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Fink HA, Hemmy LS, Linskens EJ, et al. Diagnosis and Treatment of Clinical Alzheimer’s-Type Dementia: A Systematic Review [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2020 Apr. (Comparative Effectiveness Review, No. 223.)
Diagnosis and Treatment of Clinical Alzheimer’s-Type Dementia: A Systematic Review [Internet].
Show detailsAppendix Table F.1Outcome instruments used in low/medium risk of bias studies: supplements versus placebo
| Supplement | Study Characteristics: Author/Year Risk of Bias | AD Severity | Cognition- Brief Stand-Alone Tests | Cognition- Brief Multidomain Batteries | Domain Level Tests Typically Part of a Larger Battery* | Function | Quality of Life | Global Staging | Clinical Impression of Change |
|---|---|---|---|---|---|---|---|---|---|
| Souvenaid | Schelten 2012197 Olde Rikert 2015198 Low | Mild | NR | NTB total composite z-score | NR | DAD | NR | NR | NR |
| Shah 2013199 Medium | Mild to Moderate | NR | ADAS-cog (11-item) | NR | ADCS-ADL | NR | CDR, Sum of Boxes | NR | |
| Omega-3 Fatty Acids | Freund-Levi 2006200 Eriksdotter 2015201 Medium | Mild to Moderate | MMSE | ADAS-Cog | NR | NR | NR | CDR, Sum of Boxes | NR |
Shinto 2014202 Medium | Mild to Moderate | MMSE | ADAS-cog | NR | ADL IADL | NR | NR | NR | |
| Omega-3 Fatty Acid and Alpha Lipoic Acid | Shinto 2014202 Medium | Mild to Moderate | MMSE | ADAS-cog | NR | NR | NR | ||
| Antioxidants | Cornelli 2010203 Medium | Moderate AD | MMSE | NR | NR | NR | NR | NR | NR |
| Choline Alfoscerate | De Jesus Moreno 2003204 Medium | Mild to Moderate AD | MMSE | ADAS-Cog | NR | NR | NR | GDS | CGI |
| Prolonged Release Melatonin | Wade 2014205 Medium | Mild to Moderate AD | MMSE | ADAS-Cog | NR | IADL | NR | NR | CGI |
| Sodium Selenate | Malpas 2016206 Medium | Mild to Moderate AD | MMSE | ADAS-Cog | Category Fluency Test | NR | NR | NR | NR |
| Soy Isolfavones | Gleason 2015207 Medium | Not Specified | MMSE | NR | NR | NR | NR | NR | NR |
| Copper | Kessler 2008208 Medium | Not Specified | MMSE | ADAS-Cog | NR | NR | NR | NR | NR |
| Folic Acid and Vitamin B | Aisen 2008209 Medium | Mild to Moderate AD | MMSE | ADAS-Cog | NR | ADCS-ADL | NR | CDR, Sum of Boxes | NR |
| TOTAL | 10 | 10 | 2 | 8 | 0 | 4 | 2 |
- *
Domain level tests typically part of a larger battery are tests of memory, executive function, language and/or attention:
- a
Memory;
- b
Executive Function;
- c
Language;
- d
Attention
AD=Alzheimer’s Disease; ADAS-Cog=Alzheimer’s Disease Assessment Scale-Cognitive Subscale; ADCS-ADL= Alzheimer’s Disease Cooperative Study - Activities of Daily Living; ADL=Activities of Daily Living; CDR=Clinical Dementia Rating; CGI=Clinical Global Impression; COWAT=Controlled Oral Word Association Test; DAD= Disability Assessment for Dementia; GDS=Global Deterioration Scale; IADL=Instrumental Activities of Daily Living; MMSE=Mini-Mental State Examination; NTB= Neuropsychological Test Battery; NR=Not Reported
Souvenaid
Appendix Table F.2Characteristics of eligible studies: souvenaid versus placebo
Study Characteristics: Author/Year Design Country Risk of Bias | N= | Population: AD Severity Mean Age % Female % White Education (mean yrs.) Baseline Cognition | Intervention: Intervention Mode Components Frequency Duration | Comparison: Comparison Mode Components Frequency Duration | Outcome Timing | Outcome Domain [Instrument] |
|---|---|---|---|---|---|---|
Schelten 2010210 Multinational High Kamphius 2011211 | 225 | Mild AD Mean Age 73.7 50% Female Race NR Mean Years of Education Beyond Primary School 5.75 Baseline Cognition: MMSE 24 | Souvenaid, 125 ml once a day at breakfast consumed within 1 hour | Nutritional control drink | 24 weeks | Cognitive Tests Weschler Memory Scale-revised, Delayed Recall Weschler Memory Scale-revised, Immediate Recall 13-item ADAS-cog Function Quality of Life Quality of Life in Alzheimer’s Disease Clinical Impression of Change CIBIC-plus Harms Withdrawal to AEs SAEs |
Scheltens 2012197 Multinational Low Olde Rikert 2015198 | 259 | Mild AD Mean Age 74 Race NR 34% Female Mean Years of Education Beyond Primary School 6.5 Baseline Cognition: MMSE 25 | Souvenaid, 125 ml once a day | Nutritional control drink | 24 weeks | Cognitive Tests NTB total composite z-score Function Harms SAEs Withdrawal due to AEs |
Shah 2013199 Multinational Medium | 527 | Mild to Moderate AD Mean Age 77 Race NR 52% Female Mean Years of Education Beyond Primary School 6.6 Baseline Cognition: MMSE 19.5 | 24 weeks | Cognitive Tests 11-item ADAS-cog Function Global Staging CDR, Sum of Boxes Harms SAEs Withdrawal due to AEs Confusion Falls |
Abbreviations: AD=Alzheimer’s Disease; ADAS-Cog= Alzheimer’s Disease Assessment Scale-Cognitive Subscale; ADCS-ADL= Alzheimer’s Disease Cooperative Study-Activities of Daily Living; AE=Adverse Event; CDR=Clinical Dementia Rating; CIBIC-plus: Clinician Interview-Based Impression of Change plus caregiver input; DAD=Disability Assessment for Dementia; MMSE=Mini-Mental State Examination; NTB= Neuropsychological Test Battery; NR=Not Reported; RoB=Risk of Bias; SAEs=Serious
Appendix Table F.3Risk of bias ratings: souvenaid versus placebo
Appendix Table F.4Primary outcomes summary low and medium risk of bias studies: souvenaid versus placebo
| Drug Comparison | AD Severity | Study Followup N RoB | Cognitive | Function | QoL | Global Staging | Clinical Impression of Change | Harms |
|---|---|---|---|---|---|---|---|---|
| Souvenaid vs. Placebo | Mild AD | Schelten 2012 24 weeks N=259 Low Olde Rikert 2015198 | NTB Total Composite, z-score Mean Change from Baseline (SD) I: 0.12 (0.28) C: 0.04 (0.29) p=0.04 Standardized Mean Difference (95% CI) 0.30 (0.06, 0.54) 24 week trajectory p=0.053 | No difference between groups (p=0.36) | NR | NR | NR | SAEs I: 11 SAEs (10 patients. 7.7%) C: 7 SAEs (6 patients, 4.65%) Withdrawal due to AEs I: 3/130 (2.31%) C: 2/129 (1.55%) |
| Souvenaid vs. Placebo | Mild to Moderate AD | Shah 2013199 24 weeks N=527 Medium | 11-item ADAS-cog Mean Change from Baseline (SD) I: 1.88 (6.44) C: 1.52 (5.63) p=0.55 Mean Difference Between Groups (SE) 0.37 (0.57) p=0.51 | ADCS-ADL, Total Score Mean Change from Baseline (SD) I: -3.74 (9.76) C: -3.66 (8.03) p=0.926 | NR | CDR, Sum of Boxes Mean Change from Baseline (SD) I: 0.77(1.96) C: 0.69 (1.90) p=0.68 | NR | SAEs I: 34 SAEs (27 subjects, 10.2%) C: 36 SAEs (34 subjects, 13.1%) Withdrawal due to AEs I: 2 withdrawals due to SAEs (0.76%) C: 4 withdrawals due to SAEs (1.54%) Confusion I: 0/264 C: 1/260 (0.38%) Falls I: 1/264 (0.38%) 2: 1/260 (0.38%) |
Abbreviations: AD=Alzheimer’s Disease; ADAS-Cog= Alzheimer’s Disease Assessment Scale-Cognitive Subscale; ADCS-ADL= Alzheimer’s Disease Cooperative Study-Activities of Daily Living; AE=Adverse Event; CDR=Clinical Dementia Rating; DAD= Disability Assessment for Dementia; NTB= Neuropsychological Test Battery; NR=Not Reported; RoB=Risk of Bias; SAEs=Serious Adverse Events
Appendix Table F.5Summary of strength of evidence: souvenaid versus placebo
| Outcome | AD Severity | Timing | # Studies/Design (n analyzed) | Finding or Summary Statistic | Study Limitations | Consistency | Directness | Precision | Overall Grade/Conclusion |
|---|---|---|---|---|---|---|---|---|---|
| Cognition - Brief Stand-Alone Tests | NA | NR | NR | NA | NA | NA | NA | NA | NA |
| Cognition- Brief Multidomain Batteries | Mild to Moderate CATD | 24 weeks | 2 RCTs197–199 (N=786) | Studies reported inconsistent findings about the efficacy of Souvenaid compared with placebo on global cognition measured by multidomain batteries. | Medium | Inconsistent | Direct | Imprecise | Insufficient |
| Cognition-Domain Level Tests Typically Part of a Larger Battery | NA | NR | NR | NA | NA | NA | NA | NA | NA |
| Function | Mild to Moderate CATD | 24 weeks | 2 RCTs197–199 (N=786) | Both studies reported no difference between Souvenaid and placebo in measures of function. One study reported no difference on the DAD (p=0.36). The second study found no difference in mean change from baseline on the ADCS-ADL (p=0.93). | Medium | Consistent | Direct | Imprecise | Low (No Difference) |
| Quality of Life | NA | NR | NR | NA | NA | NA | NA | NA | NA |
| Global Staging | Mild to Moderate CATD | 24 weeks | 1 RCT199 (N=527) | No difference in mean change from baseline on the CDR-SOB between Souvenaid (0.77, SD 1.96]) and placebo (0.69, SD 1.90) in function at 24 weeks (p=0.68). | Medium | Unknown | Direct | Imprecise | Insufficient |
| Clinical Impression of Change | NA | NR | NR | NA | NA | NA | NA | NA | NA |
| Serious Adverse Events | Mild to Moderate CATD | 24 weeks | 2 RCTs197–199 (N=786) | Studies reported similar rates of serious adverse events for Souvenaid compared with placebo. | Medium | Consistent | Direct | Imprecise | Low (No Difference) |
| Withdraws due to Adverse Events | Mild to Moderate CATD | 24 weeks | 2 RCTs197–199 (N=786) | Studies reported similar rates of withdrawals due to serious adverse events for Souvenaid compared with placebo. | Medium | Consistent | Direct | Imprecise | Low (No Difference) |
Omega-3 Fatty Acids
Appendix Table F.6Characteristics of eligible studies: omega-3 fatty acids versus placebo
Study Characteristics: Author/Year Design Country Risk of Bias | N= | Population: AD Severity Mean Age % Female % White Education (mean yrs.) Baseline Cognition | Intervention: Intervention Mode Components Frequency Duration | Comparison: Comparison Mode Components Frequency Duration | Outcome Timing | Outcome Domain [Instrument] |
|---|---|---|---|---|---|---|
Freund-Levi 2006200 Sweden Medium Eriksdotter 2015201 | 204 | Mild to Moderate AD Mean Age 73 54% Female Race NR Education NR Baseline Cognition: MMSE 23 | Four capsules taken daily with 430 mg DHA and 150 mg EPA | Isocaloric Placebo Oil | 6 months | Cognitive Tests Global Staging CDR, Sum of Boxes Harms Withdrawal due to AEs |
Shinto 2014202 Medium US | 26 | Mild to Moderate AD Mean Age 76 100% white 46% Female 46% College or Greater Baseline Cognition: MMSE 21 | Fish oil concentrate with 675 mg and 975 EPA, 3 grams/day taken as 2 capsules | Placebo oil capsules (2 per day) | 12 months | Cognitive Tests ADAS-cog Function Harms SAEs Mortality Falls |
Quinn 2010212 US High | 402 | Mild to Moderate AD Mean Age 76 52% Female Race NR Mean Years Education 14 Baseline Cognition: MMSE 20.7 | Algal DHA, 1 g twice a day | Placebo | 18 months | Cognitive Tests Function Quality of Life Quality of Life Alzheimer’s Disease Scale Global Staging CDR, Sums of Boxes Harms SAEs Withdrawal due to AEs Falls Mortality |
Wolkowitz 2003213 US High | 58 | Mild to Moderate AD Mean Age 76 48% Female 83% White Education NR Baseline Cognition: MMSE 22 | DHEA, 50 mg twice a day | Placebo | 6 months | Cognitive Tests Clinical Impression of Change Harms SAEs Withdrawal due to AEs |
Abbreviations: AD=Alzheimer’s Disease; ADAS-Cog: Alzheimer’s Disease Assessment Scale-Cognitive Subscale; ADL=Activities of Daily Living; AE=Adverse Event; CIBIC-plus: Clinician Interview-Based Impression of Change plus caregiver input; IADL=Instrumental Activities of Daily Living; MMSE=Mini Mental State Exam; NR=Not Reported; RoB=Risk of Bias; SAEs=Serious Adverse Events
Appendix Table F.7Risk of bias ratings: omega-3 fatty acids versus placebo
| Study | Time | Selection Bias | Attrition Bias | Performance Bias | Detection Bias | Reporting Bias | Overall Rating |
|---|---|---|---|---|---|---|---|
Freund-Levi 2006200 Eriksdotter 2015201 | 6 months | Medium | Medium | Low | Low | Low | Medium |
| Shinto 2014202 | 12 months | Low | Medium | Low | Low | Low | Medium |
| Quinn 2010212 | 18 months | Low | High | Low | Low | Low | High |
| Wolkowitz 2003213 | 6 months | Low | High | Low | Low | Low | High |
Appendix Table F.8Primary outcomes summary low and medium risk of bias studies: omega-3 fatty acids versus placebo
| Drug Comparison | AD Severity | Study Characteristics: Author/Year Followup N Risk of Bias | Cognitive | Function | QoL | Global Staging | Clinical Impression of Change | Harms |
|---|---|---|---|---|---|---|---|---|
| Omega-3 Fatty Acids | Mild to Moderate AD | Freund-Levi 2006200 6 months N=204 Medium Eriksdotter 2015201 | Mean (95% CI) No difference between groups. I: 22.8 (21.9, 23.7) C: 22.4 (21.5, 23.4) Mean (95% CI) No difference between groups. I: 27.7 (25.4, 30.0) C: 28.3 (26.0, 30.6) | NR | NR | CDR, Sum of Boxes Mean (95% CI) No difference between groups. I: 6.2 (5.4, 6.9) C: 6.5 (5.7, 7.3) | NR | Withdrawal due to AEs 18 total withdrawals due to AE |
| Mild to Moderate AD | Shinto 2014202 12 months N=26 Medium | Mean Change (SE) I: -4.3 (1.3) C: -4.6 (1.4) p=0.80 Mean Change (SE) I: 4.4 (2.2) C: 3.2 (2.1) p=0.86 | Mean Change (SE) I: 0.7 (1.0) C: 4.2 (0.9) p=<0.01 Standardized Mean Difference for Mean Change from Baseline (95% CI) -0.99 (-1.77, -0.18) Mean Change (SSE I: 2.5 (1.0) C: 2.9 (0.7) p=0.82 | NR | NR | NR | SAEs 2 SAEs Mortality I: 0/13 (0%) C: 1/13 (7.69%) Falls I: 1/13 (7.69%) C: 2/13 (15.38%) |
Abbreviations: AD=Alzheimer’s Disease; ADAS-Cog: Alzheimer’s Disease Assessment Scale-Cognitive Subscale; ADL=Activities of Daily Living; AE=Adverse Event; IADL=Instrumental Activities of Daily Living; MMSE=Mini Mental State Exam; NR=Not Reported; QoL=Quality of Life; RoB=Risk of Bias; SAEs=Serious Adverse Events
Appendix Table F.9Summary of strength of evidence: omega-3 fatty acids versus placebo
| Outcome AD Severity | Timing | # Studies/Design (n analyzed) | Finding or Summary Statistic | Study Limitations | Consistency | Directness | Precision | Overall Grade/Conclusion |
|---|---|---|---|---|---|---|---|---|
Cognition - Brief Stand-Alone Tests Mild to Moderate CATD | 6-12 months | 2 RCTs200–202 (N=230) | No difference between groups on the MMSE. One study found no difference in the post treatment mean score between intervention (22.8 [95% CI 21.9, 23.7]) and placebo (22.4 [95% CI 21.5, 23.4]). The second study found no difference between groups in mean change from baseline (p=0.80) | Medium | Consistent | Direct | Imprecise | Low (No Difference) |
Cognition - Brief Multidomain Batteries Mild to Moderate CATD | 6-12 months | 2 RCTs200–202 (N=230) | No difference between groups on the ADAS-Cog. One study found no difference in the post treatment mean score between intervention (27.7 [95% CI 25.4, 30]) and placebo (28.3 [95% CI 26.0, 30.6]). The second study found no difference between groups in mean change from baseline (p=0.86) | Medium | Consistent | Direct | Imprecise | Low (No Difference) |
| Cognition-Domain Level Tests Part of a Larger Battery | NR | NR | NA | NA | NA | NA | NA | NA |
Function Mild to Moderate CATD | 12 months | 1 RCT202 (N=26) | Inconsistent findings about the efficacy of omega-3 fatty acids on improving function. Improvements were seen in the omega-3 fatty group in IADLs compared with placebo (SMD -0.99 [95% CI 1.77, -0.18)], but not in ADLs. | Medium | Unknown | Direct | Imprecise | Insufficient |
| Quality of Life | NR | NR | NA | NA | NA | NA | NA | NA |
Global Staging Mild to Moderate CATD | 6 months | 1 RCT202 (N=204) | No difference between the omega-3 fatty acid and placebo groups on the CDR-SOB. | Medium | Unknown | Direct | Imprecise | Insufficient |
| Clinical Impression of Change | NR | NR | NA | NA | NA | NA | NA | NA |
Serious Adverse Events Mild to Moderate CATD | 12 months | 1 RCT202 (N=26) | One study reported a total of 2 serious adverse events but did not separate results between the omega-3 fatty acid and placebo groups. | Medium | Unknown | Direct | Imprecise | Insufficient |
Withdrawals due to Adverse Events Mild to Moderate CATD | 6 months | 1 RCT200, 201 (N=204) | One study reported withdrawals due to adverse events but did not separate results between omega-3 fatty acid and placebo groups. | Medium | Unknown | Direct | Imprecise | Insufficient |
Omega-3 Fatty Acid and Alpha Lipoic Acid
Appendix Table F.10Characteristics of eligible studies: omega-3 fatty acid and alpha lipoic acid versus placebo
Study Characteristics: Author/Year Design Country Risk of Bias | N= | Population: AD Severity Mean Age % Female % White Education (mean yrs.) Baseline Cognition | Intervention: Intervention Mode Components Frequency Duration | Comparison: Comparison Mode Components Frequency Duration | Outcome Timing | Outcome Domain [Instrument] |
|---|---|---|---|---|---|---|
Shinto 2014202 Medium US | 26 | Mild to Moderate AD Mean Age 76 100% White 46% Female 46% College or Greater Baseline MMSE 22 | Fish oil concentrate with 675 mg and 975 EPA (3 grams/day taken as 2 capsules) and 600 mg/day of alpha lipoic acid (1 capsule) | Placebo oil capsules (2 per day) | 12 months | Cognitive Tests ADAS-cog Function Harms SAEs Mortality Falls |
Appendix Table F.11Risk of bias ratings: omega-3 fatty acid and alpha lipoic acid versus placebo
| Study | Time | Selection Bias | Attrition Bias | Performance Bias | Detection Bias | Reporting Bias | Overall Rating |
|---|---|---|---|---|---|---|---|
| Shinto 2014202 | 12 months | Low | Medium | Low | Low | Low | Medium |
Appendix Table F.12Primary outcomes summary low and medium risk of bias studies: omega-3 fatty acid and alpha lipoic acid versus placebo
| Drug Comparison | AD Severity | Study Followup RoB | Cognitive | Function | QoL | Global Staging | Clinical Impression of Change | Harms |
|---|---|---|---|---|---|---|---|---|
| Omega-3 Fatty Acids and Alpha Lipoic Acid | Mild to Moderate AD | Shinto 2014202 12 months N=26 Medium | Mean Change (SD) I: -1.0 (0.7) C: -4.6 (1.4) p<0.01 | Mean Change (SD) I: 0.9 (1.1) C: 4.2 (0.0) p=0.01 Mean Change (SD) I: 1.3 (0.8) C: 2.9 (0.7) p=0.15 | NR | NR | NR | SAEs 2 SAEs Mortality I: 0/13 deaths C: 1/13 deaths Falls I: 0/13 falls C: 2/13 falls |
Appendix Table F.13Summary of strength of evidence: omega-3 fatty acid and alpha lipoic acid versus placebo
| Outcome | AD Severity | Timing | # Studies/Design (n analyzed) | Finding or Summary Statistic | Study Limitations | Consistency | Directness | Precision | Overall Grade/Conclusion |
|---|---|---|---|---|---|---|---|---|---|
All Outcomes Mild to Moderate CATD | 12 months | 1 RCT202 (n=26) | Unable to draw conclusions about efficacy of omega-3 fatty acids and alpha lipoic acid. | Medium | Unknown | Direct | Imprecise | Insufficient |
Antioxidant Supplementation
Appendix Table F.14Characteristics of eligible studies: antioxidant supplementation versus placebo
Study Characteristics: Author/Year Design Country Risk of Bias | N= | Population: AD Severity Mean Age % Female % White Education (mean yrs.) Baseline Cognition | Intervention: Intervention Mode Components Frequency Duration | Comparison: Comparison Mode Components Frequency Duration | Outcome Timing | Outcome Domain [Instrument] |
|---|---|---|---|---|---|---|
Cornelli 2010203 US Medium | 52 | Moderate AD Mean Age 75 Education NR Race NR Baseline Cognition: MMSE 24 | Add-on antioxidant ampoule to stable donepezil (5 mg/day), 1 ampoule/day before breakfast | Add-on placebo ampoule to stable donepezil (5 mg/day), 1 ampoule/day before breakfast | 6 months | Cognitive Tests |
Appendix Table F.15Risk of bias ratings: antioxidant supplementation versus placebo
| Study | Time | Selection Bias | Attrition Bias | Performance Bias | Detection Bias | Reporting Bias | Overall Rating |
|---|---|---|---|---|---|---|---|
| Cornelli 2010203 | 6 months | Medium | Medium | Medium | Low | Medium | Medium |
Appendix Table F.16Primary outcomes summary low and medium risk of bias studies: antioxidant supplementation versus placebo
| Drug Comparison | AD Severity | Study Followup N RoB | Cognitive | Function | QoL | Clinical Impression of Change | Global Staging | Harms |
|---|---|---|---|---|---|---|---|---|
| Add-on antioxidant ampoule vs. Placebo | Moderate AD | Cornelli 2010203 6 months N=52 Medium | Mean (SD) I: 24.3 (1.43) C: 24.2 (1.28) At least 1-point Increase on MMSE I: 12/23 C: 4/25 At least 1-point Decrease on MMSE I: 1/23 C: 2/25 | NR | NR | NR | NR | NR |
Appendix Table F.17Summary of strength of evidence: antioxidant supplementation versus placebo
| Outcome | AD Severity | Timing | # Studies/Design (n analyzed) | Finding or Summary Statistic | Study Limitations | Consistency | Directness | Precision | Overall Grade/Conclusion |
|---|---|---|---|---|---|---|---|---|---|
| MMSE | Moderate AD | 6 months | 1 RCT203 (n=52) | Unable to draw conclusions about efficacy of add-on antioxidant supplementation. | Medium | Unknown | Direct | Imprecise | Insufficient |
Abbreviations: AD=Alzheimer’s Disease
Choline Alfoscerate
Appendix Table F.18Characteristics of eligible studies: choline alfoscerate versus placebo
Study Characteristics: Author/Year Design Country Risk of Bias | N= | Population: AD Severity Mean Age % Female % White Education (mean yrs.) Baseline Cognition | Intervention: Intervention mode Components Frequency Duration | Comparison: Comparison mode Components Frequency Duration | Outcome Timing | Outcome Domain [Instrument] |
|---|---|---|---|---|---|---|
De Jesus Moreno 2003204 Mexico Medium | 261 | Mild to Moderate AD Mean Age 72 76% Female 98% Hispanic Education NR Baseline Cognition: MMSE 18 | Choline alfoscerate, 400 mg/pill, 3 pills a day | Placebo | 180 days | Cognitive Tests Global Staging Clinical Impression of Change CGI Harms Withdrawal due to AEs |
Appendix Table F.19Risk of bias ratings: choline alfoscerate versus placebo
| Study | Time | Selection Bias | Attrition Bias | Performance Bias | Detection Bias | Reporting Bias | Overall Rating |
|---|---|---|---|---|---|---|---|
| De Jesus Moreno 2003204 | 180 days | Low | Medium | Low | Low | Medium | Medium |
Appendix Table F.20Primary outcomes summary low and medium risk of bias studies: choline alfoscerate versus placebo
| Drug Comparison | AD Severity | Study Characteristics: Author/Year Followup N Risk of Bias | Cognitive | Function | QoL | Global Staging | Clinical Impression of Change | Harms |
|---|---|---|---|---|---|---|---|---|
| Choline Alfoscerate vs. Placebo | Mild to Moderate AD | De Jesus Moreno 2003204 180 days N=261 Medium | Mean (SD) I: 32.32 (8.19) C: 39.64 (7.47) p<0.001 At least 2.20 point difference considered clinically relevant Responders (4-point Improvement) I: 61/132 (46.2%) C: 13/129 (10.1%) p<0.001 Complete Responders (7-point Improvement) I: 47/132 (35.6%) C: 5/129 (3.9%) p<0.001 Mean Change from Baseline I: -3.20 C: 2.90 p<0.001 Mean (SD) I: 24.52 (3.82) C: 17.12 (4.04) p<0.001 Mean Change from Baseline I: 6.33 C: -0.50 P<0.001 | NR | NR | Mean (SD) I: 2.78 (0.76) C: 3.91 (0.78) p<0.001 Mean Change from Baseline I: 0.95 C:0.19 p<0.001 | CGI Mean (SD) I: 2.90 (0.66) C: 3.93 (0.69) p<0.001 Mean Change from Baseline I:1.02 C:0.16 p<0.001 | Withdrawal due to AEs No withdrawals due to AEs |
Abbreviations: AD=Alzheimer’s Disease; RoB=Risk of Bias; SAEs=Serious Adverse Events AD=Alzheimer’s Disease; ADAS-Cog= Alzheimer’s Disease Assessment Scale-Cognitive Subscale; AEs=Adverse Events; CGI=Clinical Global Impression; GDS=Global Deterioration Scale; MMSE=Mini Mental State Exam; NR=Not Reported; QoL=Quality of Life; RoB=Risk of Bias
Appendix Table F.21Summary of strength of evidence: choline alfoscerate versus placebo
| Outcome | AD Severity | Timing | # Studies/Design (n analyzed) | Finding or Summary Statistic | Study Limitations | Consistency | Directness | Precision | Overall Grade/Conclusion |
|---|---|---|---|---|---|---|---|---|---|
| All Outcomes | Mild to Moderate AD | 108 days | 1 RCT204 (n=261) | Unable to draw conclusions about efficacy of choline alfoscerate. | Medium | Unknown | Direct | Imprecise | Insufficient |
Abbreviations: AD=Alzheimer’s Disease
Prolonged Release Melatonin
Appendix Table F.22Characteristics of eligible studies: prolonged release melatonin versus placebo
Study Design Country RoB | N= | Population AD Severity Age (mean) Sex (% female) Race (% White) Education (mean years) Baseline Cognition | Intervention Mode Components Frequency Duration | Comparison Mode Components Frequency Duration | Outcome Timing | Outcome Domain [Instrument] |
|---|---|---|---|---|---|---|
Wade 2014205 Multinational Medium | 80 | Mild to Moderate AD Mean Age 75 49% Female Race NR Education NR Baseline Cognition: 51% with MMSE >20 | Add-on Prolonged release melatonin (stable on acetylcholinest erase inhibitor), 2 mg/day before bedtime | Placebo | 24 weeks | Cognitive Tests Function Clinical Impression of Change CGI Harms SAEs Withdrawal due to AEs Mortality |
Appendix Table F.23Risk of bias ratings: prolonged release melatonin versus placebo
| Study | Time | Selection Bias | Attrition Bias | Performance Bias | Detection Bias | Reporting Bias | Overall Rating |
|---|---|---|---|---|---|---|---|
| Wade 2014205 | 24 weeks | Low | Medium | Low | Low | High | Medium |
Appendix Table F.24Primary outcomes summary low and medium risk of bias studies: prolonged release melatonin versus placebo
| Drug Comparison | AD Severity | Study Characteristics: Author/Year Followup Risk of Bias | Cognitive | Function | QoL | Global Staging | Clinical Impression of Change | Harms |
|---|---|---|---|---|---|---|---|---|
| Prolonged Release Melatonin vs. Placebo | Mild to Moderate AD | Wade 2014205 24 weeks N=80 Medium | Mean Change from Baseline (SD) I: 0.45 (5.0) C: 0.19 (6.28) p=0.45 Mean Change from Baseline (SD) I: -0.3 (2.8) C: -1.9 (3.5) P=0.04 | Mean Change from Baseline (SD) I: 0.77 (1.41) C: 1.62 (1.67) p=0.004 | NR | NR | CGI No data reported | SAEs I: 3 SAEs (2 patients, 5.1%) C: 9 SAEs (5 patients, 14.7%) p=0.24 Withdrawal due to AEs I: 0 patients C: 2 patients (5.9%) Mortality No deaths during study period. |
Appendix Table F.25Summary of strength of evidence: prolonged release melatonin versus placebo
| Outcome | AD Severity | Timing | # Studies/Design (n analyzed) | Finding or Summary Statistic | Study Limitations | Consistency | Directness | Precision | Overall Grade/Conclusion |
|---|---|---|---|---|---|---|---|---|---|
| All Outcomes | Mild to Moderate AD | 24 weeks | 1 RCT205 (n=80) | Unable to draw conclusions about efficacy of prolonged release melatonin. | Medium | Unknown | Direct | Imprecise | Insufficient |
Abbreviations: AD=Alzheimer’s Disease
Sodium Selenate
Appendix Table F.26Characteristics of eligible studies: sodium selenate versus placebo
Study Characteristics: Author/Year Design Country Risk of Bias | N= | Population: AD Severity Mean Age % Female % White Education (mean yrs.) Baseline Cognition | Intervention: Intervention mode Components Frequency Duration | Comparison: Comparison mode Components Frequency Duration | Outcome Timing | Outcome Domain [Instrument] |
|---|---|---|---|---|---|---|
Malpas 2016206 Australia Medium | 40 | Mild to Moderate AD Mean Age 71 58% Female Race NR Education NR Baseline Cognition: MMSE 20 | Sodium Selenate, 10 mg taken 3 times/day | Placebo or 320 µg of Sodium Selenate taken 3 times/day | 28 weeks | Cognitive Tests Category Fluency Test Harms SAEs Withdrawal due to AEs |
Appendix Table F.27Risk of bias ratings: sodium selenate versus placebo
| Study | Time | Selection Bias | Attrition Bias | Performance Bias | Detection Bias | Reporting Bias | Overall Rating |
|---|---|---|---|---|---|---|---|
| Malpas 2016206 | 28 weeks | Low | Low | Low | Low | High | Medium |
Appendix Table F.28Primary outcomes summary low and medium risk of bias studies: sodium selenate versus placebo
| Drug Comparison | AD Severity | Study Followup N RoB | Cognitive | Function | QoL | Global Staging | Clinical Impression of Change | Harms |
|---|---|---|---|---|---|---|---|---|
| Sodium Selenate vs. Placebo | Mild to Moderate AD | Malpas 2016206 28 weeks N=40 Medium | Mean Change from Baseline (95% CI) I: 2.65 (0.12, 5.18) C: 0.14 (-3.04, 3.33) No difference between groups. Mean Change from Baseline (95% CI) I: -1 (-3, 1) C: -1 (-2, 0) No difference between groups Mean Change from Baseline (95% CI) I: –5 (–8, –2) C: –1 (–5, 4) No difference between groups Category Fluency Test Mean Change from Baseline (95% CI) I: 0 (–2, 0.2) C: 1 (–2, 4) No difference between groups | NR | NR | NR | NR | SAEs I: 1/20 (5%) C: 0/20 Withdrawal due to AEs I: 2/20 (10%) C: 0/20 |
Appendix Table F.29Summary of strength of evidence: sodium selenate versus placebo
| Outcome | AD Severity | Timing | # Studies/Design (n analyzed) | Finding or Summary Statistic | Study Limitations | Consistency | Directness | Precision | Overall Grade/Conclusion |
|---|---|---|---|---|---|---|---|---|---|
| All Outcomes | Mild to Moderate AD | 28 weeks | 1 RCT206 (n=40) | Unable to draw conclusions about efficacy of sodium selenate. | Medium | Unknown | Direct | Imprecise | Insufficient |
Abbreviations: AD=Alzheimer’s Disease
Soy Isoflavones
Appendix Table F.30Characteristics of eligible studies: soy isoflavones versus placebo
Study Characteristics: Author/Year Design Country Risk of Bias | N= | Population: AD Severity Mean Age % Female % White Education (mean yrs.) Baseline Cognition | Intervention: Intervention mode Components Frequency Duration | Comparison: Comparison mode Components Frequency Duration | Outcome Timing | Outcome Domain [Instrument] |
|---|---|---|---|---|---|---|
Gleason 2015207 US Medium | 65 | Severity Not Specified Mean Age 76 52% Female Race NR Mean Years of Education 14.5 Baseline Cognition: MMSE 23 | Soy Isoflavones, 50 mg/day | Placebo | 6 months | Cognitive Tests Harms Mortality |
Appendix Table F.31Risk of bias ratings: soy isoflavones versus placebo
| Study | Time | Selection Bias | Attrition Bias | Performance Bias | Detection Bias | Reporting Bias | Overall Rating |
|---|---|---|---|---|---|---|---|
| Gleason 2015207 | 6 months | Medium | Low | Low | Low | Low | Medium |
Appendix Table F.32Primary outcomes summary low and medium risk of bias studies: soy isoflavones versus placebo
Appendix Table F.33Summary of strength of evidence: soy isoflavones versus placebo
| Outcome | AD Severity | Timing | # Studies/Design (n analyzed) | Finding or Summary Statistic | Study Limitations | Consistency | Directness | Precision | Overall Grade/Conclusion |
|---|---|---|---|---|---|---|---|---|---|
| All Outcomes | Mild to Moderate AD | 6 months | 1 RCT207 (n=65) | Unable to draw conclusions about efficacy of soy isoflavones. | Medium | Unknown | Direct | Imprecise | Insufficient |
Abbreviations: AD=Alzheimer’s Disease
Copper Add-On Treatment
Appendix Table F.34Characteristics of eligible studies: copper add-on treatment versus placebo
Study Characteristics: Author/Year Design Country Risk of Bias | N= | Population: AD Severity Mean Age % Female % White Education (mean yrs.) Baseline Cognition | Intervention: Intervention mode Components Frequency Duration | Comparison: Comparison mode Components Frequency Duration | Outcome Timing | Outcome Domain [Instrument] |
|---|---|---|---|---|---|---|
Kessler 2008208 Germany Medium | 68 | Severity Not Specified Mean Age 70 56% Female Race NR Mean Years Education 11 Baseline Cognition: Clock Drawing Test 2.8 | Copper (verum) to stable donepezil, 8 mg/day | Placebo | 12 months | Cognitive Tests Harms SAEs Withdrawal due to AEs |
Appendix Table F.35Risk of bias ratings: copper add-on treatment versus placebo
| Study | Time | Selection Bias | Attrition Bias | Performance Bias | Detection Bias | Reporting Bias | Overall Rating |
|---|---|---|---|---|---|---|---|
| Kessler 2008208 | 12 months | Medium | Medium | Medium | Low | Low | Medium |
Appendix Table F.36Primary outcomes summary low and medium risk of bias studies: copper add-on treatment versus placebo
| Drug Comparison | AD Severity | Study Followup RoB | Cognitive | Function | QoL | Global Staging | Clinical Impression of Change | Harms |
|---|---|---|---|---|---|---|---|---|
| Copper Add-on vs. Placebo | Mild to Moderate | Kessler 2008208 12 months Medium | Percent Increase in Scores I: 8.8% C: 15.5% p=0.78 Percent Decrease in Scores I: -10.5% C: -9.5% p=0.88 | NR | NR | NR | SAEs I: 3/35 (8.5%) C: 0 Withdrawal due to AEs I: 3/35 (8.5%) C: 0/33 |
Appendix Table F.37Summary of strength of evidence: copper add-on treatment versus placebo
| Outcome | AD Severity | Timing | # Studies/Design (n analyzed) | Finding or Summary Statistic | Study Limitations | Consistency | Directness | Precision | Overall Grade/Conclusion |
|---|---|---|---|---|---|---|---|---|---|
| All Outcomes | All CATD | 12 months | 1 RCT208 (n=68) | Unable to draw conclusions about efficacy of copper add-on treatment. | Medium | Unknown | Direct | Imprecise | Insufficient |
Abbreviations: AD=Alzheimer’s Disease
Folic Acid and Vitamin B
Appendix Table F.38Characteristics of eligible studies: folic acid and vitamin B versus placebo
Study Characteristics: Author/Year Design Country Risk of Bias | N= | Population: AD Severity Mean Age % Female % White Education (mean yrs.) Baseline Cognition | Intervention: Intervention mode Components Frequency Duration | Comparison: Comparison mode Components Frequency Duration | Outcome Timing | Outcome Domain [Instrument] |
|---|---|---|---|---|---|---|
Aisen 2008209] US Medium | 409 | Mild to Moderate AD Mean Age 76 56% Female Race NR Mean Years Education 13.9 Baseline Cognition: MMSE 20.95 | Folic acid and vitamin B supplement consisting of 5 mg/d of folic acid, 1 mg/d of vitamin B12 and 25 mg/d of vitamin B6 | Placebo | 18 months | Cognitive Tests Function Global Staging CDR-Sum of Boxes Harms SAEs Withdrawal due to AEs Mortality |
Abbreviations: AD=Alzheimer’s Disease; ADAS-Cog: Alzheimer’s Disease Assessment Scale-Cognitive Subscale; ADCS-ADL= Alzheimer Disease Cooperative Study Activities of Daily Living; AE=Adverse Event; CDR=Clinical Dementia Rating; MMSE=Mini Mental State Exam; NR=Not Reported; RoB=Risk of Bias; SAEs=Serious Adverse Events
Appendix Table F.39Risk of bias ratings: folic acid and vitamin B versus placebo
| Study | Time | Selection Bias | Attrition Bias | Performance Bias | Detection Bias | Reporting Bias | Overall Rating |
|---|---|---|---|---|---|---|---|
| Aisen 2008209 | 18 months | Low | Medium | Low | Low | Medium | Medium |
Appendix Table F.40Primary outcomes summary low and medium risk of bias studies: folic acid and vitamin B versus placebo
| Drug Comparison | AD Severity | Study Followup RoB | Cognitive | Function | QoL | Global Staging | Clinical Impression of Change | Harms |
|---|---|---|---|---|---|---|---|---|
| Vitamin B vs. Placebo | Mild to Moderate AD | Aisen 2008209 18 months Medium | Mean Change from Baseline (SD) I: 7.38 (9.72) C: 6.54 (8.17) p=0.52 (over 18 months) Rate of Change I: 0.40 points/month C: 0.37 points/month p=0.52 95% CI of rate difference [-0.06, 0.12] Mean Change from Baseline, I: −2.65 (4.56) C: −3.08 (4.46) p=0.69 (over 18 months) | Mean Change from Baseline (SD) I: −10.96 (12.36) C: −10.00 (11.09) p=0.42 (over 18 months) | NR | CDR, Sum of Boxes Mean Change from Baseline (SD) I: 2.58 (2.45) C: 2.51 (2.57) p=0.57 (over 18 months) | NR | SAEs I: 123/240 (51.3%) C: 95/169 (56.2%) p=0.37 Withdrawal due to AEs I: 3/240 (1.3%) C: 2/169 (1.2%) Mortality I: 3/240 (1.3%) C: 4/169 (2.4%) p=0.39 |
Abbreviations: AD=Alzheimer’s Disease; ADAS-Cog: Alzheimer’s Disease Assessment Scale-Cognitive Subscale; ADCS-ADL= Alzheimer Disease Cooperative Study Activities of Daily Living; AE=Adverse Event; CDR=Clinical Dementia Rating; MMSE=Mini Mental State Exam; NR=Not Reported; Qol=Quality of Life; RoB=Risk of Bias; SAEs=Serious Adverse Events
Appendix Table F.41Summary of strength of evidence: folic acid and vitamin B versus placebo
| Outcome AD Severity | AD Severity | Timing | # Studies/Design (n analyzed) | Finding or Summary Statistic | Study Limitations | Consistency | Directness | Precision | Overall Grade/Conclusion |
|---|---|---|---|---|---|---|---|---|---|
| All Outcomes | Mild to Moderate CT | 18 months | 1 RCT209 [(n=409) | Unable to draw conclusions about efficacy of folic acid and vitamin B supplementation. | Medium | Unknown | Direct | Imprecise | Insufficient |
Abbreviations: AD=Alzheimer’s Disease
Appendix Table F.42Characteristics of eligible studies: supplements versus placebo, high risk of bias studies
| Supplement | Study Design Country RoB | N= | Population AD Severity Age (mean) Sex (% female) Race (% White) Education (mean years) Baseline Cognition | Intervention Mode Components Frequency Duration | Comparison Mode Components Frequency Duration | Outcome Timing | Outcome Domain [Instrument] |
|---|---|---|---|---|---|---|---|
| Ginseng | Lee 2008214 Korea High | 97 | Severity Not Specified Mean Age 66 64% Female Race NR Education NR Baseline Cognition: MMSE 22 | Panax ginseng powder. 4.5 g/day | Control (Not described) | 24 weeks | Cognitive Tests Harms Mortality |
Heo 2012215 South Korea High | 40 | Moderate AD Mean Age 73 75% Female Race NR Education NR Baseline Cognition: MMSE 13.7 | Heat processed ginseng, 1.5, 3, or 4.5 g/day | Control (Not described) | 24 weeks | Cognitive Tests Global Staging Harms Withdrawal due to AEs | |
Heo 2011216 South Korea | 61 | Severity Not Specified Mean Age 67 61% Female Race NR Education NR Baseline Cognition MMSE 21.6 | Korean Red Ginseng, 4.5 or 9 g/day | Control (Not described) | 24 weeks | Cognitive Tests MMSE (Korean Version) Global Staging Harms Withdrawal due to AEs | |
| Ginkgo Biloba | Le Bars 1997217 US High Le Bars 2000218 Le Bars 2002219 | 236 | All CATD Mean Age 86 58% Female Race NR Median Years Education 14 Baseline Cognition: MMSE 21.2 | Ginkgo Biloba (EGb 761), 120 mg/day | Placebo | 52 weeks | Cognitive Tests Function Geriatric Evaluation by Relative’s Rating Instrument Clinical Impression of Change CGI-C Harms SAEs Withdrawal due to AEs Mortality |
Kanowski 1996220 Germany High Kanowski 2003221 | 222 | Mild to Moderate AD Mean Age 70 67% Female Race NR Education NR Baseline Cognition NR | Ginkgo Biloba (EGb 761), 240 mg/day | Placebo | 24 weeks | Cognitive Tests Syndrom-Kurztest Harms Withdrawals due to AEs SAEs | |
Ihl 2012222 Ukraine High | 333 | Mild to Moderate AD Mean Age 64 66% Female Race NR Education NR Baseline Cognition: SKT 16.7 | Ginkgo Biloba (EGb 761), 240 mg/day | Placebo | 24 weeks | Cognitive Tests Verbal Fluency Test (Animal Fluency) Function ADL (International Scale) Quality of Life Quality of Life Scale Clinical Impression of Change Harms SAEs | |
McCarney 2008223 England High | 176 | Mild to Moderate AD Mean Age 80 61% Female 95% White Median Years Education 10 Baseline Cognition: Median MMSE 22 | Ginkgo Biloba (EGb 761), 120 mg/day | Placebo | 6 months | Cognitive Tests Function Geriatric Evaluation by Relative’s Rating Instrument Quality of Life QoL-AD Harms SAEs Withdrawal due to AEs | |
Schneider 2005224 US High | 513 | Mild to Moderate AD Mean Age 78 52% Female 87% White Education NR Baseline Cognition: MMSE 18 | Ginkgo Biloba (EGb 761), 120 or 240 mg/day | Placebo | 26 weeks | Cognitive Tests Function Geriatric Evaluation by Relative’s Rating Instrument Clinical Impression of Change Harms Withdrawal due to AEs SAEs | |
Mazza 2006135 Italy High | 51 | Mild to Moderate AD Mean Age 68 57% Female Race NR Education NR Baseline Cognition: MMSE 18.8 | Ginkgo Biloba, 160 mg/day | Placebo | 24 weeks | Cognitive Tests Harms Withdrawal due to AEs | |
| Acetyl-L-carnitine | Livingston 1991225 UK High | 71 | All CATD Age 65+ 82% Female Race NR Education NR Baseline Cognition: MMSE 16 | Acetyl-L-carnitine (dose not specified) | Placebo | 24 weeks | Cognitive Tests Kenwood Object Learning Test Word Fluency Drawing Recognition Memory for Words Recognition Memory for Pictures Modified Name Learning Test Function Performance ADL Clinical Impression of Change CGI Harms Mortality |
Rai 1990226 UK High | 36 | Mild to Moderate AD Mean Age 79 72% Female Race NR Education NR Baseline Cognition: Reisberg Global Deterioration Score 3.0 | Acetyl-L-carnitine, 1 gram twice daily | Placebo | 24 weeks | Cognitive Tests Kendrick Battery Tests (Object Learning, Digit Copying) Word Fluency Test Automated Classification and Digit Recall Tests Function Harms Withdrawals due to AE | |
Sano 1992227 US High | 30 | Mild to Moderate AD Mean Age 69 Sex NR Race NR Mean Years Education 14.7 Baseline Cognition: MMSE 19 | Acetyl Levocarnitine Hydrochloride, 2.5 g/day for 3 months followed by 3 g/day for 3 months | Placebo | 6 months | Cognitive Tests Selective Reminding Test Total Recall Weschler Memory Scale Benton Visual Retention Test Cancellations Verbal Fluency (Category and Letter) Digit Span Test Clinical Impression of Change CGI Harms Mortality | |
Spagnoli 1991228 Italy High | 130 | All AD Mean Age 75 71% Female Race NR 7.7% with a Higher Degree Baseline Cognition NR | Acetyl-L-carnitine, 2 g/day | Placebo | 1 year | Cognitive Tests Blessed Information Memory Concentration Test Verbal Judgement and Mental Calculation Test Visual Search on Matrices of Digits Prose Memory Test Supra-span Verbal Learning Block-tapping Task Token Test Word Association Test Function Blessed Dementia Scale Harms SAEs | |
Thal 1996229 US High | 431 | Mild to Moderate AD Mean Age 72 56% Female 94% White 32% College Graduate or Postgraduate Baseline Cognition: MMSE 20 | Acetyl-L-Carnitine Hydrochloride, 3 g/day | Placebo | 12 months | Cognitive Tests Function Clinical Impression of Change CGI-C Global Staging Harms Withdrawal due to AE Mortality | |
| Vitamin E | Dyksen 2014180 US High | 304 | Mild to Moderate AD Mean Age 79 3% Female 86% White 24% With College or Advanced Degree Baseline Cognition: MMSE 21.1 | Vitamin E (alpha tocopherol, 1000 IU, twice a day) | Placebo | 2.5 years | Cognitive Tests Function Harms SAEs Mortality |
Sano 1997230 US High | 169 | Moderate AD Mean Age 74 63% Female Race NR Mean Years Education 12.5 Baseline Cognition: MMSE 13.1 | Vitamin E (alpha tocopherol, 1000 IU, twice a day | Placebo | 2 years | Cognitive Tests Function Blessed Dementia Scale Dependence Scale Harms Mortality | |
| Curcumin | Baum 2008231 China High | 34 | Severity Not Specified Mean Age 73 Race NR Education NR Baseline Cognition: MMSE 15.5 | Curcumin, 1 or 4 g/day | Placebo | 6 months | Cognitive Tests |
Ringman 2012232 US High | 36 | Mean Age 74 63% Female Race NR Mean Years of Education 15.2 Baseline Cognition: MMSE 22.5 | Curcumin C3 Complex®, 2 or 4 g/day | Placebo | 24 weeks | Cognitive Tests Function Harms Withdrawal due to AEs | |
| Lecithin | Little 1993233 UK High | 63 | Mild to Moderate AD Mean Age 76 % Female NR Race NR Education NR Baseline Cognition NR | Purified soya lecithin, 20-25 g/day | Placebo | 6 months | Cognitive Tests Paired-Associate Learning Test Immediate and Delayed) Verbal Fluency Orientation Questionnaire Function |
| Heyman 1987234 US | 37 | Mild to Moderate AD Mean Age 63 % Female NR Race NR Education NR Baseline Cognition: CDR 1.6 | Dehydrated soup with high purity lecithin, 2 daily servings | Placebo soup mixture | 6 months | Patients who remained stable Patients who worsened | |
| Thiamine | Nolan 1991235 US High | 15 | All CATD Mean Age 76 67% Female Race NR Education NR Baseline Cognition: MMSE 16.4 | Thiamine Hydrochloride, 3 g/day | Lactose placebo | 12 months | Cognitive Tests |
| Coconut Oil | Chan 2017236 Malaysia High | 40 | Mild to Moderate AD 58% between age 70 and 79 65% Female 85% Chinese 43% Primary School Education Baseline Cognition NR | Cold Pressed Coconut Oil, 60 ml daily divided into two doses | Placebo (Water and Coconut Essence) | 6 months | Cognitive Tests Clock Drawing Test Harms Withdrawal due to Adverse Event |
| Folic Acid Supplementation | Connelly 2008237 UK High | 57 | All CATD Mean Age 77 51% Female Race NR Education NR Baseline Cogntion: MMSE 23.5 | Folic Acid Supplementation, 1 mg/day | Placebo | 6 months | Cognitive Tests Digit Symbol Substitution Test Function Harms SAEs |
| Colostrinin® | Leszek 1999238 Poland High | All CATD Mean Age 69 71% Female Race NR 9.6% with College Education Baseline Cognition NR | Colostrinin®,1 00 μg per tablet, every second day | Placebo | 12 months | Cognitive Tests Harms Mortality | |
| Selenium | Leszek 1999238 Poland High | 31 | All CATD Mean Age 69 71% Female Race NR 9.6% with College Education Baseline Cognition NR | Selenium, 100 μg per tablet, every second day | Placebo | 12 months | Cognitive Tests Harms Mortality |
| Multivitamin | Sun 2007239 Taiwan High | 89 | Mild to Moderate AD Mean Age 75 49% Female Race NR Education NR Baseline Cognition: MMSE 18.7 | Multivitamin Supplement with Mecobalamin (0.5 mg) add-on to Donepezil | Placebo (Add-on to Donepezil) | 26 weeks | Cognitive Tests 11-item ADAS-Cog (Chinese Version) Function Harms SAEs Withdrawal due to AEs Delirium |
| Oral Nicotinamide Adenine Dinucleotide | Demarin 2004240 Croatia High | 26 | Severity Not Specified Median Age 68.5 % Female NR Race NR Education NR Baseline Cognition: Median MMSE 19.2 | Stable Oral Nicotinamide Adenine Dinucleotide, 10 mg/day | Placebo | 6 months | Cognitive Tests Mattis Dementia Rating Scale Hopkins Verbal Learning Test Verbal Fluency Test Global Staging Harms SAEs |
| Ninjin’yoeito | Kudoh 2016241 Japan High | 23 | Mild to Moderate AD Mean Age 76 27% Female Race NR Education NR Baseline Cognition: MMSE 20.4 | Ninjin’yoeito (7.5 g/day) added-on to Donepezil (5 mg/day) | Continue Donepezil, 5 mg/day | 24 months | Cognitive Tests ADAS-Cog (Japanese Version) Harms Withdrawal due to AEs |
| Resveratrol | Turner 2015242 US High | 119 | Mild to Moderate AD Mean Age 71 57% Female Race NR Mean Years Education 15.1 Baseline Cognition: MMSE 20.4 | Resveratrol, 500 mg/day | Placebo | 52 weeks | Cognitive Tests Function ADCD-ADL Global Staging CDR, Sums of Boxes Harms SAEs Withdrawal due to AEs |
Abbreviations: AD=Alzheimer’s Disease; ADAS-Cog= Alzheimer’s Disease Assessment Cognitive Subscale; ADCS-ADL=Alzheimer’s Disease Cooperative Study-Activities of Daily Living; ADCS-CGIC= Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change; AEs=Adverse Events; CDR=Clinical Dementia Rating; CGI=Clinical Global Impression; DEMQOL-proxy=Dementia Quality of Life Measure; IADL=Instrumental Activities of Daily Living; MMSE=Mini-Mental State Examination; NR=Not Reported; QoL=Quality of Life; RCT=Randomized Controlled Trial; RoB=Risk of Bias; SAEs=Serious Adverse Events; SKT=Short Cognitive Performance Test
Appendix Table F.43Risk of bias ratings: supplements versus placebo, high risk of bias studies
| Supplement | Study | Time | Selection Bias | Attrition Bias | Performance Bias | Detection Bias | Reporting Bias | Overall Rating* |
|---|---|---|---|---|---|---|---|---|
| Ginseng | Lee 2008214 | 24 weeks | Medium | High | Low | Low | Low | High |
| Heo 2012215 | 24 weeks | Low | High | Medium | Low | Medium | High | |
| Heo 2011216 | 24 weeks | Low | High | Low | Low | Medium | High | |
| Ginkgo Biloba | Le Bars 1997217 Le Bars 2000218 Le Bars 2002219 | 52 weeks | Low | High | Low | Low | Medium | High |
Kanowski 1996220 Kanowski 2003221 | 24 weeks | Low | High | Low | Low | Low | High | |
| Ihl 2012222 | 24 weeks | Low | High | Low | Low | Low | High | |
| McCarney 2008223 | 6 months | Low | High | Low | Low | Medium | High | |
| Schneider 2005224 | 26 weeks | Low | High | Low | Low | Medium | High | |
| Mazza 2006135 | 24 weeks | Low | High | Low | Low | Low | High | |
| Acetyl-L-carnitine | Livingston 1991225 | 24 weeks | Low | High | Low | Low | Low | High |
| Rai 1990226 | 24 weeks | Low | High | Low | Low | Medium | High | |
| Sano 1992227 | 6 months | Medium | Medium | Low | Low | High | High | |
| Spagnoli 1991228 | 1 year | Low | High | Low | Low | Low | High | |
| Thal 1996229 | 1 year | Low | High | Low | Low | Medium | High | |
| Vitamin E | Dyksen 2014180 | 2.5 years | Low | High | Low | Low | Low | High |
| Sano 1997230 | 2 years | Low | Low | Low | High | High | High | |
| Curcumin | Baum 2008231 | 6 months | Medium | High | Medium | Low | Low | High |
| Ringman 2012232 | 24 weeks | Low | High | Medium | Low | Low | High | |
| Lecithin | Little 1993233 | 12 months | Medium | High | Medium | Medium | Medium | High |
| Heyman 1987234 | 6 months | Medium | Low | Medium | High | High | High | |
| Thiamine | Nolan 1991235 | 12 months | Low | High | Medium | Low | Medium | High |
| Coconut Oil | Chan 2017236 | 6 months | Low | High | Medium | Low | Medium | High |
| Folic Acid Supplementation | Connelly 2008237 | 6 months | Low | High | Low | Low | High | High |
| Colostrinin® | Leszek 1999238 | 12 months | Low | High | Medium | Low | High | High |
| Selenium | Leszek 1999238 | 12 months | Low | High | Medium | Low | High | High |
| Multivitamin | Sun 2007239 | 26 weeks | Low | High | Low | Low | Low | High |
| Oral Nicotinamide Adenine Dinucleotide | Demarin 2004240 | 6 months | High | Low | Medium | Low | Low | High |
| Ninjin’yoeito | Kudoh 2016241 | 6 months, 24 months | High | Low | Medium | Low | Medium | High |
| Resveratrol | Turner 2015242 | 52 weeks | Low | High | Low | Low | Low | High |
- Key Question 4: Efficacy and Harms of Supplements Versus Placebo for Cognition, ...Key Question 4: Efficacy and Harms of Supplements Versus Placebo for Cognition, Function, and Quality of Life - Diagnosis and Treatment of Clinical Alzheimer’s-Type Dementia: A Systematic Review
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