mauro K, Nelson EB, Van Dyck C, et al. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA. 2010;304:1903-11. [PMID: 21045096]
183. Sun Y, Lu CJ, Chien KL, Chen ST, Chen RC. Efficacy of multivitamin supplementation containing vitamins B6 and B12 and folic acid as adjunctive treatment with a cholinesterase inhibitor in Alzheimer's disease: a 26-week, randomized, double-blind, placebo-controlled study in Taiwanese patients. Clin Ther. 2007;29:2204-14. [PMID: 18042476]
184. van Uffelen JG, Chinapaw MJ, van Mechelen W, Hopman-Rock M. Walking or vitamin B for cognition in older adults with mild cognitive impairment? A randomised controlled trial. Br J Sports Med. 2008;42:344-51. [PMID: 18308888]
185. Yurko-Mauro K, McCarthy D, Rom D, Nelson EB, Ryan AS, Blackwell A, et al; MIDAS Investigators. Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline. Alzheimers Dement. 2010;6:456-64. [PMID: 20434961]
186. Belle SH, Burgio L, Burns R, Coon D, Czaja SJ, Gallagher-Thompson D, et al; Resources for Enhancing Alzheimer's Caregiver Health (REACH) II Investigators. Enhancing the quality of life of dementia caregivers from different ethnic or racial groups: a randomized, controlled trial. Ann Intern Med. 2006;145:727-38. [PMID: 17116917]
187. Brodaty H, Gresham M. Effect of a training programme to reduce stress in carers of patients with dementia. BMJ. 1989;299:1375-9. [PMID: 2513967]
188. Burgio L, Stevens A, Guy D, Roth DL, Haley WE. Impact of two psychosocial interventions on white and African American family caregivers of individuals with dementia. Gerontologist. 2003;43:568-79. [PMID: 12937335]
189. Chu H, Yang CY, Liao YH, Chang LI, Chen CH, Lin CC, et al. The effects of a support group on dementia caregivers' burden and depression. J Aging Health. 2011;23:228-41. [PMID: 20847363]
190. Coon DW, Thompson L, Steffen A, Sorocco K, Gallagher-Thompson D. Anger and depression management: psychoeducational skill training interventions for women caregivers of a relative with dementia. Gerontologist. 2003;43:678-89. [PMID: 14570964]
191. Gallagher-Thompson D, Coon DW, Solano N, Ambler C, Rabinowitz Y, Thompson LW. Change in indices of distress among Latino and Anglo female caregivers of elderly relatives with dementia: site-specific results from the REACH national collaborative study. Gerontologist. 2003;43:580-91. [PMID: 12937336]
192. de Rotrou J, Cantegreil I, Faucounau V, Wenisch E, Chausson C, Jegou D, et al. Do patients diagnosed with Alzheimer's disease benefit from a psycho-educational programme for family caregivers? A randomised controlled study. Int J Geriatr Psychiatry. 2011;26:833-42. [PMID: 20922772]
193. Gallagher-Thompson D, Gray HL, Dupart T, Jimenez D, Thompson LW. Effectiveness of cognitive/behavioral small group intervention for reduction of depression and stress in non-Hispanic white and Hispanic/Latino women dementia family caregivers: outcomes and mediators of change. J Ration Emot Cogn Behav Ther. 2008;26:286-303.
194. Hébert R, Leclerc G, Bravo G, Girouard D, Lefrançois R. Efficacy of a support group programme for care-givers of demented patients in the community: a randomized controlled trial. Arch Gerontol Geriatr. 1994;18:1-14. [PMID: 15374309]
195. Hepburn KW, Tornatore J, Center B, Ostwald SW. Dementia family caregiver training: affecting beliefs about caregiving and caregiver outcomes. J Am Geriatr Soc. 2001;49:450-7. [PMID: 11347790]
196. Kurz A, Wagenpfeil S, Hallauer J, Schneider-Schelte H, Jansen S; AENEAS Study. Evaluation of a brief educational program for dementia carers: the AENEAS study. Int J Geriatr Psychiatry. 2010;25:861-9. [PMID: 19946869]
197. Losada A, Márquez-González M, Romero-Moreno R. Mechanisms of action of a psychological intervention for dementia caregivers: effects of behavioral activation and modification of dysfunctional thoughts. Int J Geriatr Psychiatry. 2011;26:1119-27. [PMID: 21061414]
198. Ostwald SK, Hepburn KW, Caron W, Burns T, Mantell R. Reducing caregiver burden: a randomized psychoeducational intervention for caregivers of persons with dementia. Gerontologist. 1999;39:299-309. [PMID: 10396888]
199. Ulstein ID, Sandvik L, Wyller TB, Engedal K. A one-year randomized controlled psychosocial intervention study among family carers of dementia patients—effects on patients and carers. Dement Geriatr Cogn Disord. 2007;24:469-75. [PMID: 17986818]
200. Waldorff FB, Buss DV, Eckermann A, Rasmussen ML, Keiding N, Rishøj S, et al. Efficacy of psychosocial intervention in patients with mild Alzheimer's disease: the multicentre, rater blinded, randomised Danish Alzheimer Intervention Study (DAISY). BMJ. 2012;345:e4693. [PMID: 22807076]
201. Chang BL. Cognitive-behavioral intervention for homebound caregivers of persons with dementia. Nurs Res. 1999;48:173-82. [PMID: 10337848]
202. Ducharme FC, Lévesque LL, Lachance LM, Kergoat MJ, Legault AJ, Beaudet LM, et al. “Learning to become a family caregiver” efficacy of an intervention program for caregivers following diagnosis of dementia in a relative. Gerontologist. 2011;51:484-94. [PMID: 21383112]
203. Gitlin LN, Corcoran M, Winter L, Boyce A, Hauck WW. A randomized, controlled trial of a home environmental intervention: effect on efficacy and upset in caregivers and on daily function of persons with dementia. Gerontologist. 2001;41:4-14. [PMID: 11220813]
204. Gitlin LN, Belle SH, Burgio LD, Czaja SJ, Mahoney D, Gallagher-Thompson D, et al; REACH Investigators. Effect of multicomponent interventions on caregiver burden and depression: the REACH multisite initiative at 6-month follow-up. Psychol Aging. 2003;18:361-74. [PMID: 14518800]
205. Gitlin LN, Winter L, Burke J, Chernett N, Dennis MP, Hauck WW. Tailored activities to manage neuropsychiatric behaviors in persons with dementia and reduce caregiver burden: a randomized pilot study. Am J Geriatr Psychiatry. 2008;16:229-39. [PMID: 18310553]
206. Gitlin LN, Winter L, Dennis MP, Hodgson N, Hauck WW. A biobehavioral home-based intervention and the well-being of patients with dementia and their caregivers: the COPE randomized trial. JAMA. 2010;304:983-91. [PMID: 20810376]
207. Gitlin LN, Winter L, Dennis MP, Hodgson N, Hauck WW. Targeting and managing behavioral symptoms in individuals with dementia: a randomized trial of a nonpharmacological intervention. J Am Geriatr Soc. 2010;58:1465-74. [PMID: 20662955]
208. Graff MJ, Vernooij-Dassen MJ, Thijssen M, Dekker J, Hoefnagels WH, Rikkert MG. Community based occupational therapy for patients with dementia and their care givers: randomised controlled trial. BMJ. 2006;333:1196. [PMID: 17114212]
209. Hébert R, Lévesque L, Vézina J, Lavoie JP, Ducharme F, Gendron C, et al. Efficacy of a psychoeducative group program for caregivers of demented persons living at home: a randomized controlled trial. J Gerontol B Psychol Sci Soc Sci. 2003;58:S58-67. [PMID: 12496309]
210. Hinchliffe AC, Hyman IL, Blizard B, Livingston G. Behavioural complications of dementia—can they be treated? Int J Geriatr Psychiatry. 1995;10:839-47.
211. Huang HL, Shyu YI, Chen MC, Chen ST, Lin LC. A pilot study on a home-based caregiver training program for improving caregiver self-efficacy and decreasing the behavioral problems of elders with dementia in Taiwan. Int J Geriatr Psychiatry. 2003;18:337-45. [PMID: 12673611]
212. Marriott A, Donaldson C, Tarrier N, Burns A. Effectiveness of cognitive-behavioural family intervention in reducing the burden of care in carers of patients with Alzheimer's disease. Br J Psychiatry. 2000;176:557-62. [PMID: 10974962]
213. Martín-Carrasco M, Martín MF, Valero CP, Millán PR, García CI, Montalbán SR, et al. Effectiveness of a psychoeducational intervention program in the reduction of caregiver burden in Alzheimer's disease patients' caregivers. Int J Geriatr Psychiatry. 2009;24:489-99. [PMID: 18949763]
214. Martin-Cook K, Davis BA, Hynan LS, Weiner MF. A randomized, controlled study of an Alzheimer's caregiver skills training program. Am J Alzheimers Dis Other Demen. 2005;20:204-10. [PMID: 16136843]
215. Roberts J, Browne G, Milne C, Spooner L, Gafni A, Drummond-Young M, et al. Problem-solving counseling for caregivers of the cognitively impaired: effective for whom? Nurs Res. 1999;48:162-72. [PMID: 10337847]
216. Schoenmakers B, Buntinx F, Delepeleire J. Supporting family carers of community-dwelling elder with cognitive decline: a randomized controlled trial. Int J Family Med. 2010;2010:184152. [PMID: 22332005]
217. Spijker A, Wollersheim H, Teerenstra S, Graff M, Adang E, Verhey F, et al. Systematic care for caregivers of patients with dementia: a multicenter, cluster-randomized, controlled trial. Am J Geriatr Psychiatry. 2011;19:521-31. [PMID: 21358385]
218. Voigt-Radloff S, Graff M, Leonhart R, Schornstein K, Jessen F, Bohlken J, et al. A multicentre RCT on community occupational therapy in Alzheimer's disease: 10 sessions are not better than one consultation. BMJ Open. 2011;1:e000096. [PMID: 22021760]
219. Williams VP, Bishop-Fitzpatrick L, Lane JD, Gwyther LP, Ballard EL, Vendittelli AP, et al. Video-based coping skills to reduce health risk and improve psychological and physical well-being in Alzheimer's disease family caregivers. Psychosom Med. 2010;72:897-904. [PMID: 20978227]
220. Wright LK, Litaker M, Laraia MT, DeAndrade S. Continuum of care for Alzheimer's disease: a nurse education and counseling program. Issues Ment Health Nurs. 2001;22:231-52. [PMID: 11885210]
221. Brennan PF, Moore SM, Smyth KA. The effects of a special computer network on caregivers of persons with Alzheimer's disease. Nurs Res. 1995;44:166-72. [PMID: 7761293]
222. Finkel S, Czaja SJ, Schulz R, Martinovich Z, Harris C, Pezzuto D. E-care: a telecommunications technology intervention for family caregivers of dementia patients. Am J Geriatr Psychiatry. 2007;15:443-8. [PMID: 17463195]
223. Mahoney DF, Tarlow BJ, Jones RN. Effects of an automated telephone support system on caregiver burden and anxiety: findings from the REACH for TLC intervention study. Gerontologist. 2003;43:556-67. [PMID: 12937334]
224. Joling KJ, van Marwijk HW, Smit F, van der Horst HE, Scheltens P, van de Ven PM, et al. Does a family meetings intervention prevent depression and anxiety in family caregivers of dementia patients? A randomized trial. PLoS One. 2012;7:e30936. [PMID: 22303473]
225. Mittelman MS, Brodaty H, Wallen AS, Burns A. A three-country randomized controlled trial of a psychosocial intervention for caregivers combined with pharmacological treatment for patients with Alzheimer disease: effects on caregiver depression. Am J Geriatr Psychiatry. 2008;16:893-904. [PMID: 18978250]
226. Callahan CM, Boustani MA, Unverzagt FW, Austrom MG, Damush TM, Perkins AJ, et al. Effectiveness of collaborative care for older adults with Alzheimer disease in primary care: a randomized controlled trial. JAMA. 2006;295:2148-57. [PMID: 16684985]
227. Chu P, Edwards J, Levin R, Thomson J. The use of clinical case management for early stage Alzheimer's patients and their families. Am J Alzheimers Dis Other Demen. 2000;15:284-90.
228. Eloniemi-Sulkava U, Notkola IL, Hentinen M, Kivelä SL, Sivenius J, Sulkava R. Effects of supporting community-living demented patients and their caregivers: a randomized trial. J Am Geriatr Soc. 2001;49:1282-7. [PMID: 11890485]
229. Eloniemi-Sulkava U, Saarenheimo M, Laakkonen ML, Pietilä M, Savikko N, Kautiainen H, et al. Family care as collaboration: effectiveness of a multicomponent support program for elderly couples with dementia. Randomized controlled intervention study. J Am Geriatr Soc. 2009;57:2200-8. [PMID: 20121986]
230. Fortinsky RH, Kulldorff M, Kleppinger A, Kenyon-Pesce L. Dementia care consultation for family caregivers: collaborative model linking an Alzheimer's association chapter with primary care physicians. Aging Ment Health. 2009;13:162-70. [PMID: 19347683]
231. Jansen AP, van Hout HP, Nijpels G, Rijmen F, Dröes RM, Pot AM, et al. Effectiveness of case management among older adults with early symptoms of dementia and their primary informal caregivers: a randomized clinical trial. Int J Nurs Stud. 2011;48:933-43. [PMID: 21356537]
232. Lam LC, Lee JS, Chung JC, Lau A, Woo J, Kwok TC. A randomized controlled trial to examine the effectiveness of case management model for community dwelling older persons with mild dementia in Hong Kong. Int J Geriatr Psychiatry. 2010;25:395-402. [PMID: 19606455]
233. Vickrey BG, Mittman BS, Connor KI, Pearson ML, Della Penna RD, Ganiats TG, et al. The effect of a disease management intervention on quality and outcomes of dementia care: a randomized, controlled trial. Ann Intern Med. 2006;145:713-26. [PMID: 17116916]
234. Logiudice D, Waltrowicz W, Brown K, Burrows C, Ames D, Flicker L. Do memory clinics improve the quality of life of carers? A randomized pilot trial. Int J Geriatr Psychiatry. 1999;14:626-32. [PMID: 10489653]
235. Charlesworth G, Shepstone L, Wilson E, Reynolds S, Mugford M, Price D, et al. Befriending carers of people with dementia: randomised controlled trial. BMJ. 2008;336:1295-7. [PMID: 18505757]
236. Pillemer K, Suitor JJ. Peer support for Alzheimer's caregivers: is it enough to make a difference? Res Aging. 2002;24:171-92.
237. Winter L, Gitlin LN. Evaluation of a telephone-based support group intervention for female caregivers of community-dwelling individuals with dementia. Am J Alzheimers Dis Other Demen. 2006;21:391-7. [PMID: 17267370]
238. Connell CM, Janevic MR. Effects of a telephone-based exercise intervention for dementia caregiving wives: a randomized controlled trial. J Appl Gerontol. 2009;28:171-194. [PMID: 21709757]
239. Hirano A, Suzuki Y, Kuzuya M, Onishi J, Ban N, Umegaki H. Influence of regular exercise on subjective sense of burden and physical symptoms in community-dwelling caregivers of dementia patients: a randomized controlled trial. Arch Gerontol Geriatr. 2011;53:e158-63. [PMID: 20850878]
240. King AC, Baumann K, O'Sullivan P, Wilcox S, Castro C. Effects of moderate-intensity exercise on physiological, behavioral, and emotional responses to family caregiving: a randomized controlled trial. J Gerontol A Biol Sci Med Sci. 2002;57:M26-36. [PMID: 11773209]
241. Bass DM, Clark PA, Looman WJ, McCarthy CA, Eckert S. The Cleveland Alzheimer's managed care demonstration: outcomes after 12 months of implementation. Gerontologist. 2003;43:73-85. [PMID: 12604748]
242. Chapman SB, Weiner MF, Rackley A, Hynan LS, Zientz J. Effects of cognitive-communication stimulation for Alzheimer's disease patients treated with donepezil. J Speech Lang Hear Res. 2004;47:1149-63. [PMID: 15603468]
243. Buschert VC, Friese U, Teipel SJ, Schneider P, Merensky W, Rujescu D, et al. Effects of a newly developed cognitive intervention in amnestic mild cognitive impairment and mild Alzheimer's disease: a pilot study. J Alzheimers Dis. 2011;25:679-94. [PMID: 21483095]
244. Tsolaki M, Kounti F, Agogiatou C, Poptsi E, Bakoglidou E, Zafeiropoulou M, et al. Effectiveness of nonpharmacological approaches in patients with mild cognitive impairment. Neurodegener Dis. 2011;8:138-45. [PMID: 21135531]
245. Olazarán J, Muñiz R, Reisberg B, Peña-Casanova J, del Ser T, Cruz-Jentoft AJ, et al. Benefits of cognitive-motor intervention in MCI and mild to moderate Alzheimer disease. Neurology. 2004;63:2348-53. [PMID: 15623698]
246. Quayhagen MP, Quayhagen M, Corbeil RR, Roth PA, Rodgers JA. A dyadic remediation program for care recipients with dementia. Nurs Res. 1995;44:153-9. [PMID: 7761291]
247. Kinsella GJ, Mullaly E, Rand E, Ong B, Burton C, Price S, et al. Early intervention for mild cognitive impairment: a randomised controlled trial. J Neurol Neurosurg Psychiatry. 2009;80:730-6. [PMID: 19332424]
248. Rapp S, Brenes G, Marsh AP. Memory enhancement training for older adults with mild cognitive impairment: a preliminary study. Aging Ment Health. 2002;6:5-11. [PMID: 11827617]
249. Troyer AK, Murphy KJ, Anderson ND, Moscovitch M, Craik FI. Changing everyday memory behaviour in amnestic mild cognitive impairment: a randomised controlled trial. Neuropsychol Rehabil. 2008;18:65-88. [PMID: 17943615]
250. Burgener SC, Yang Y, Gilbert R, Marsh-Yant S. The effects of a multimodal intervention on outcomes of persons with early-stage dementia. Am J Alzheimers Dis Other Demen. 2008;23:382-94. [PMID: 18453642]
251. Cahn-Weiner DA, Malloy PF, Rebok GW, Ott BR. Results of a randomized placebo-controlled study of memory training for mildly impaired Alzheimer's disease patients. Appl Neuropsychol. 2003;10:215-23. [PMID: 14690802]
252. Clare L, Linden DE, Woods RT, Whitaker R, Evans SJ, Parkinson CH, et al. Goal-oriented cognitive rehabilitation for people with early-stage Alzheimer disease: a single-blind randomized controlled trial of clinical efficacy. Am J Geriatr Psychiatry. 2010;18:928-39. [PMID: 20808145]
253. Greenaway MC, Duncan NL, Smith GE. The memory support system for mild cognitive impairment: randomized trial of a cognitive rehabilitation intervention. Int J Geriatr Psychiatry. 2013;28:402-9. [PMID: 22678947]
254. Schwenk M, Zieschang T, Oster P, Hauer K. Dual-task performances can be improved in patients with dementia: a randomized controlled trial. Neurology. 2010;74:1961-8. [PMID: 20445152]
255. Kurz A, Thöne-Otto A, Cramer B, Egert S, Frölich L, Gertz HJ, et al. CORDIAL: cognitive rehabilitation and cognitive-behavioral treatment for early dementia in Alzheimer disease: a multicenter, randomized, controlled trial. Alzheimer Dis Assoc Disord. 2012;26:246-53. [PMID: 21986341]
256. Baker LD, Frank LL, Foster-Schubert K, Green PS, Wilkinson CW, McTiernan A, et al. Effects of aerobic exercise on mild cognitive impairment: a controlled trial. Arch Neurol. 2010;67:71-9. [PMID: 20065132]
257. Lam LC, Chau RC, Wong BM, Fung AW, Lui VW, Tam CC, et al. Interim follow-up of a randomized controlled trial comparing Chinese style mind body (Tai Chi) and stretching exercises on cognitive function in subjects at risk of progressive cognitive decline. Int J Geriatr Psychiatry. 2011;26:733-40. [PMID: 21495078]
258. Lautenschlager NT, Cox KL, Flicker L, Foster JK, van Bockxmeer FM, Xiao J, et al. Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial. JAMA. 2008;300:1027-37. [PMID: 18768414]
259. Nagamatsu LS, Handy TC, Hsu CL, Voss M, Liu-Ambrose T. Resistance training promotes cognitive and functional brain plasticity in seniors with probable mild cognitive impairment. Arch Intern Med. 2012;172:666-8. [PMID: 22529236]
260. Steinberg M, Leoutsakos JM, Podewils LJ, Lyketsos CG. Evaluation of a home-based exercise program in the treatment of Alzheimer's disease: the Maximizing Independence in Dementia (MIND) study. Int J Geriatr Psychiatry. 2009;24:680-5. [PMID: 19089875]
261. Suzuki T, Shimada H, Makizako H, Doi T, Yoshida D, Tsutsumimoto K, et al. Effects of multicomponent exercise on cognitive function in older adults with amnestic mild cognitive impairment: a randomized controlled trial. BMC Neurol. 2012;12:128. [PMID: 23113898]
262. Teri L, Logsdon RG, McCurry SM. Exercise interventions for dementia and cognitive impairment: the Seattle protocols. J Nutr Health Aging. 2008;12:391-4. [PMID: 18548177]
263. Tsai PF, Chang JY, Beck C, Kuo YF, Keefe FJ. A pilot cluster-randomized trial of a 20-week Tai Chi program in elders with cognitive impairment and osteoarthritic knee: effects on pain and other health outcomes. J Pain Symptom Manage. 2013;45:660-9. [PMID: 23017610]
264. Venturelli M, Lanza M, Muti E, Schena F. Positive effects of physical training in activity of daily living-dependent older adults. Exp Aging Res. 2010;36:190-205. [PMID: 20209421]
265. Vreugdenhil A, Cannell J, Davies A, Razay G. A community-based exercise programme to improve functional ability in people with Alzheimer's disease: a randomized controlled trial. Scand J Caring Sci. 2012;26:12-9. [PMID: 21564154]
266. Bellantonio S, Kenny AM, Fortinsky RH, Kleppinger A, Robison J, Gruman C, et al. Efficacy of a geriatrics team intervention for residents in dementia-specific assisted living facilities: effect on unanticipated transitions. J Am Geriatr Soc. 2008;56:523-8. [PMID: 18179497]
267. Meeuwsen EJ, Melis RJ, Van Der Aa GC, Golüke-Willemse GA, De Leest BJ, Van Raak FH, et al. Effectiveness of dementia follow-up care by memory clinics or general practitioners: randomised controlled trial. BMJ. 2012;344:e3086. [PMID: 22589500]
268. Nourhashemi F, Andrieu S, Gillette-Guyonnet S, Giraudeau B, Cantet C, Coley N, et al; PLASA Group. Effectiveness of a specific care plan in patients with Alzheimer's disease: cluster randomised trial (PLASA study). BMJ. 2010;340:c2466. [PMID: 20522656]
269. Richard E, Van den Heuvel E, Moll van Charante EP, Achthoven L, Vermeulen M, Bindels PJ, et al. Prevention of Dementia by Intensive Vascular Care (PreDIVA): a cluster-randomized trial in progress. Alzheimer Dis Assoc Disord. 2009;23:198-204. [PMID: 19812459]
270. Wolfs CA, Kessels A, Dirksen CD, Severens JL, Verhey FR. Integrated multidisciplinary diagnostic approach for dementia care: randomised controlled trial. Br J Psychiatry. 2008;192:300-5. [PMID: 18378994]
271. Beer C, Horner B, Flicker L, Scherer S, Lautenschlager NT, Bretland N, et al. A cluster-randomised trial of staff education to improve the quality of life of people with dementia living in residential care: the DIRECT study. PLoS One. 2011;6:e28155. [PMID: 22140531]
272. Menn P, Holle R, Kunz S, Donath C, Lauterberg J, Leidl R, et al. Dementia care in the general practice setting: a cluster randomized trial on the effectiveness and cost impact of three management strategies. Value Health. 2012;15:851-9. [PMID: 22999135]
273. Boada-Rovira M, Brodaty H, Cras P, Baloyannis S, Emre M, Zhang R, et al; 322 Study Group. Efficacy and safety of donepezil in patients with Alzheimer's disease: results of a global, multinational, clinical experience study. Drugs Aging. 2004;21:43-53. [PMID: 14715043]
274. Relkin NR, Reichman WE, Orazem J, McRae T. A large, community-based, open-label trial of donepezil in the treatment of Alzheimer's disease. Dement Geriatr Cogn Disord. 2003;16:15-24. [PMID: 12714795]
275. Babai S, Auriche P, Le-Louët H. Comparison of adverse drug reactions with donepezil versus memantine: analysis of the French Pharmacovigilance Database. Therapie. 2010;65:255-9. [PMID: 20699079]
276. Hernandez RK, Farwell W, Cantor MD, Lawler EV. Cholinesterase inhibitors and incidence of bradycardia in patients with dementia in the veterans affairs New England healthcare system. J Am Geriatr Soc. 2009;57:1997-2003. [PMID: 19793162]
277. Park-Wyllie LY, Mamdani MM, Li P, Gill SS, Laupacis A, Juurlink DN. Cholinesterase inhibitors and hospitalization for bradycardia: a population-based study. PLoS Med. 2009;6:e1000157. [PMID: 19787032]
278. Dunn NR, Pearce GL, Shakir SA. Adverse effects associated with the use of donepezil in general practice in England. J Psychopharmacol. 2000;14:406-8. [PMID: 11198060]
279. Pariente A, Sanctussy DJ, Miremont-Salamé G, Moore N, Haramburu F, Fourrier-Réglat A; l'Association Française des Centres Régionaux de Pharmacovigilance (CRPV). Factors associated with serious adverse reactions to cholinesterase inhibitors: a study of spontaneous reporting. CNS Drugs. 2010;24:55-63. [PMID: 20030419]
280. Froelich L, Andreasen N, Tsolaki M, Foucher A, Kavanagh S, Baelen BV, et al. Long-term treatment of patients with Alzheimer's disease in primary and secondary care: results from an international survey. Curr Med Res Opin. 2009;25:3059-68. [PMID: 19852697]
281. Vidal JS, Lacombe JM, Dartigues JF, Pasquier F, Robert P, Tzourio C, et al. Memantine therapy for Alzheimer disease in real-world practice: an observational study in a large representative sample of French patients. Alzheimer Dis Assoc Disord. 2008;22:125-30. [PMID: 18525283]
282. Van Der Putt R, Dineen C, Janes D, Series H, McShane R. Effectiveness of acetylcholinesterase inhibitors: diagnosis and severity as predictors of response in routine practice. Int J Geriatr Psychiatry. 2006;21:755-60. [PMID: 16906631]
283. Gill SS, Anderson GM, Fischer HD, Bell CM, Li P, Normand SL, et al. Syncope and its consequences in patients with dementia receiving cholinesterase inhibitors: a population-based cohort study. Arch Intern Med. 2009;169:867-73. [PMID: 19433698]
284. Raschetti R, Maggini M, Sorrentino GC, Martini N, Caffari B, Vanacore N. A cohort study of effectiveness of acetylcholinesterase inhibitors in Alzheimer's disease. Eur J Clin Pharmacol. 2005;61:361-8. [PMID: 15912389]
285. Fosbøl EL, Peterson ED, Holm E, Gislason GH, Zhang Y, Curtis LH, et al. Comparative cardiovascular safety of dementia medications: a cross-national study. J Am Geriatr Soc. 2012;60:2283-9. [PMID: 23176182]
286. Stephenson A, Seitz DP, Fischer HD, Gruneir A, Bell CM, Gershon AS, et al. Cholinesterase inhibitors and adverse pulmonary events in older people with chronic obstructive pulmonary disease and concomitant dementia: a population-based, cohort study. Drugs Aging. 2012;29:213-23. [PMID: 22332932]
287. Förstl H, Stamouli SS, Janetzky W, Galanopoulos A, Karageorgiou C, Tzanakaki M. Memantine in everyday clinical practice: a comparison of studies in Germany and Greece. Dement Geriatr Cogn Disord. 2011;32:267-72. [PMID: 22237255]
288. Requena C, Maestú F, Campo P, Fernández A, Ortiz T. Effects of cholinergic drugs and cognitive training on dementia: 2-year follow-up. Dement Geriatr Cogn Disord. 2006;22:339-45. [PMID: 16954689]
289. Burns A, Gauthier S, Perdomo C. Efficacy and safety of donepezil over 3 years: an open-label, multicentre study in patients with Alzheimer's disease. Int J Geriatr Psychiatry. 2007;22:806-12. [PMID: 17199235]
290. Wilkinson D, Róman G, Salloway S, Hecker J, Boundy K, Kumar D, et al. The long-term efficacy and tolerability of donepezil in patients with vascular dementia. Int J Geriatr Psychiatry. 2010;25:305-13. [PMID: 19623601]
291. Munoz DG, Feldman H. Causes of Alzheimer's disease. CMAJ. 2000;162:65-72. [PMID: 11216203]
292. Aronson S, Van Baelen B, Kavanagh S, Schwalen S. Optimal dosing of galantamine in patients with mild or moderate Alzheimer's disease: post hoc analysis of a randomized, double-blind, placebo-controlled trial. Drugs Aging. 2009;26:231-9. [PMID: 19358618]
293. Ott BR, Blake LM, Kagan E, Resnick M; Memantine MEM-MD-11AB Study Group. Open label, multicenter, 28-week extension study of the safety and tolerability of memantine in patients with mild to moderate Alzheimer's disease. J Neurol. 2007;254:351-8. [PMID: 17345042]
294. Kadir A, Darreh-Shori T, Almkvist O, Wall A, Grut M, Strandberg B, et al. PET imaging of the in vivo brain acetylcholinesterase activity and nicotine binding in galantamine-treated patients with AD. Neurobiol Aging. 2008;29:1204-17. [PMID: 17379359]
295. Teri L, Gibbons LE, McCurry SM, Logsdon RG, Buchner DM, Barlow WE, et al. Exercise plus behavioral management in patients with Alzheimer disease: a randomized controlled trial. JAMA. 2003;290:2015-22. [PMID: 14559955]
296. Quayhagen MP, Quayhagen M. Testing of a cognitive stimulation intervention for dementia caregiving dyads. Neuropsychol Rehabil. 2001;11:319-32.
297. Boustani M, Peterson B, Harris R, Lux LJ, Krasnov C, Sutton SF, et al. Screening for dementia [Internet]. Systematic Evidence Reviews. 2003. [PMID: 20722116]
298. Brodaty H, Low LF, Gibson L, Burns K. What is the best dementia screening instrument for general practitioners to use? Am J Geriatr Psychiatry. 2006;14:391-400. [PMID: 16670243]
299. Russ TC, Morling JR. Cholinesterase inhibitors for mild cognitive impairment. Cochrane Database Syst Rev. 2012;9:CD009132. [PMID: 22972133]
300. National Institute for Health and Clinical Excellence. Donepezil, Galantamine, Rivastigmine and Memantine for the Treatment of Alzheimer's Disease. NICE Technology Appraisal Guidance 217. London: National Institute for Health and Clinical Excellence; 2011.
301. Vernooij-Dassen M, Draskovic I, McCleery J, Downs M. Cognitive reframing for carers of people with dementia. Cochrane Database Syst Rev. 2011:CD005318. [PMID: 22071821]
302. Goy E, Kansagara D, Freeman M. A systematic evidence review of interventions for non-professional caregivers of individuals with dementia. VA Evidence-based Synthesis Program Reports. 2010. [PMID: 21155197]
303. Chien LY, Chu H, Guo JL, Liao YM, Chang LI, Chen CH, et al. Caregiver support groups in patients with dementia: a meta-analysis. Int J Geriatr Psychiatry. 2011;26:1089-98. [PMID: 21308785]
304. Tam-Tham H, Cepoiu-Martin M, Ronksley PE, Maxwell CJ, Hemmelgarn BR. Dementia case management and risk of long-term care placement: a systematic review and meta-analysis. Int J Geriatr Psychiatry. 2013;28:889-902. [PMID: 23188735]
305. Olazarán J, Reisberg B, Clare L, Cruz I, Peña-Casanova J, Del Ser T, et al. Nonpharmacological therapies in Alzheimer's disease: a systematic review of efficacy. Dement Geriatr Cogn Disord. 2010;30:161-78. [PMID: 20838046]
306. Woods B, Aguirre E, Spector AE, Orrell M. Cognitive stimulation to improve cognitive functioning in people with dementia. Cochrane Database Syst Rev. 2012;2:CD005562. [PMID: 22336813]
307. Reijnders J, van Heugten C, van Boxtel M. Cognitive interventions in healthy older adults and people with mild cognitive impairment: a systematic review. Ageing Res Rev. 2013;12:263-75. [PMID: 22841936]
308. Kurz AF, Leucht S, Lautenschlager NT. The clinical significance of cognition-focused interventions for cognitively impaired older adults: a systematic review of randomized controlled trials. Int Psychogeriatr. 2011;23:1364-75. [PMID: 21740614]
309. Pitkälä K, Savikko N, Poysti M, Strandberg T, Laakkonen ML. Efficacy of physical exercise intervention on mobility and physical functioning in older people with dementia: a systematic review. Exp Gerontol. 2013;48:85-93. [PMID: 22960590]
310. Prince M, Bryce R, Ferri C. World Alzheimer Report 2011. The Benefits of Early Diagnosis and Intervention. London: Alzheimer's Disease International; 2011.
311. Rockwood K, Dai D, Mitnitski A. Patterns of decline and evidence of subgroups in patients with Alzheimer's disease taking galantamine for up to 48 months. Int J Geriatr Psychiatry. 2008;23:207-14. [PMID: 17621382]
Figure 1. Summary of evidence search and selection.
SER = systematic evidence review.
Figure 1 displays the literature search results and article flow for the evidence review. A total of 15,684 articles were identified through database searching, 313 through selected systematic evidence reviews, and 182 through other sources. 16,179 articles were screened after duplicates were removed. 1,190 full-text articles were assessed for eligibility. No articles were included for key question 1; 64 articles (55 studies) were included for key question 2; two articles (one study) were included for key question 3; 167 articles (131 studies) were included for key question 4; and 78 articles (66 studies) were included for key question 5.
Figure 2. Meta-analyses of effects of AChEIs and memantine on global cognitive function, measured by the ADAS-cog.
Weights are from random-effects analysis. AChEI = acetylcholinesterase inhibitor; AD = Alzheimer disease; ADAS-cog = Alzheimer's Disease Assessment Scale-Cognitive Subscale; MCI = mild cognitive impairment; MMSE = Mini-Mental State Examination; VaD = vascular dementia.
* Included in the systematic review by Raina and colleagues, 200814.
Figure 2 displays a forest plot of acetylcholinesterase inhibitor and memantine studies reporting the difference in mean change for the intervention group versus the control group for global cognitive function measured by the ADAS-cog.
Figure 3. Meta-analyses of effects of AChEIs and memantine on withdrawals due to adverse events.
Weights are from random-effects analysis. AChEI = acetylcholinesterase inhibitor; RR = relative risk.
* Included in the systematic review by Raina and colleagues, 200814.
Figure 3 displays a forest plot of acetylcholinesterase inhibitor and memantine studies reporting the relative risk for the intervention group versus the control group for withdrawals due to adverse events.
Figure 4. Meta-analyses of effects of psychoeducational caregiver interventions on caregiver burden.
Weights are from random-effects analysis. REACH = Resources for Enhancing Alzheimer's Caregiver Health.
Figure 4 displays a forest plot of psychoeducational caregiver intervention studies reporting the Hedge g statistic for the intervention group versus the control group for caregiver burden.
Figure 5. Meta-analyses of effects of psychoeducational caregiver interventions on caregiver depression.
Weights are from random-effects analysis. REACH = Resources for Enhancing Alzheimer's Caregiver Health.
Figure 5 displays a forest plot of psychoeducational caregiver intervention studies reporting the Hedge g statistic for the intervention group versus the control group for caregiver depression.
Appendix Table 1. Inclusion Criteria
|1–3 (screening)||Community-dwelling older adults (including persons in senior communities, assisted living facilities, and adult foster care), excluding populations referred or selected for cognitive impairment (including memory clinics, psychogeriatric clinics, and AD research centers).
Brief screening instrument (administration time ≤ 10 min or can be self-administered in ≤ 20 min).
Any decision-making outcomes (patient, family, or clinician), patient health or safety outcomes, family or caregiver burden or health outcomes, or societal outcomes (KQ 1); diagnostic accuracy (sensitivity and specificity for dementia or MCI) outcomes (KQ 2); or harms (unwanted or unexpected direction of effect on health outcomes, psychological harms, harms due to labeling, or poor adherence to diagnostic follow-up) (KQ 3).
Screening studies of efficacy limited to trials (KQ 1); diagnostic accuracy studies, excluding case–control studies (KQ 2)*; and any study design for harms of screening (KQ 3).
|4–5 (treatment)||Treatment and management of MCI or mild to moderate dementia.
Pharmacologic interventions, including FDA-approved medications used to treat patients with AD to prevent or delay cognitive decline (i.e., donepezil, galantamine, rivastigmine, and memantine) and medications primarily aimed at cardiovascular risk reduction for treatment of VaD, including antiplatelet medication, antihypertensive medication, and HMG-CoA reductase inhibitors; NSAIDs; gonadal steroids (i.e., estrogen, progesterone, and testosterone); and dietary supplements (i.e., vitamins, minerals, and antioxidants).
Nonpharmacologic interventions aimed at patients or their nonprofessional caregivers, including multicomponent, support-only, education-only, exercise, or cognitive interventions and excluding interventions primarily aimed at noncognitive symptom management (e.g., music therapy, light therapy, or nighttime home monitoring systems) and respite care or day care interventions.
Any decision-making outcomes (e.g., health care planning, including advance directives, screening and diagnostic decisions, safety planning, or legal and financial planning), patient health or safety outcomes (e.g., cognitive function, physical function, overall function, HRQL, safety, medication use or adherence, neuropsychiatric symptoms [e.g., insomnia, depression, agitation, aggression, or wandering], emergency department use, hospitalizations, or institutionalization), caregiver outcomes (e.g., caregiver burden or HRQL), or societal outcomes (e.g., automobile accidents).
Treatment studies of efficacy were limited to good-quality systematic reviews of trials or trials with a true control group (KQ 4); harms studies included all trials that were included for KQ 4, open-label extensions of included drug trials, and large cohort or case–control studies (n ≥ 1000) (KQ 5).
AD = Alzheimer disease; FDA = U.S. Food and Drug Administration; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; HRQL = health-related quality of life; KQ = key question; MCI = mild cognitive impairment; NSAID = nonsteroidal anti-inflammatory drug; VaD = vascular dementia.
* We excluded case–control diagnostic accuracy studies in which patients were selected on the basis of having known dementia or MCI. Distorted selection of patients in selective recruitment or case–control designs has repeatedly been shown to overestimate sensitivity due to spectrum bias.23-27
Appendix Table 2. Diagnostic Accuracy of Brief Cognitive Screening Instruments in Primary Care for Dementia
|Very brief (≤5 min)|
|CDT50–55, 77||6*||2170||Fair||67–97.9 (39–100)||69–94.2 (54–97.1)||Inconsistency may be due to difference in population or scoring methods.||Wide range of prevalence; unclear optimum scoring.|
|Mini-Cog50, 56–58||4||1570||Fair||76–100 (54–100)||54–85.2 (43–88.4)||Inconsistency may be due to difference in population or scoring methods.||Wide range of prevalence; unclear optimum cut point.|
|MIS or MIS-T54, 56, 59–61||5||1971||Fair||43–86 (24–96)||93–97 (56–100)||2 best-quality studies with low sensitivities.||Wide range of prevalence.|
|MSQ or SPMSQ53, 62–64||4||1057||Fair||92.3–100 (29–100)||86.5–100 (76–100)||Inconsistency may be due to cut points.||Wide range of prevalence; only 1 study in English; unclear optimum cut point.|
|Verbal fluency50, 53, 54, 59, 65, 77||6||2083||Fair||37–89.5 (19–100)||43–97 (33–99)||Test performance overlapped regardless of cut point.||Wide range of prevalence.|
|Cut point of 12 or 13 points50, 54, 59||3||1041||-||37–89.5 (19–100)||62–97 (48–99)||-||-|
|Cut point of 14 or 15 points54, 59, 65||3||905||-||57–88 (35–NR)||43–94 (33–97)||-||-|
|Brief (6–10 min)|
|MMSE†51, 57, 62, 63, 65–84, 88||14‡||10,185||Fair||88.3§ (81.3–92.9)||86.2§ (81.8–89.7)||Test performance overlapped regardless of cut point.||Wide range of prevalence and languages; optimum cut point for low education is lower.|
|AMT63, 66, 80, 81||4||824||Fair||42–100 (16–100)||83–95.4 (76–99)||Unclear whether inconsistency due to difference in populations.||Wide range of prevalence; only 1 study in English (none in United States).|
|FCSRT53, 54||2||734||Fair||86–100 (41–100)||73–87.2 (56–96)||Only 2 studies; different populations and cut points.||Only 1 study in English; unclear optimum cut point.|
|7MS53, 85||2||553||Fair||66.7–100 (NR–100)||95.1–100 (86.8–100)||Only 2 studies; different populations and cut points.||Only 1 study in English; unclear optimum cut point.|
|TICS59, 86||2||677||Fair||74–88 (54–96)||86–97 (81–91)||Only 2 studies; different populations and cut points.||Only 1 study in English; unclear optimum cut point.|
|Self-administered (≤20 min)|
|IQCODE54, 68, 74, 79, 87||5||1251||Fair||75–87.6 (41–100)||65–91.1 (59–100)||Test performance overlapped for different cut points.||Unclear optimum cut point; cut point recommended by test developers not supported by evidence.|
7MS = 7-Minute Screen; AMT = Abbreviated Mental Test; CDT = Clock Drawing Test; FCSRT = Free and Cued Selective Reminding Test; IQCODE = Informant Questionnaire on Cognitive Decline in the Elderly; MIS = Memory Impairment Screen; MIS-T = Memory Impairment Screen by Telephone; MMSE = Mini-Mental State Examination; MSQ = Mental Status Questionnaire; NR = not reported; SPMSQ = Short Portable Mental Status Questionnaire; TICS = Telephone Interview for Cognitive Status.
* Six of 7 included studies reported sensitivity and specificity.
† Cut point of 23 of 24 points or 24 of 25 points.
‡ Fourteen of 25 included studies reported sensitivity and specificity at these specific cut points.
§ Pooled analysis.
Appendix Table 3. Benefits and Harms of Interventions for Mild to Moderate Dementia and MCI
|Quality||Summary of Findings||Consistency||Applicability|
|Effectiveness of pharmacologic interventions|
|AChEIs102–149||48||18,390||Fair||Donepezil (κ = 24; n = 7553), galantamine (κ = 12; n = 6008), and rivastigmine (κ =1 2; n = 4829) had statistically significant benefits on global cognitive function in the short term (change of approximately 1 to 3 points on the ADAS-cog). In a subset of trials, donepezil, galantamine, and rivastigmine had a small benefit on global function, as measured using the CIBIC-plus, in the short term. Physical function was only reported in half of the trials and showed mixed results.
Only 4 trials (3 for donepezil and 1 for galantamine) in MCI were found. Although small, statistically significant benefits were shown for donepezil: 2 trials showed no difference in progression of MCI to dementia at 3 y.
|Generally consistent findings of benefit for cognitive and global function outcomes. Inconsistent findings on physical function; cannot evaluate inconsistency given sparse reporting.||Most trials in moderate dementia, primarily AD (few trials in VaD); few trials in MCI; populations primarily from North America and western Europe; doses of medications applicable to common use.|
|Memantine150–159||10||3465||Fair||Statistically significant but clinically marginal benefits in cognitive function in the short term (κ = 9; n = 3323) were found. Benefits were mixed in global (κ = 7; n = 1880) and physical (κ = 5; n = 1962) function. Benefits seemed to be limited to persons with moderate AD.||Consistent findings in global cognitive function.
Inconsistent findings of benefit in global function and physical function. Cannot determine whether differences in population or study characteristics explain inconsistencies.
|Most trials in moderate dementia, primarily AD (2 trials in VaD); populations from North America and western Europe; doses of medications applicable to common use.|
|Aspirin160, 161||2||459||Fair||No benefit was found in global cognitive or physical function for low-dose aspirin.||Consistent finding of no benefit.||Mild to moderate dementia and MCI, primarily AD; populations from United States and western Europe; low-dose aspirin.|
|HMG-CoA reductase inhibitors162–165||4||1153||Fair||No benefit was found in global cognitive function, physical function, or neuropsychiatric symptoms for simvastatin or atorvastatin.||Consistent finding of no benefit.||Mild to moderate dementia, primarily AD; populations from United States and western Europe; doses of medications applicable to common use.|
|NSAIDs166–169||4||959||Fair||No benefit was found in global cognitive or physical function for ibuprofen, naproxen, indomethacin, or celecoxib. Other outcomes were sparsely reported.||Consistent finding of no benefit regardless of type of NSAID.||Mild to moderate dementia; populations from United States and western Europe; doses of medications applicable to common use.|
|Gonadal steroids170–174||5||295||Fair||No benefit was found in global cognitive or physical function for estrogen with or without progesterone (κ = 4; n = 277). No benefit was found in global cognitive function for testosterone (κ = 1; n = 18). Other outcomes were sparsely reported.||Consistent finding of no benefit regardless of type of hormone.||Mild to moderate dementia, only in AD; populations from United States, Europe, and Asia; doses of medications applicable to common use.|
|Dietary supplements161, 175–185||12||2608||Fair||No benefit was found in global cognitive or physical function for dietary supplements, including multivitamins (κ = 1; n = 89), B vitamins (κ = 7; n = 1294), vitamin E with or without vitamin C (κ = 3; n = 522), or ω-3 fatty acids (κ = 4; n = 1145). Other outcomes were sparsely reported.||Consistent finding of no benefit regardless of type of dietary supplement.||Mild to moderate dementia and MCI, primarily AD; populations from United States, northern Europe, and Asia.|
|Effectiveness of nonpharmacologic interventions|
|Caregiver (or dyad) interventions41, 42, 186–241||59||8932||Fair||Most trials evaluated caregiver interventions with a psychoeducational component. Small to very small benefit was found in caregiver burden and caregiver depression for a broad range of caregiver interventions with a psychoeducational component in the short term (generally 3 to 12 mo). Pooled analyses for caregiver burden (κ = 24; n = 2679) and depression (κ = 30; n = 3537) outcomes showed a small benefit (caregiver burden SMD, −0.23 [95% CI, −0.35 to −0.12]; I2 = 52.7; depression SMD, −0.21 [CI, -0.30 to -0.13]; I2 = 34.1). Other outcomes were sparsely reported.||Generally consistent for caregiver burden and depression outcomes; large clinical and statistical heterogeneity of interventions limits interpretation of point estimates from pooled analyses.||Most trials in moderate dementia; populations from North America, Europe, Australia, and Asia; wide range of types and intensities of interventions.|
|Cognitive training, rehabilitation, or stimulation, with or without motor training104, 242–255||15||1128||Fair||Cognitive interventions had inconsistent findings of benefit. Cognitive stimulation with or without cognitive training can improve cognitive function in persons with MCI or mild dementia. Pooled analyses for global cognitive outcomes (κ = 6; n = 513) showed a moderate benefit at 6 to 12 mo (SMD, −0.59 [CI, −0.93 to −0.25]; I2 = 52.7%). Because CIs were wide, the effect on global cognitive functioning could range from very small to moderate. Other outcomes were sparsely reported.||Unclear whether inconsistency in findings for cognitive function was due to differences in study quality, populations, intervention type or intensity, or outcomes measured.||Mild to moderate dementia and MCI; populations in North America, Europe, and Australia.|
|Exercise interventions256–265||10||1033||Fair||Findings about benefit from exercise interventions were inconsistent. However, some well-conducted studies suggest small benefits in cognitive function in persons with MCI (κ = 2; n = 220) and in physical function and HRQL in persons with dementia (κ = 1; n = 153). Other outcomes were sparsely reported.||Inconsistent; unclear whether inconsistency due to differences in study quality, population, intervention, or outcomes measured.||Mild to moderate dementia and MCI; populations in North America, Australia, and Hong Kong.|
|Multidisciplinary interventions266–270||5||1766||Fair||Multidisciplinary care interventions involving assessment and care coordination showed no benefit in global cognitive function, physical function, institutionalization, or HRQL.||Consistent finding of no benefit.||Mild to moderate dementia or MCI; only 1 trial in the United States (done in an assisted living facility); remaining trials done in Europe.|
|Education only271, 272||2||741||Fair||Two trials aimed at educating residential care staff and/or GPs treating persons with dementia found no benefit to HRQL, neuropsychiatric disturbances, hospitalization, or institutionalization.||Consistent finding of no benefit.||Persons with mild to moderate dementia living in residential care facility in Australia; GP practices in Germany.|
|Harms of interventions with evidence of benefit|
|Pharmacologic interventions102, 103, 105–107, 109–114, 116–130, 132–136, 138–142, 144–147, 149–159, 273–287, 289, 290, 292, 293, 311||71||228,155||Fair||Discontinuation from AChEI (κ = 45), but not memantine (κ = 12), was more common than from placebo. Across trials, there did not seem to be a difference in total serious adverse events for any of these medications.
Observational studies examining AChEIs (κ = 13; n = 197,811) suggest that the most common serious adverse events are CNS, heart rate/rhythm, and gastrointestinal disorders and that bradycardia and adverse events related to bradycardia (e.g., fall or syncope) are increased with their use.
|Generally consistent findings by drug class effect; estimation of frequency of adverse events may be higher in observational studies because of population selection.||Mild to moderate dementia and MCI; populations from North America, Europe, Australia, and Asia.|
|Nonpharmacologic interventions258–260, 264||4||439||Fair||Harms were not reported for caregiver or cognitive interventions. There was no evidence of increased total or serious adverse effects due to exercise interventions.||Few hypothesized harms; however, unclear consistency given that adverse effects were rarely reported.||Mild to moderate dementia and MCI; populations restricted to trial populations.|
AChEI = acetylcholinesterase inhibitor; AD = Alzheimer disease; ADAS-cog = Alzheimer's Disease Assessment Scale-Cognitive Subscale; CIBIC-plus = Clinician Interview-Based Impression of Change Plus Caregiver Input; CNS = central nervous system; GP = general practitioner; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; HRQL = health-related quality of life; MCI = mild cognitive impairment; NSAID = nonsteroidal anti-inflammatory drug; SMD = standardized mean difference; VaD = vascular dementia.
Internet Citation: Evidence Summary: Cognitive Impairment in Older Adults: Screening. U.S. Preventive Services Task Force. October 2013.