European Review for Medical and Pharmacological Sciences 2016; 20: 4801-4817 Cholinesterase inhibitors and non-steroidal anti-inflammatory drugs as Alzheimer’s disease therapies: an updated umbrella review of systematic reviews and meta-analyses

C.-H. WANG1, L.-S. WANG2, N. ZHU3

1Department of Neurology, Beijing Tian Tan Hospital, Capital Medical University, Beijing, China 2Department of Clinical Medicine, Harbin Medical University, Harbin, China 3National Institute for Viral Disease Control and Prevention, China Center for Disease Control and Prevention, Beijing, China

Abstract. – OBJECTIVE: Alzheimer’s Disease Key Words: (AD) is a major neurological disorder marked Risk factors, Alzheimer’s Disease, ChEI, Memantine, by an amyloid-beta plaque and neurofibrillary NSAID, Therapy. tau-tangle depositions in the brain. Cognitive dysfunction is the key manifestation of AD. In this study, we conducted an umbrella review of Introduction meta-analyses on the risk factors and therapeu- tics targeting cognitive impairment and AD. MATERIALS AND METHODS: We searched Alzheimer’s Disease (AD) is a neurodegenera- PubMed from January 2000-August, 2016, and tive disorder characterized by manifestations of screened systematic reviews and meta-analy- forgetfulness, cognitive impairment, behavioural ses of studies that examined the effects of cho- changes, confusion, language trouble and thin- linesterase inhibitors in AD patients. We also king inability1. If left untreated, symptoms of included studies on non-steroidal anti-inflam- AD worsen with time, impeding the day-to-day matory drugs and AD. The studies comprised 1 meta-analyses of randomized controlled trials normal functioning of the patient . It has been and prospective cohorts, with 95% confidence claimed by the AD-International that more than interval. We considered the heterogeneity be- 30 million people worldwide are victims of de- tween different studies, denoted by I2. mentia, and the prevalence of AD is 60-80%2. RESULTS: We scanned a total of 750 novel me- More than 5 million Americans are reported to ta-analyses on the topics, “risk factors for AD” be living with AD3, and in Japan, around 15% of and “cholinesterase inhibitors and NSAIDs” that 4,5 target the disease. The search yielded three rele- the >65-year-old population suffers from AD . vant studies on risk factors, and seven and three AD is also emerging as a major threat to the de- studies for ChEIs and NSAIDs respectively. A veloping countries, accounting for about 58% of thorough examination of the studies reinforced the total population, and is speculated to escalate the therapeutic role of ChEIs in AD. A combina- to about 70% by 20506. tion of the glutamatergic inhibitor, memantine, The key pathological hallmarks of AD are with ChEIs also proved effective in ameliorat- (Ab) plaques and neurofibrillary ing AD progression and occurrence. Contradict- tangles (NFT) that accumulate in the gaps betwe- ing the observational studies, therapeutic role of 7 NSAIDs in AD seemed uncertain. Nonetheless, en nerve cells and synaptic junctions . The Ab the studies showed variability in the severity of and NFTs are generally deposited within the dementia and number of patient trials. Hence, brain hippocampus, the site for memory and we claim the need for detailed meta-analyses cognition, thereby impairing neuronal commu- and superior-quality cohort studies on a larger nication and resulting in neuronal cell death8-10. patient population of AD. CONCLUSIONS: The major risk factors for AD comprise growing Overall, our umbrella system- 11-13 atic review offers a unique and immensely helpful age and family history . While aging accounts resource for researchers and clinicians in the field for more than 95% of AD cases, familial AD for- of AD, and identifies vital gaps as well. ms around 2-3% of all cases and demonstra-

Corresponding Author: Na Zhu, MD; e-mail: [email protected] 4801 C.-H. Wang, L.-S. Wang, N. Zhu tes AD-like manifestations at an early age14,15. of AD is the damaged cholinergic neurons, resul- The genetic factors, particularly Apolipoprotein, ting in decreased neuronal choline levels30. Thus, APOE-e4 gene, have an immense impact and drugs inhibiting the functions of acetylcholine- markedly increase the risk for AD pathogene- sterase that degrades acetylcholine neu- sis16,17. Additionally, the deregulated processing rotransmitter are clinically used for attenuating of amyloid precursor protein, which causes a shift AD pathology31. The main therapies that attenuate towards the amyloidogenic pathway rather than AD symptoms include cholinesterase inhibitors the non-amyloidogenic, is a major cause for Ab (ChEIs), donepezil, galantamine and rivastigmi- generation18. ne and the NMDA antagonist, MEM, Altered expression of the neurotransmitters, or their combinations32,33. Meta-analysis studies especially acetylcholine and N-methyl-D-aspar- showed the combination therapy of MEM and do- tate (NMDA), and neuro-inflammation are major nepezil to be quite effective in treating moderate mechanisms inducing AD pathogenesis19,20. Hen- to severe stages of AD34,35. However, there have ce, cholinesterase inhibitors (ChEIs) and drugs been contradictions in this concept, and several targeting the NMDA receptor, and the non-steroi- studies hardly claimed any difference between the dal anti-inflammatory drugs (NSAID) are usual- ChEI+MEM-treated patients and placebo exami- ly used to attenuate the progression of AD21-23. ned through the Alzheimer’s Disease Assessment Anti-amyloid agents that reduce inflammation, Scale-cognitive subscale (ADAS-cog; Rosen et oxidative stress, hypercholesterolaemia and cho- al36) or the standardized Mini-Mental State Exa- linergic dysfunction are known to block Ab ge- mination (SMMSE; Molloy and Standish, 1997)35. neration and aggregation24. Drugs that promote Similarly, meta-analysis studies that determined cholinergic neurotransmission are also useful in the relation between classical NSAIDs and AD attenuating AD pathogenesis25. These agents may appeared to have contradictions as well. While reduce apoptosis in the hippocampal neurons, few scores failed to show any impact of NSAID and thereby inhibit AD progression26. Enhanced treatment, several others demonstrated an asso- functioning of growth factors and neurotrophins ciation28,37,38. Thus, heterogeneity in the results that function via the tropomyosin receptor kinase demanded the need for an umbrella review and A contribute in protecting against AD-induced meta-analysis that include all these meta-analy- neuronal damage27. ses. Hence, the present and Some documented research studies21-23 are meta-analysis included the data on modifiable available that demonstrate the role of neuro- risk factors for AD. It comprised results obtained transmitters and inflammation in AD. Choliner- from cognitive assessments following treatments gic neuromodulators, such as tacrine, donepezil, with the cholinesterase inhibitors, NMDA recep- rivastigmine and galantamine, NMDA-receptor tor antagonists and NSAIDs in AD. The methods antagonist, memantine (MEM), and NSAIDs ha- of assessment mainly included Severe Impair- ve also been reported to affect AD pathogene- ment Battery. The data included precise details sis. Additionally, systematic review and meta-a- about the disease condition, study population, nalyses28,29 on the effects of the therapeutics on study design, results, significant observations and AD features, particularly cognitive impairments, the limitations as well. have been carried out. However, to the best of knowledge, an umbrella review of the systematic reviews and meta-analyses of AD risk factors Materials and Methods and targeted therapies has not been done so far. In the current study, we performed a systematic Umbrella Review Concept overview of meta-analyses and an exploratory We carried out an umbrella systematic re- collective analysis of previous meta-analyses to view on the meta-analysis studies to identify assess the risk factors of AD and the effects of the modifiable risk factors for AD. Rather than neurotransmitter modulators and NSAIDs in AD executing the systematic reviews from the be- pathology. ginning, the current umbrella review combines the available reviews and meta-analyses of the Umbrella Meta-analysis Design risk factors of AD and the potential therapies. The central cholinergic system significantly We particularly selected cholinergic damage and regulates cognition and learning-memory perfor- inflammation as the two major factors promo- mances30. One of the major pathological features ting AD, and examined the effects of ChEIs and

4802 A systematic umbrella review and meta-analysis of Alzheimer’s disease therapies

Table I. Essential factors examined for meta-analysis.

Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Q11

Kobayashi et al Y Y Y Y Y Y Y Y Y Y N Xu et al Y Y Y Y NA Y Y N Y Y N Tariot et al Y Y Y Y Y Y Y N Y N N Jansen et al Y Y Y Y Y Y Y N Y N Y Jiang et al Y Y Y Y Y Y Y N Y N Y Leinonen et al Y Y Y Y Y Y Y N Y N Y Matsunaga et al Y Y Y Y Y Y Y N Y Y N Miguel-Alvarez et al Y Y Y Y Y Y Y N Y Y N Gupta et al Y Y Y Y Y Y Y N Y N Y Szekely et al Y Y Y Y Y Y Y N Y Y Y Tsoi et al Y Y Y Y Y Y Y N Y Y Y Wang et al Y Y Y Y Y Y Y Y Y Y Y Abbreviations used: Y-Yes; N-No and NA-Not applicable Q1: Is the objective of the review and meta-analysis article precise and prominent? Q2: Was the article relevant in terms of the search? Q3: Was the study population well defined? Q4: Was the strategy of the study relevant and proper? Q5: Were the techniques appropriate? Q6: Were the data reliable? Q7: Was the study statistically significant? Q8: Were there too many limitations in the study? Q9: Did the study offer any new view on the concept? Q10: Was there any bias assessment? Q11: Were there any future directions for the study?

NSAIDs on the disease progression. The present Search Strategy and Eligibility Criteria umbrella review and meta-analyses followed the A two-step search strategy was used to screen standardized methods and principles described all pertinent studies and reviews on meta-analy- before39-41. ses published in PUBMED. Studies published in English, and between January 2000 to August 2016 were included in our search. The titles and Inclusion criteria abstracts were first examined. From the screened articles, the references were checked and the Type of Participants cross-references were searched for additional me- AD patients belonging to different age groups, ta-analyses studies and reviews. We scanned the stage and severity were selected for the umbrella key words, “Alzheimer’s disease”, “risk factors”, review. “inflammation”, “NSAID” and “acetylcholineste- rase inhibitors”. “Alzheimer’s disease” was com- Kind of Exposure mon along with all other search words (Figure 1). The studies included patients exposed to the ChEIs, donepezil, galantamine and rivastigmine, Data Extraction and Synthesis and the NMDA receptor antagonist, MEM, or The data collected included minute details regar- their combinations. Our umbrella review also ding the dietary factors, age, sex, education, study comprised meta-analyses of the effects of NSAID protocol, statistical analysis methods, results and im- exposure in AD patients. plications. We considered studies that included health controls. The included reviews and meta-analyses Outcome Category provided the risk estimates of odds ratio (OR), risk The preventive effects of ChEIs, MEM and ratio (RR), standardized mean difference (SMD), NSAIDs in attenuating the symptoms of AD confidence intervals (CI) and population size. We were the outcome measures. Adverse side-ef- checked for overlapping references and research stu- fects and drug-induced toxicities have also been dies within the systemic reviews and meta-analyses. noted.

Study Types Results Systematic reviews and meta-analyses were generally included. Meta-analyses that were not Patient Health Factors-Risk Factors in AD part of organized reviews had been excluded The systematic reviews and meta-analyses that from our study (Table I). had been examined considered the diet and ge-

4803 C.-H. Wang, L.-S. Wang, N. Zhu

Figure 1. Flow chart of the strategy adopted for searching and selecting relevant reviews and meta-analyses on AD, risk fac- tors, ChEIs and NSAIDs. neral health status of AD patients. There were individuals were devoid of cardiac problems15. two sets of factors; firstly, diet, psychological The male and female participants were com- condition and lifestyle, and secondly age, gender, pared independently15. Additionally, as per the literacy and education (Table II). Newcastle-Ottawa scale, following proper OR/ RR assessments, no exclusion criteria were in- Diet, Psychological Condition corporated in the study15. For obtaining a statisti- and Lifestyle cally significant data (95% probability) through Search studies had been conducted for poten- the I2 statistic (Egger test and Stata V.12.0), a tial cohort and retrospective case-control studies pooled data from several studies were obtained15. from Database of Systematic Reviews Firstly, the controls, and then the AD population and PUBMED15. The studies were particularly underwent examination15. The risk factor analysis based upon the meta-analysis of “Observational was performed, and the conclusions were drawn Studies in Epidemiology Group” and the “PRI- as grade-I, II-B and II, based upon the hetero- SMA 2009 guidelines for systematic review and geneities of >5000 (I2≥50%), <5000 (I2≥50%) meta-analysis”42-44. The inclusion criteria com- and <5000 (indicating prominent heterogeneity), prised data on OR and RR of AD among a ge- respectively15,45. With a relatively larger pooled neral population, and for the exposures that were population (>5000, grade I and II-A), seven fac- known to affect AD15. The control population tors, such as neuroticism, Aβ42/40 ratio, fish included the arbitrarily chosen healthy indivi- eating habits, dietary pattern, education status, duals with no history of cognitive failures. The physical activities and smoking habits in Asian

4804 A systematic umbrella review and meta-analysis of Alzheimer’s disease therapies

Table II. Meta-analyses of risk factors in AD.

Risk factors Parameters tested Population size OR and RR CI Heterogeneity

Diet (Xu et al) Fish eating habits Applied 95% I2 statistic applied and dietary pattern

Sex, Both male and female (Xu et al; Jansen et al)

Cancer history (Xu et al) Both cancerous and >5000 non-cancerous population

Osteoporosis Both osteoporotic and (Xu et al) non-osteoporotic patients

Family history (Xu et al) Cancer and dementia

Habits (Xu et al) Smoking

Education (Jansen et al) Literacy and awareness 7583 NA 95% I2 statistic applied (>50%) Apo E genotype status Apo E alleles (Jansen et al)

Age (Jansen et al, Morris et al) MCI, aging 241 NA 95% I2 statistic applied and amnesia

CNS disorders Cerebrovascular (Jansen et al, Morris et al) dysfunction and depression Abbreviations used: OR-Odds ratios (OR); RR-Relative risk or risk ratio; CI-Confidence intervals; ApoE-Apolipoprrotein E; MCI-Mild cognitive impairment.

populations (Table II) appeared as the key factors and prominent cognitive impairments46. The risk for meta-analysis15. Neurodegeneration, marked factors examined were age, gender, literacy, edu- by impaired gait and behavioral aberrations, and cation and the ApoE genotype status46,47. To iden- cancer and malignancy served as major factors tify statistical relevance, the meta-analyses were regulating AD development15. While degenera- carried out on the total study population directly, tion and failed health conditions promoted the and after combining data, the generalized estima- probabilities of AD, persons with cancer history ting equations were examined, based on the fre- had reduced possibilities, to the extent of about quency and OR46,48. The meta-analyses revealed 37-40% attenuation in the likelihood of develo- that APOE-ε4 carriers and non-carriers, and age ping AD15. The importance of Ca2+ ion transpired factor played a marked role in enhancing amyloid from a meta-analysis study that demonstrated burden and cognitive dysfunction46,49. Notably, AD risk, with scores of RR=2.07 and CI value of while the sex of individuals had no significant im- 1.22-2.92 in osteoporotic patients15. Supporting pact, education status bore a prominent link with this concept, exposure to sunshine and treatment the amyloid count46. Mild cognitive impairment with vitamin D attenuated the chances of deve- (MCI) appeared as a risk factor, and differences loping AD15. were observed for patients with non-amnestic MCI and amnestic MCI, the latter demonstrating Age, Gender, Literacy and Education a greater amyloid burden46,47. However, although Individual data meta-analysis to understand amnestic MCI showed strong association with AD the occurrence of cerebral amyloid pathology was pathology, certain other central nervous system conducted on participants having normal memory disorders, such as cerebrovascular dysfunction, performances in comparison with those with mild depression and hippocampal sclerosis, marked

4805 C.-H. Wang, L.-S. Wang, N. Zhu by neuronal loss and gliosis also exhibited MCI prominently better effect for the ChEI compared features46. Comparative analysis of APOE-ε3 and to MEM56,57. However, the adverse side-effects the APOE-ε4 alleles revealed the latter to be more of MEM were relatively less than ChEI31,55. No- at risk for AD, being expressed at an early age netheless, the studies had some deficits. Critically as well46,50. Contrarily, APOE-ε2 allele appeared assessing the studies, we inferred that the early protective, and a comparatively higher APOE-ε4 and late time points had not been defined clearly, level led to the clinical manifestations of AD46,51. and the follow-up duration was not enough. The Thus, all these factors served as inclusion criteria patients used for the meta-analyses showed very for our umbrella review of meta-analyses on AD slow and little cognitive loss55, and we assumed targeted therapies. that there was a probable heterogeneity in the physical status of patients. Hence, to reach a perfect conclusion for early versus late treatment Cholinesterase Inhibitors effects, we presume that more studies may be and Memantine as AD Therapies needed with larger patient size and an extended follow-up time following MEM or ChEI treat- ChEI+MEM Therapy ments (Table III). Meta-analysis using neuropsychiatric inven- tory (NPI) of three studies indicated that ChEI+- Donepezil+MEM Therapy MEM in combination was a true therapy for For meta-analysis of ChEI and MEM, a pooled moderate-to-severe forms of AD, with a high data revealed an MMSE range of 5-14 for some significance, p=0.0000135. To explore this aspect, studies and 10-22 for few others58-60. However, a search through Review Manager that included all the groups preferred a combination therapy seven pooled-up studies on randomized control- compared with individual. For the study by Tariot led trials (RCTs) for the combination treatments et al58 with AD patients suffering from severe de- in 2182 patients was performed35. MEDLINE mentia, a statistical significant improvement appe- and Cochrane database, Google Scholar, Excerp- ared in the SIB score following combinatorial tre- ta Medica database (EMBASE), CINAHL and atments58. Furthermore, for donepezil and MEM PsycINFO citations were searched, and a range treatments in Moderate to Severe Alzheimer’s of drugs and ChEIs were scanned35. The outco- Disease (DOMINO) trial, a significant difference mes assessed were cognition and neurobeha- between the combination therapy and individual vior, through Severe Impairment Battery (SIB), donepezil treatment was hardly apparent59. The ADAS-cog, SMMSE, MMSE and NPI52. The MMSE study for DOMINO showed a comparable statistical analysis, using the DerSimonian-Laird effect for combination therapy and donepezil alo- random-effects model, was based on mean stan- ne treatment59. A similar trend was also observed dard deviation (MSD) data with 95% confidence for the mild to moderate AD61, particularly in the intervals53. The NPI for behavioural assessment open-label trials62. In another meta-analysis that for combination therapy showed better resul- had been conducted for a long span of time, from ts than placebo54. However, contradictions were 1997-2005, an identical pattern was observed63. observed in the NPI statistical data, and it could We deduced from the pooled up data for studies be inferred that meta-analyses and studies with on donepezil+MEM therapy that patient hetero- higher sample numbers may be essential to con- geneity and more importantly an extended period clude about use of ChEI+MEM as AD therapy. of enrolment may have been the pertinent reasons A meta-analysis study revealed that AD drug behind the differential observations. The Alzhei- treatment, whether early or late, had the same mer’s Disease Co-operative Study - Activities of effects on cognition, behavioral aspects and other Daily Living Inventory (ADCS-ADL) analysis physical and physiological status55. Using the method, based on SMD calculation of the results SMD of data obtained from meta-analysis, and from blinded-randomized clinical trials, signi- pooling the data of about 1415 patients and for ficantly favored combination therapies for AD eight trials tested for cognition, revealed no signi- compared to MEM monotherapy in the DOMI- ficant difference between early and late treatmen- NO trial58. However, the data appeared quite dis- ts55. A meta-analysis study by another group that similar for donepezil58, indicating a better effect compared the effects of ChEIs and MEM with of the drug alone. A variation was observed for the placebo for an AD population, along with the different ADCS-ADL studies. While AD- a follow-up period of 3 to 12 months showed a SC-ADL-19 version of measurement in moderate

4806 A systematic umbrella review and meta-analysis of Alzheimer’s disease therapies

Table III. Meta-analyses of ChEI and memantine therapy in AD.

Treatments Search strategy Scale Statistics Outcomes Limitations

AChEI+memantine i. MEDLINE i. SIB 95% CI Beneficial for Contradictions (Matsunga et al) ii. Cochrane database ii. ADAS-cog and SMD moderate-to-severe in NPI iii. Google Scholar iii. SMMSE values AD statistical data iv. EMBASE iv. MMSE v. CINAHL v. NPI vi. PsycINFO

AChEI, donepezil, i. MEDLINE, i. Cognition 95% CI Early drug treatment i. Clinical galantamine, ii. EMBASE, ii. SIB and SMD based upon heterogeneity rivastigmine iii. AMMED iii. NPI values earlier diagnosis ii.Treatment or memantine iv. ADCS-ADL poses no advantage conducted (Tsoi et al) v. MMSE in attenuating iii. MMSE very high vi. Physical AD manifestations function for short term

Donepezil+ Not mentioned i. SIB SD value Detected inaccuracies i. Claimed inclusion memantine ii. MMSE in previous of patients of Tariot et al) iii. CIBIC-Plus meta-analyses studies heterogeneous categories ii. Comparisons were not appropriate

Comparative i. PubMed i. ADAS-Cog 95% CrI i. Demonstrated i. Variability in efficacies of ChEIs ii. EMBASE ii. NPI modest beneficial role study size (Kobayashi et al) iii. Cochrane iii. CIBIC of ChEIs ii. The number dementia iv. CGIC ii. Detected beneficial of trials were effects for donepezil very small and rivastigmine, iii. Used flexible but not for drug doses galantamine iv. Drug tolerability less examined

ChEIs and atypical i. PubMed, NPI and safety 95% CI ChEIs and atypical i. NPI appeared antipsychotics ii. EMBASE, outcome SMD antipsychotics could comprehensive (Wang et al) iii. Cochrane ITT analysis improve ii. Use of other Controlled Trials MMSE neuropsychiatric drugs consumed iv. Cochrane Database symptoms in AD was unrecorded of Systematic Reviews patients, but with iii. Trial number bad safety outcomes. few for antipsychotics, antidepressants and mood stabilisers iv. Patients had physiological variability while pooling data

Abbreviations used: EMBASE-Excerpta Medica database; CINAHL-Current nursing and allied health Literature; AMMED-Ar- my medical department; SIB-Self-injurious behavior; ADAS-cog-Alzheimer’s disease assessment scale-cognitive; SMMSE: Standardized mini-mental state examination; MMSE-Mini mental state exam; CIBIC-Plus: Clinician’s interview-based impres- sion of change Plus caregiver input; NPI: Narcisistic personality inventory (NPI); ADCS-ADL: Alzheimer’s disease cooperative studies activities of daily living inventory; ITT: Intention-to-treat; CGIC: Clinical global impression of change; CI-Confidence intervals; CrI-Credible interval; SMD- Standardized mean difference to severe dementia showed improvements with do so60. Diverse observations were also obtai- donepezil treatments, ADCS-ADL-23 failed to ned for primary and secondary outcome measu-

4807 C.-H. Wang, L.-S. Wang, N. Zhu res. In Clinician’s Interview-Based Impression of Change69. A comparative effect of drugs was of Change Plus Caregiver Input (CIBIC)-Plus examined68. Severe AD patients, with an MMSE method, results showed prominent improvements value <10, and patients treated at either very high with the donepezil therapies for mild to moderate or minimum doses of the ChEI inhibitors were patients in case of primary outcome measure58, not included in the study68. The data extraction whereas the findings were entirely different for process was performed and cross-checked by secondary outcome measure, showing no im- more than two people68. At first, heterogeneities provements at all60. The CIBIC-Plus method of were assessed using the conventional meta-a- measurement also proved to be less consistent nalysis procedure of I2 statistic and funnel plots, and quite insensitive64,65. NPI analysis as a secon- followed by Metafor package68. The comparative dary outcome measure also favored combination NMA was conducted for two doses of donepe- therapy58, especially when compared with MEM zil (5 and 10 mg), galantamine (16 and 24 mg) monotherapy59. Nonetheless, we found that these and rivastigmine (6 and 12 mg)68. Following studies had some limitations in assessment of le- this, the assessments were performed through the arning-memory and functional outcomes. We ob- Bayesian hierarchical model using Markov chain served that a certain degree of variability entered Monte Carlo estimation and the GeMTC network in the statistical analysis, and a few data had been meta-analysis package as a support70. The study calculated based on standard errors (SEs) and revealed that ChEIs improved cognitive perfor- some on standard deviation (SD), and the quanti- mances, but failed to cause improvements in fication for SMD was also on dissimilar versions neuropsychiatric symptoms, as evident from the of scales59. There were some variations in the funnel plot that hardly showed any change in di- patient conditions as well, where some had been stribution pattern68. Secondly, donepezil and riva- suffering from severe forms of AD while others stigmine appeared effective in the clinical global quite milder59. Minimal clinically important dif- change data evaluated by the CIBIC+Clinicians’ ference score (MCID) appears to be another me- global impression of change (CGIC), whereas ta-analysis score that well correlates the results galantamine failed to show any remarkable im- with the chances at the clinical levels66. Of RCTs, provement relative to the placebo68. However, the study elaborated by Howard et al59 was the cognitive tests demonstrated galantamine dose only one that considered MCID score, while for of 24 mg to be helpful68. The I2 values had a the others, such as Tariot et al58 and Posteinsson heterogeneity score of 44-53% and CGIC showed et al60, results were based upon CIBIC-Plus score I2 heterogeneity between 64-51% respectively68. merely67. A prominently big patient sample size Tolerability assessments for nausea, dizziness, and a minimum of one year proved essential for drowsiness, vomiting, diarrhea and dysentery, the MCID score67 (Table III). and withdrawal effects were the minimum for do- nepezil and maximum for rivastigmine68. Thus, Comparative Effects of Donepezil, supporting an earlier study, donepezil seemed to Galantamine and Rivastigmine be the safest ChEI for AD treatment71. Using AD and ChEIs as key words in PUBMED Another study methodically searched for AD, and EMBASE, a recent systematic meta-analysis ChEI treatments and the disease manifestations and Bayesian network meta-analysis (NMA) of through PubMed, EMBASE, Cochrane Database donepezil, galantamine and rivastigmine were of Systematic Reviews and Cochrane Controlled carried out to understand their comparative ef- Trials Register72. In addition to cognitive and ficacy and safety in mild to moderate AD68. A neuropsychiatric symptoms, the scan also in- total of 19 studies were performed on these three cluded dementia and general behaviour72. Other drugs with AD patients from North America than the typical ChIEs, the effects of a wide-ran- and Europe. The average age of the patients was ge of other closely associated drugs, such as around 69 to 78, with about 62% being women68. anti-depressants, anti-convulsants, sedatives and The MMSE score varied between 15-21, and the psychotropic drugs were searched72. Double-blin- ADAS-Cog and NPI were between 20-35 and 10- ded, RCTs against placebo controls were included 35 respectively68. The cognitive effects were pri- in the study72. Both crossover and non-crossover marily taken into consideration68. Inclusion and trials had been carried out, and the patients were exclusion criteria and data extraction were based all prone to AD72. The assessment ranges of doses on RCTs, and the scores included ADAS-Cog, for these drugs were wide, and the NPI was found NPI, CIBIC-plus and Clinical Global Impression to range between 10 to 1272. The sample size,

4808 A systematic umbrella review and meta-analysis of Alzheimer’s disease therapies age, gender, race, treatment schedule and side-ef- ts who belonged to one group and about 120-124 fects were assembled72, and the total search was patients in the other using anti-depressants, such performed by three reviewers72. The statistical as sertraline, fluoxetine, citalopram and trazo- analysis generated SMD data of NPI-10, NPI-12 done, was carried out72. However, the NPI score and NPI- with 0.05% p-values72. The RR analysis showed a non-significant difference between the was accomplished and heterogeneity was exami- placebo and treated patient population, indica- ned visually and by a combination of chi-squared ting minimum beneficial effects of anti-depres- test (χ²) and I2 tests72. The data analysis and sta- sants among the patients72. An RCT on 13-14 tistical software, STATA12.0, was used and Bias AD patients using a valproate mood stabilizer detection funnel plots and Begg’s test method treatment for six weeks, followed by a two-week were adopted72. A total of 32 studies were analy- observation showed marked changes in the NPI zed that included RCTs and placebo-controlled scores72. Meta-analysis study for MEM for eight trials72. Sixteen trials were on a single dose of RCTs that involved around 1500 MEM-treated drugs, and the others on dose range of the drugs72. AD patients compared to 1333 placebo patients The number of treated patients in trials was close showed no significant effects in the NPI score, to 7000 and placebo was around 500072. The dru- indicating the non-beneficial effects of MEM72. gs included ChEIs, anti-depressants, anti-psycho- However, the heterogeneity existed (I2=70-80%), tics, mood-elevators, MEM, etc. The patients be- based upon variations in age, race, span of drug longed to the age group of 74-86, and the MMSE treatment (3-7 months), MMSE, etc.72. Assessing was between values of 4.5 to 21, and the patient the neuropsychiatric changes through NPI or population was from Europe and North Ameri- another new scale, the Behavioural Pathology in ca72. Fifteen studies that included donepezil (eight Alzheimer’s Disease also revealed significant im- trials), galantamine (four trials) and metrifonate provements by ChEIs and anti-psychotics (ChEIs, (three trials), and the fifteen RCTs for ChEI tre- SMD −0.11; 95% CI −0.20 to −0.01; atypical an- atment showed significant (p<0.05) behavioral tipsychotics, SMD -0.18; 95% CI −0.27 to −0.09). improvements for all drugs72. The meta-analysis The impacts of MEM and anti-depressants were study revealed marked improvement in NPI sco- very little (MEM, 95% CI −0.27 to 0.01; antide- re, with a standardized mean difference of 0.12 pressants, 95% CI −0.35 to 0.37)72 (Table III). and CI of 0.2572. A substantial heterogeneity (I2) was observed72, probably due to the difference in Treatment Impact of NSAID in AD ages, medicine sub-types and brands, population AD is a neuro-inflammatory disorder, and heterogeneity, racial differences, MMSE, treat- NSAIDs are used in attenuating the disease pa- ment period, etc. The sensitivity assessment for thogenesis19. A meta-analysis search through the studies that used intention-to-treat method PUBMED, Cochrane Database and biological ab- revealed beneficial effects of ChEIs against pla- stracts using the words, AD, NSAID and inflam- cebo73. However, the effects were comparatively matory diseases was conducted38. The screening better for galantamine (SMD −0.13; 0.05%, CI identified around 2000 abstract and 35 relevant −0.2 to −0.03 and I2=0%) in terms of impro- and interesting studies38. The detail regarding vements in neurobehavior and neuropsychiatric the participants, such as, location, age, gender, symptoms compared to donepezil (p<0.0, CI family, etc., was taken into consideration38. Ad- value between 0.2-0.10 and I2 around 7)73. The ditionally, the disease onset-time and NSAID tre- meta-analysis also revealed marked benefits with atments were all thoroughly inspected38. The stu- anti-psychotic drugs, quetiapine, olanzapine, ari- dies that included drug treatments for 2-3 years or piprazole, ziprasidone, olanzapine and clozapine, life-long were included and the Stata 7.0 software compared to placebo on the NPI score scale72. package was used for the quantitative analysis. Bias risk assessment through Begg’s test and The I2 heterogeneity and statistical program, the Funnel Plot demonstrated little publication such as, Q-statistic, Egger’s plots and Begg’s bias (z=0.60)72. Comparing the impacts of the funnel plots were used for the meta-analysis38. anti-psychotics proved that olanzapine was the Of all the studies analyzed, about eleven of them most effective in improving neurobehavior and appeared to have a tangible link between NSAID neuropsychiatric symptoms (SMD −0.20; p-value and AD risk. Of these, there were eight studies of 0.0%, CI −0.30 to −0.0 and I2 -0) followed by that demonstrated an apparent association betwe- aripiprazole (SMD −0.20; p-value of 0.0%, CI en NSAID treatment and AD74-76. Both non-pro- −0.30 to −0.04; I2-1)72. RCT on 20-24 AD patien- spective (seven) and prospective (four) studies that

4809 C.-H. Wang, L.-S. Wang, N. Zhu included OR and RR respectively was examined, performances79. The third scale used for memory and the results from the prospective groups that impairment was MMSE, where the scale ranged involved NSAID treatment as preventives appe- from 0-30, and scores <10 suggested severe forms ared more conclusive38. Non-prospective studies, of AD77. Statistical examination of the studies on the other hand, involved retrograde method was based on SD of the changeable variables of data assessment, and showed a chronological and the size of samples assessed through Begg’s association between NSAID treatment and AD38. test80. The measurements were carried out in A certain degree of discrepancy appeared in MIX 2.0 Pro for Excel software, and a 95% p-va- the meta-analysis, where the prospective studies lue was considered significant80. Interestingly, indicated a 25% and 60% lesser risk for AD for despite a rigorous examination through enough the 2-3 years and continued life-long treatments patient sample size and relevant controls, the respectively38. The study also emphasized upon effect of NSAID through the meta-analysis study the fact that treatment with NSAIDs delayed the appeared less significant, with p-values > 0.0528. onset of AD38. Thus, it could be inferred from Analyzing the study, it could be inferred that a the meta-analysis that a prolong treatment with prior treatment with NSAID may probably have a NSAIDs could be more effective compared to a better impact compared to its treatment following shorter span. Analyzing the data from the Cana- diagnosis28. Hence, it may also be presumed that dian Study of Health and Aging revealed a mar- because the study lacked subjects from preventive ked resemblance in the OR values for NSAID and groups, the observations showed little therapeutic its link with AD and the inflammatory disease, effects for the NSAIDs28. Secondly, the number arthritis76. Meta-analyses were performed to cle- of NSAIDs used in meta-analysis was small28. arly understand the usefulness of NSAIDS, ibu- However, although the data appeared negative, profen, , , , , this meta-analysis is one of the very few on , tarenflurbil and indomethacin as the- NSAID and AD, and appears important as it rapeutics for AD28. The experimental population emphasized the need for newer studies in this included AD patients undergoing NSAID treat- context28. Another meta-analysis that explored ment, and patients with three-month follow-up28. the relationship between NSAIDs and AD ba- The search was carried out using the “Patient sed on RCTs, PUBMED search, EMBASE and Population or Problem, Intervention treatment, Cochrane Database Search Strategy also contra- Comparison, Outcomes, and Setting method”, dicted the therapeutic role of NSAIDs in AD37. and the Cochrane Library electronic databases The search included seven studies that compri- in combination with PUBMED28. The PRISMA sed ADAS-cog and MMSE measures for clinical guidelines were followed, where a total of 963 ar- drug trails in AD37. The Neyeloff et al81 method ticles were reviewed77. Following initial screening for statistical assessment of SMD with 95% pro- for pertinent publications, the inclusion criteria bability factors was adopted81. The I2 statistic were adopted, and Cochrane Collaboration tool method of heterogeneity at a range of 0-40%, was applied28. Age, APOEe4 allele carriers, dose, 30-60%, 50-90% and 70% to 100% showed duration and frequency of NSAID treatments of non-heterogeneity, modest, considerable and ex- the participating patients were the major factors tensive heterogeneity respectively37. Neither the taken into considerations28. The cognitive perfor- ADAS-cog nor MMSE showed any changes in mances of patients were examined, and scores NSAID-treatments compared to the placebo and were determined and the outcome reported as differed considerably from the observational fin- ADAS-cog28. The ADAS-cog scale was found to dings82. Additionally, the search from this study be between 0-70, and a lower score indicated bet- revealed a match with the “Alzheimer’s Disease ter performance78. The second measurement scale Anti-inflammatory Prevention Trial study” that was “Clinical Dementia Rating Scale sum-of- demonstrated the failure of NSAIDS, naproxen boxes” that examined learning memory perfor- or celecoxib, to ameliorate cognitive impair- mances, rationality, difficulty in solving ability, ments in an RCT study of USA83. Nonetheless, social behaviour, domestic affairs and personal supporting the data obtained from the above hobbies28. Another vital factor contemplated was study, it could be inferred that the RCT for long whether the drug had any impact on the ability to term (more than a year) NSAID exposure may cope with activities of daily living. It was found be more important for meta-analysis37. Secondly, that each factor was between a scale of 0-3, and the amount of NSAID that reaches the brain, the total maximum score was 18, signifying worst and whether that is sufficient for being effective

4810 A systematic umbrella review and meta-analysis of Alzheimer’s disease therapies also needed investigation37. Because of these diet, psychological condition, lifestyle, age, gen- negative results from the meta-analysis studies der, literacy, education and genotype status as on NSAIDs and clinical trials on AD, few stu- major determinants of AD. The current review dies have been conducted along this line. Hence, also supports that administration of ChEIs and studies on a larger cohort of RCTs and cognition MEM may attenuate AD progression. However, are needed. Moreover, it is viewed that rather although observational studies claim NSAIDs to than the conventional NSAIDs, studies may be playing a major therapeutic role in AD, our better be conducted with the selective Cyclo- umbrella review fails to reinforce this existing oxygenase (COX)-2 inhibitors as treatments for concept. AD84. Meta-analysis of RCTs with a mixture of This appears to be the first complete and NSAID and COX-2 inhibitors may as well be precise systematic umbrella review and meta-a- beneficial for the purpose84 (Table IV). nalysis to date, which considers nearly all known variable risk factors for the neurodegenerative disorder, AD. Our work involves a detailed search Discussion of meta-analyses studies of risk factors that could be intervened by life-style changes, or through To our knowledge, this appears to be the first preventive, prophylactic, therapeutic and clinical updated umbrella review of meta-analyses that measures. Our findings highlighted the hetero- examines a wide range, from risk factors to the geneity of variable risk factors for AD and also most prevalent therapies in AD. We identified pointed at the intricacies of the disease etiology.

Table IV. Meta-analyses of NSAID therapy in AD.

Treatments Search strategy Scale Statistics Outcomes Limitations

NSAID: , i. MEDLINE, i. ADAS-cog. 95% CI and Non-beneficial effect All NSAIDs indomethacin ii. Science Direct ii. CDR-SOB standard deviation of NSAIDs for AD were given naproxen, , iii. Cochrane Library iii. MMSE equal tarenflurbil consideration, naproxen, ibuprofen despite or tarenflurbil differences (Miguel-Alvarez et al). in efficacies

COX-inhibitors i. MEDLINE, i. MMSE 95% CI and As opposed to i. Clinical (Gupta et al) ii. EMBASE, ii. ADAS-cog standard deviation observational heterogeneity iii. COCHRANE studies, effects ii. Treatment databases in the meta-analysis conducted for study showed short term non-significant iii. MMSE effects of NSAID very high in AD

Non-aspirin NSAIDs i. Medline, i. Cognitive i. Stata 7.0 Prospective and i. Claimed Szekely et al) ii. Biological abstracts, score software package non-prospective inclusion on iii. Cochrane Library ii. Activities of ii. Q statistic tudies showed that observational iv. DSM daily living score (Stata meta program) NSAIDs reduced settings v. NINCDS-ADRDA iii. SIB iii. Begg’s funnel AD risk iv. MMSE plots and Egger’s plots ii. History of v. CIBIC-Plus iv. Stata metabias patients less known iii. Inappropriate comparisons

Abbreviations used: NSAID: Non-steroidal anti-inflammatory drugs; EMBASE: Excerpta Medica database; SIB: Self-injurious behavior; ADAS-cog: Alzheimer’s disease assessment scale-cognitive; SMMSE: Standardized mini-mental state examination; MMSE-Mini mental state exam; CIBIC-Plus: Clinician’s interview-based impression of change Plus caregiver input; CI-Con- fidence intervals; CDR-SOB-Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB); NINCDS-ADRDA-National Insti- tute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association; DSM-Diagnostic and Statistical Manual.

4811 C.-H. Wang, L.-S. Wang, N. Zhu

The analysis suggested that a careful conside- ceptors86. These two contradictory features may ration of the dietary patterns, education status, have nullified the effects of each other, resulting physical activities and smoking habits may pre- in a net non-effectiveness in improving cogniti- vent AD pathogenesis. The results indicate that ve performances in AD patients. Interestingly, potential interventions in behavioral conditions, the results of Tsoi et al55 showed that patients mental and physical degeneration, pre-existing exposed to early diagnosis and early treatment disorders, such as cancer, vascular dysfunctions, with the ChEIs and MEM had a small beneficial bone erosion, etc., may be promising selective effect on the cognitive performances in AD pa- strategies for preventing AD15. Additionally, age, tients55. Thus it may be deduced that, although low education level, and most importantly ApoE early recognition of dementia and AD symptoms genotype status played vital determining role in may perhaps have psychosocial advantages, an AD46,50, and thus deserve special attention. Based early therapeutic intervention may not be very on our data, additional studies on AD risk factors, beneficial. Thus, future investigations on ex- particularly the physiological conditions and risk tended follow-up observations may clear the genotypes of patients appear predominantly es- doubts on early and late treatments with targe- sential. Good-quality and large population-based ted drugs and the repercussions in AD patients. investigations and RCTs are also needed to con- Another meta-analysis study proved that ChEIs clude upon the risk factors. Moreover, increased not only improved the cognitive abilities, but surveillance and awareness spread may as well also played a beneficial role in attenuating the be promising ways for preventing the disease neuropsychiatric problems72. The effects were progression, particularly for the less-educated less prominent for anti-depressants and MEM72, and economically backward class. suggesting the superior role of ChEIs in ame- A major conclusion of this umbrella review liorating cognitive deficits and neuropathology and meta-analysis is the evidence for the effecti- in AD. Neuropsychiatric aberrations comprise veness and safety of ChEIs in AD patients. The a vital manifestation in AD87,88. Prior to Wang’s current review analyzed the effects of ChEIs group, very few studies related the ChEIs with and memantine from several reports and found neuropsychiatric abnormalities, and thus throu- diverse effects. Meta-analysis study by Kobaya- gh our umbrella review, we claim the need for shi et al68 detected that ChEI treatment si- future research on neuropsychiatric outcomes gnificantly improved cognitive performances in and ChEIs in AD. AD68. However, the effects on neuropsychiatric Neuroinflammation is a well-known risk fac- symptoms appeared inconclusive. The Bayesian tor for AD19. Ab and p-tau proteins stimulate NMA data offered a comparative participation astroglial and microglial activations that induce of donepezil, galantamine and rivastigmine in neuronal apoptosis, and thereby cognitive failu- attenuating AD symptoms, and eventually pro- res in AD19. Additionally, inflammation also pro- ved greater therapeutic efficacies of donepezil motes the generation of Ab and p-tau, leading and galantamine relative to rivastigmine68. We to a cycle of neurodegenerative events19. Thus, found the paper by Kobayashi et al68 to be a the current review that has brought together rare and essential one in terms of ChEI and AD. observations from the meta-analysis studies on However, we observed that few groups sugge- NSAID and AD seems very useful and appro- sted ChEI+MEM as a better therapeutic strategy priate. Our work also underscores the contra- compared to ChEI monotherapy35,55. Matsunaga dictory findings of NSAIDs, and rationalizes et al35 reported that ChEI+MEM combination the discrepancies. Preliminary evidence from therapy was more effective for moderate-to-se- the research of Miguel-Alvarez et al28 failed to vere AD35. Comparing the studies, we inferred find any prominent improvements in cognition that therapeutic strategies in AD are essentially and severity of the disease manifestation when dependent on the heterogeneity of stage and se- treated with NSAIDs28. However, these findings verity of AD. However, even for moderate-to-se- had a medical interest because other than the vere AD, the combination of galantamine and cognitive abilities, factors, such as social beha- MEM failed to show any prominent impact35. viour, attentiveness, language proficiency, and This discrepancy could be explained by the dif- the ability to carry along with the daily activity ferences in their functioning. While galantami- had been examined as well28. Based upon the ne alters the functioning of nicotinic receptors85, compiled data from ADAS-cog and MMSE sco- MEM has the potential to block the same re- res, observations of Gupta et al37 were almost

4812 A systematic umbrella review and meta-analysis of Alzheimer’s disease therapies similar to that of Miguel-Alvarez et al28. The re- Conclusions sults hardly showed any difference between the NSAID-treated and untreated groups28,37. The This systematic umbrella review and meta-a- results from the two meta-analysis studies were nalysis has identified and compiled relevant me- close to that observed in Alzheimer’s Disease ta-analysis studies and reviews on risk factors of Anti-Inflammatory Prevention Trial study that AD and therapies, particularly, ChEIs, MEM and showed a non-significant effect of naproxen and NSAIDs. Our paper offers a profoundly helpful celecoxib in AD89. On the contrary, prospective resource and reference for researchers and clini- and non-prospective studies by Szekely et al38 cians in the field of Alzheimer’s neurodegenera- strongly indicate that NSAIDs have a protective tion and therapies. Our umbrella review provides function in ameliorating AD and also preventing a pooled meta-analysis data on the advantages the disease occurrence38. However, a sustained and disadvantages of ChEIs, MEM and NSAIDs treatment with NSAIDs was essential to atte- as effective treatments for AD. Nonetheless, fur- nuate the risk of AD38. Examining the study, we ther research is essential to deduce a strong and could infer that a long-term NSAID exposure robust recommendation for the use of these ther- is essential for treating AD. The previous me- apies in attenuating symptoms of the dreaded ta-analysis studies that failed to link AD and neurodegenerative disease. NSAIDs may have fallen short in terms of tre- atment duration. Acknowledgement Limitations and Future Research This work was supported by National Natural Science Although the meta-analysis studies and reviews Foundation of China (81301430). accessed provided an idea on risk factors of AD and its therapies, particularly ChEIs, memantine and NSAIDs, the studies had several limitations. Conflicts of interest The primary drawback was the heterogeneity in The authors declare no conflicts of interest. the sample size, population, duration and physio- logical condition. Most of the studies involved patients of varied severities and low number of References trials. The number of epidemiological and clini- cal studies were also few. Hence, higher number 1) Tarawneh R, Holtzman DM. The clinical problem of of human with careful consideration symptomatic Alzheimer disease and mild cogni- of study population traits, exposure assessment, tive impairment. Cold Spring Harb Perspect Med age, gender specification, etc. is essential to draw 2012; 2: a006148. Schierle GS, Michel CH, Gasparini L. a perfect conclusion from meta-analyses. Statisti- 2) Advanced imaging of tau pathology in Alzheimer disease: cal analysis needs more precision, with distinct new perspectives from super resolution micro- SE, SD and SMD data. Moreover, the findings scopy and label-free nanoscopy. Microsc Res for meta-analysis were obtained from published Tech 2016; 79: 677-683. articles only, and hence a publication bias also 3) Koller D, Bynum JP. Dementia in the USA: state va- appeared in the studies. For studies that recruited riation in prevalence. J Public Health (Oxf) 2015; patient population through advertisements invol- 37: 597-604. ved self-selection bias. 4) Naganuma T, Takemoto Y, Shoji T, Shima H, Ishimura E, Okamura M, Nakatani T. Hence, more detailed meta-analyses and su- Cerebral white mat- ter hyperintensity predicts cardiovascular events perior-quality cohort studies are needed on risk in haemodialysis patients. Nephrology (Carlton) factors, therapies and AD that report age, rela- 2013; 18: 676-681. ted drug treatments, neuropsychiatric symptoms, 5) Asada T. [Prevalence of dementia in Japan: past, treatment span, etc. The definition of type and present and future]. Rinsho Shinkeigaku 2012; 52: intensity of cognitive loss deserves special con- 962-964. sideration. The cerebrovascular status that also 6) Singhal BS, Khadilkar SV. Neurology in the deve- determines the extent of AD pathogenesis [90] loping world. Handb Clin Neurol 2014; 121: 1773- demands investigation. Most importantly, for all 1782. Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT. meta-analysis studies, RCTs with larger sample 7) Neuropathological alterations in Alzheimer di- size and population and for longer follow-up pe- sease. Cold Spring Harb Perspect Med 2011; 1: riods are essential. a006189.

4813 C.-H. Wang, L.-S. Wang, N. Zhu

8) Stancu IC, Ris L, Vasconcelos B, Marinangeli C, synaptic function during aging and Alzheimer’s Goeminne L, Laporte V, Haylani LE, Couturier J, disease. Behav Brain Res 2016; S0166-4328: Schakman O, Gailly P, Pierrot N, Kienlen-Campard P, 30278-30279 Octave JN, Dewachter I. Tauopathy contributes to 21) Owen RT. Memantine and donepezil: a fixed drug synaptic and cognitive deficits in a murine model combination for the treatment of moderate to se- for Alzheimer’s disease. FASEB J 2014; 28: 2620- vere Alzheimer’s dementia. Drugs Today (Barc) 2631. 2016; 52: 239-248. Hollands C, Bartolotti N, Lazarov O 9) . Alzheimer’s 22) Auriel E, Regev K, Korczyn AD. Nonsteroidal an- disease and hippocampal adult neurogenesis; ti-inflammatory drugs exposure and the central exploring shared mechanisms. Front Neurosci nervous system. Handb Clin Neurol 2014; 119: 2016; 10: 178. 577-584. Raskin J, Cummings J, Hardy J, Schuh K, Dean RA. 10) 23) Anand P, Singh B. A review on cholinesterase inhi- Neurobiology of Alzheimer’s disease: integrated bitors for Alzheimer’s disease. Arch Pharm Res molecular, physiological, anatomical, biomarker, 2013; 36: 375-399. and cognitive dimensions. Curr Alzheimer Res Singh S, Kushwah AS, Singh R, Farswan M, Kaur 2015; 12: 712-722. 24) R. Current therapeutic strategy in Alzheimer’s Scarabino D, Gambina G, Broggio E, Pelliccia F, 11) disease. Eur Rev Med Pharmacol Sci 2012; 16: Corbo RM . Influence of family history of dementia 1651-1664. in the development and progression of late-onset 25) Noshita T, Murayama N, Nakamura S. Effect of nico- Alzheimer’s disease. Am J Med Genet B Neurop- tine on neuronal dysfunction induced by intrace- sychiatr Genet 2016; 171B: 250-256. rebroventricular infusion of amyloid-beta peptide Lardenoije R, Iatrou A, Kenis G, Kompotis K, Steinbu- 12) in rats. Eur Rev Med Pharmacol Sci 2015; 19: sch HW, Mastroeni D, Coleman P, Lemere CA, Hof 334-343. PR, van den Hove DL, Rutten BP. The epigenetics 26) Cheng XL, Li MK. Effect of topiramate on apopto- of aging and neurodegeneration. Prog Neurobiol sis-related protein expression of hippocampus in 2015; 131: 21-64. model rats with Alzheimers disease. Eur Rev Med 13) Hullinger R, Puglielli L. Molecular and cellular Pharmacol Sci 2014; 18: 761-768. aspects of age-related cognitive decline and Al- 27) Guo CN, Sun L, Liu GL, Zhao SJ, Liu WW, Zhao YB. zheimer’s disease. Behav Brain Res 2016; may Protective effect of nicotine on the cultured rat ba- 16. sal forebrain neurons damaged by beta-Amyloid 14) Ryan NS, Rossor MN. Correlating familial Alzhei- (Abeta)25-35 protein cytotoxicity. Eur Rev Med mer’s disease gene mutations with clinical phe- Pharmacol Sci 2015; 19: 2964-2972. notype. Biomark Med 2010; 4: 99-112. 28) Miguel-Alvarez M, Santos-Lozano A, Sanchis-Gomar 15) Xu W, Tan L, Wang HF, Jiang T, Tan MS, Tan L, F, Fiuza-Luces C, Pareja-Galeano H, Garatachea N, Zhao QF, Li JQ, Wang J, Yu JT. Meta-analysis of Lucia A. Non-steroidal anti-inflammatory drugs as modifiable risk factors for Alzheimer’s disease. a treatment for Alzheimer’s disease: a systematic J Neurol Neurosurg Psychiatry 2015; 86: 1299- review and meta-analysis of treatment effect. 1306. Drugs Aging 2015; 32: 139-147. 16) Lyall DM, Ward J, Ritchie SJ, Gail D, Cullen B, 29) Wang J, Tan L, Wang HF, Tan CC, Meng XF, Wang C, Celis C, Bailey ME, Anderson J, Evans J, McKay DF, Tang SW, Yu JT. Anti-inflammatory drugs and risk McIntosh AM, Sattar N, Smith DJ, Deary IJ, Pell of Alzheimer’s disease: an updated systematic JP. Alzheimer disease genetic risk factor APOE review and meta-analysis. J Alzheimers Dis 2015; e4 and cognitive abilities in 111,739 UK Biobank 44: 385-396. participants. Age Ageing 2016; 45: 511-517. 30) Inestrosa NC, Sagal JP, Colombres M. Acetylcholine- 17) Shi J, Lepore N, Gutman BA, Thompson PM, Baxter sterase interaction with Alzheimer amyloid beta. LC, Caselli RJ, Wang Y. Alzheimer’s disease neu- Subcell Biochem 2005; 38: 299-317. roimaging I. Genetic influence of apolipoprotein 31) Tan CC, Yu JT, Wang HF, Tan MS, Meng XF, Wang C, E4 genotype on hippocampal morphometry: An Jiang T, Zhu XC, Tan L. Efficacy and safety of done- N = 725 surface-based Alzheimer’s disease neu- pezil, galantamine, rivastigmine, and memantine roimaging initiative study. Hum Brain Mapp 2014; for the treatment of Alzheimer’s disease: a syste- 35: 3903-3918. matic review and meta-analysis. J Alzheimers Dis 18) Wang YQ, Qu DH, Wang K. Therapeutic approa- 2014; 41: 615-631. ches to Alzheimer’s disease through stimulating 32) Galimberti D, Scarpini E. Old and new acetylcholi- of non-amyloidogenic processing of amyloid pre- nesterase inhibitors for Alzheimer’s Disease. cursor protein. Eur Rev Med Pharmacol Sci 2016; Expert Opin Investig Drugs 2016; 25: 1181- 20: 2389-2403. 1187. 19) Rogers JT, Lahiri DK. Metal and inflammatory tar- 33) Plosker GL. Memantine extended release (28 mg gets for Alzheimer’s disease. Curr Drug Targets once daily): a review of its use in Alzheimer’s 2004; 5: 535-551. disease. Drugs 2015; 75: 887-897. 20) Foster TC, Kyritsopoulos C, Kumar A. Central role for 34) Thompson S, Lanctot KL, Herrmann N. The benefits NMDA receptors in redox mediated impairment of and risks associated with cholinesterase inhibitor

4814 A systematic umbrella review and meta-analysis of Alzheimer’s disease therapies

therapy in Alzheimer’s disease. Expert Opin Drug MF, Grimmer T, Hampel H, Hausner L, Hellwig S, Saf 2004; 3: 425-440. Herukka SK, Hildebrandt H, Ishihara L, Ivanoiu A, Jagust WJ, Johannsen P, Kandimalla R, Kapaki E, 35) Matsunaga S, Kishi T, Iwata N. Combination therapy Klimkowicz-Mrowiec A, Klunk WE, Kohler S, Koglin with cholinesterase inhibitors and memantine for N, Kornhuber J, Kramberger MG, Van Laere K, Landau Alzheimer’s disease: a systematic review and me- SM, Lee DY, de Leon M, Lisetti V, Lleo A, Madsen K, ta-analysis. Int J Neuropsychopharmacol 2014; Maier W, Marcusson J, Mattsson N, de Mendonca 28: 18 pii: pyu115. A, Meulenbroek O, Meyer PT, Mintun MA, Mok V, Rosen WG, Mohs RC, Davis KL. 36) A new rating scale Molinuevo JL, Mollergard HM, Morris JC, Mroczko for Alzheimer’s disease. Am J Psychiatry 1984; B, Van der Mussele S, Na DL, Newberg A, Nordberg 141: 1356-1364. A, Nordlund A, Novak GP, Paraskevas GP, Parnetti 37) Gupta PP, Pandey RD, Jha D, Shrivastav V, Kumar S. L, Perera G, Peters O, Popp J, Prabhakar S, Rabinovici Role of traditional nonsteroidal anti-inflammatory GD, Ramakers IH, Rami L, Resende de Oliveira C, Rinne drugs in Alzheimer’s disease: a meta-analysis of JO, Rodrigue KM, Rodriguez-Rodriguez E, Roe CM, randomized clinical trials. Am J Alzheimers Dis Rot U, Rowe CC, Ruther E, Sabri O, Sanchez-Juan Other Demen 2015; 30: 178-182. P, Santana I, Sarazin M, Schroder J, Schutte C, Seo 38) Szekely CA, Thorne JE, Zandi PP, Ek M, Messias E, SW, Soetewey F, Soininen H, Spiru L, Struyfs H, Teu- Breitner JC, Goodman SN. Nonsteroidal anti-in- nissen CE, Tsolaki M, Vandenberghe R, Verbeek MM, flammatory drugs for the prevention of Alzhei- Villemagne VL, Vos SJ, van Waalwijk van Doorn LJ, mer’s disease: a systematic review. Neuroepide- Waldemar G, Wallin A, Wallin AK, Wiltfang J, Wolk miology 2004; 23: 159-169. DA, Zboch M, Zetterberg H. Prevalence of cerebral 39) Catalan-Matamoros D, Gomez-Conesa A, Stubbs B, amyloid pathology in persons without dementia: a Vancampfort D. Exercise improves depressive meta-analysis. JAMA 2015; 313: 1924-1938. symptoms in older adults: an umbrella review of 47) Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni systematic reviews and meta-analyses. Psychia- L, Wahlund LO, Nordberg A, Backman L, Albert M, try Res 2016; 244: 202-209. Almkvist O, Arai H, Basun H, Blennow K, de Leon 40) Bellou V, Belbasis L, Tzoulaki I, Evangelou E, Ioanni- M, DeCarli C, Erkinjuntti T, Giacobini E, Graff C, dis JP. Environmental risk factors and Parkinson’s Hardy J, Jack C, Jorm A, Ritchie K, van Duijn C, Visser disease: an umbrella review of meta-analyses. P, Petersen RC. Mild cognitive impairment-beyond Parkinsonism Relat Disord 2016; 23: 1-9. controversies, towards a consensus: report of the 41) Campbell JM, Stephenson MD, Bateman E, Peters MD, International Working Group on Mild Cognitive Keefe DM, Bowen JM. Irinotecan-induced toxicity Impairment. J Intern Med 2004; 256: 240-246. pharmacogenetics: an umbrella review of syste- 48) Higgins JP, Thompson SG, Deeks JJ, Altman DG. Me- matic reviews and meta-analyses. Pharmacoge- asuring inconsistency in meta-analyses. Br Med nomics J 2016; doi: 10.1038/tpj.2016.58. [Epub J 2003; 327: 557-560. ahead of print] 49) Jack CR, Jr., Wiste HJ, Weigand SD, Knopman DS, 42) Green S, McDonald S. Cochrane Collaboration: Vemuri P, Mielke MM, Lowe V, Senjem ML, Gunter JL, more than systematic reviews? Intern Med J Machulda MM, Gregg BE, Pankratz VS, Rocca WA, Pe- 2005; 35: 3-4. tersen RC. Age, sex, and APOE epsilon4 effects on 43) Stroup DF, Berlin JA, Morton SC, Olkin I, William- memory, brain structure, and beta-amyloid across son GD, Rennie D, Moher D, Becker BJ, Sipe TA, the adult life span. JAMA Neurol 2015; 72: 511-519. Thacker SB. Meta-analysis of observational studies 50) [Morris JC, Roe CM, Xiong C, Fagan AM, Goate in epidemiology: a proposal for reporting. Meta-a- AM, Holtzman DM, Mintun MA. APOE predicts nalysis Of Observational Studies in Epidemiology amyloid-beta but not tau Alzheimer pathology in (MOOSE) group. JAMA 2000; 283: 2008-2012. cognitively normal aging. Ann Neurol 2010; 67: 44) Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. 122-131. Preferred reporting items for systematic reviews 51) Suri S, Heise V, Trachtenberg AJ, Mackay CE. The and meta-analyses: the PRISMA statement. Int J forgotten APOE allele: a review of the evidence Surg 2010; 8: 336-341. and suggested mechanisms for the protective 45) Barnes DE, Yaffe K. The projected effect of risk fac- effect of APOE varepsilon2. Neurosci Biobehav tor reduction on Alzheimer’s disease prevalence. Rev 2013; 37: 2878-2886. Lancet Neurol 2011; 10: 819-828. 52) Folstein MF, Folstein SE, McHugh PR. “Mini-mental 46) Jansen WJ, Ossenkoppele R, Knol DL, Tijms BM, Schel- state”. A practical method for grading the cogni- tens P, Verhey FR, Visser PJ, Amyloid Biomarker Study tive state of patients for the clinician. J Psychiatr G, Aalten P, Aarsland D, Alcolea D, Alexander M, Res 1975; 12: 189-198. Almdahl IS, Arnold SE, Baldeiras I, Barthel H, van DerSimonian R, Laird N. Berckel BN, Bibeau K, Blennow K, Brooks DJ, van 53) Meta-analysis in clinical Buchem MA, Camus V, Cavedo E, Chen K, Chetelat trials. Control Clin Trials 1986; 7: 177-188. G, Cohen AD, Drzezga A, Engelborghs S, Fagan 54) Riverol M, Slachevsky A, Lopez OL. Efficacy and AM, Fladby T, Fleisher AS, van der Flier WM, Ford tolerability of a combination treatment of me- L, Forster S, Fortea J, Foskett N, Frederiksen KS, mantine and donepezil for Alzheimer’s disease: a Freund-Levi Y, Frisoni GB, Froelich L, Gabryelewicz literature review evidence. Eur Neurol J 2011; 3: T, Gill KD, Gkatzima O, Gomez-Tortosa E, Gordon 15-19.

4815 C.-H. Wang, L.-S. Wang, N. Zhu

55) Tsoi KK, Hirai HW, Chan JY, Kwok TC. Time to treat- 67) Burback D, Molnar FJ, St John P, Man-Son-Hing ment initiation in people with Alzheimer disease: M. Key methodological features of randomized a meta-analysis of randomized controlled trials. J controlled trials of Alzheimer’s disease therapy. Am Med Dir Assoc 2016; 17: 24-30. Minimal clinically important difference, sample si- 56) Lin JS, O’Connor E, Rossom RC, Perdue LA, Eckstrom ze and trial duration. Dement Geriatr Cogn Disord E. Screening for cognitive impairment in older 1999; 10: 534-540. adults: a systematic review for the U.S. Preven- 68) Kobayashi H, Ohnishi T, Nakagawa R, Yoshizawa K. tive Services Task Force. Ann Intern Med 2013; The comparative efficacy and safety of choline- 159: 601-612. sterase inhibitors in patients with mild-to-mode- 57) Lin JS, O’Connor E, Rossom RC, Perdue LA, Burda rate Alzheimer’s disease: a Bayesian network BU, Thompson M, Eckstrom E. In: editors. Scree- meta-analysis. Int J Geriatr Psychiatry 2016; 31: ning for cognitive impairment in older adults: an 892-904. evidence update for the U.S. Preventive Services 69) Schneider LS, Olin JT, Doody RS, Clark CM, Morris Task Force. Rockville (MD): Agency for healthca- JC, Reisberg B, Schmitt FA, Grundman M, Thomas re research and quality (US); 2013; Report No.: RG, Ferris SH. Validity and reliability of the Alzhei- 14-05198-EF-1. mer’s disease cooperative study-clinical global 58) Tariot PN, Farlow MR, Grossberg GT, Graham SM, Mc- impression of change. The Alzheimer’s Disease Donald S, Gergel I, Memantine Study G. Memantine tre- Cooperative Study. Alzheimer Dis Assoc Disord atment in patients with moderate to severe Alzheimer 1997; 11 Suppl 2: S22-32. disease already receiving donepezil: a randomized 70) van Valkenhoef G, Lu G, de Brock B, Hillege H, Ades controlled trial. JAMA 2004; 291: 317-324. AE, Welton NJ. Automating network meta-analy- 59) Howard R, McShane R, Lindesay J, Ritchie C, Baldwin sis. Res Synth Methods 2012; 3: 285-299. A, Barber R, Burns A, Dening T, Findlay D, Holmes 71) Hansen RA, Gartlehner G, Webb AP, Morgan LC, C, Hughes A, Jacoby R, Jones R, Jones R, McKeith I, Moore CG, Jonas DE. Efficacy and safety of do- Macharouthu A, O’Brien J, Passmore P, Sheehan B, nepezil, galantamine, and rivastigmine for the Juszczak E, Katona C, Hills R, Knapp M, Ballard C, treatment of Alzheimer’s disease: a systematic Brown R, Banerjee S, Onions C, Griffin M, Adams J, review and meta-analysis. Clin Interv Aging 2008; Gray R, Johnson T, Bentham P, Phillips P. Donepezil 3: 211-225. and memantine for moderate-to-severe Alzhei- 72) Wang J, Yu JT, Wang HF, Meng XF, Wang C, Tan mer’s disease. N Engl J Med 2012; 366: 893-903. CC, Tan L. Pharmacological treatment of neurop- 60) Porsteinsson AP, Grossberg GT, Mintzer J, Olin JT, sychiatric symptoms in Alzheimer’s disease: a Memantine MEMMDSG. Memantine treatment in systematic review and meta-analysis. J Neurol patients with mild to moderate Alzheimer’s dise- Neurosurg Psychiatry 2015; 86: 101-109. ase already receiving a cholinesterase inhibitor: 73) Lyketsos CG, Reichman WE, Kershaw P, Zhu Y. a randomized, double-blind, placebo-controlled Long-term outcomes of galantamine treatment trial. Curr Alzheimer Res 2008; 5: 83-89. in patients with Alzheimer disease. Am J Geriatr 61) Schneider LS, Insel PS, Weiner MW, Alzheimer’s Dise- Psychiatry 2004; 12: 473-482. ase Neuroimaging I . Treatment with cholinesterase 74) Landi F, Cesari M, Onder G, Russo A, Torre S, inhibitors and memantine of patients in the Al- Bernabei R. Non-steroidal anti-inflammatory drug zheimer’s Disease Neuroimaging Initiative. Arch (NSAID) use and Alzheimer disease in communi- Neurol 2011; 68: 58-66. ty-dwelling elderly patients. Am J Geriatr Psychia- 62) Riepe MW, Adler G, Ibach B, Weinkauf B, Tracik F, try 2003; 11: 179-185. Gunay I. Domain-specific improvement of cogni- 75) Zandi PP, Anthony JC, Hayden KM, Mehta K, Mayer tion on memantine in patients with Alzheimer’s L, Breitner JC, Cache County Study I. Reduced disease treated with rivastigmine. Dement Geriatr incidence of AD with NSAID but not H2 receptor Cogn Disord 2007; 23: 301-306. antagonists: the Cache County Study. Neurology 63) Atri A, Shaughnessy LW, Locascio JJ, Growdon JH. 2002; 59: 880-886. Long -term course and effectiveness of combina- 76) Lindsay J, Laurin D, Verreault R, Hebert R, Helliwell tion therapy in Alzheimer disease. Alzheimer Dis B, Hill GB, McDowell I. Risk factors for Alzhei- Assoc Disord 2008; 22: 209-221. mer’s disease: a prospective analysis from the 64) Quinn J, Moore M, Benson DF, Clark CM, Doody R, canadian study of health and aging. Am J Epide- Jagust W, Knopman D, Kaye JA. A videotaped CIBIC miol 2002; 156: 445-453. for dementia patients: validity and reliability in a si- 77) Hamrick I, Hafiz R, Cummings DM. Use of days of mulated . Neurology 2002; 58: 433-437. the week in a modified mini-mental state exam 65) Joffres C, Bucks RS, Haworth J, Wilcock GK, Rockwo- (M-MMSE) for detecting geriatric cognitive im- od K. Patterns of clinically detectable treatment pairment. J Am Board Fam Med 2013; 26: 429- effects with galantamine: a qualitative analysis. 435. Dement Geriatr Cogn Disord 2003; 15: 26-33. 78) Kolibas E, Korinkova V, Novotny V, Vajdickova K, 66) Jaeschke R, Singer J, Guyatt GH. Measurement of Hunakova D. ADAS-cog (Alzheimer’s disease as- health status. Ascertaining the minimal clinically sessment scale-cognitive subscale)-validation of important difference. Control Clin Trials 1989; 10: the slovak version. Bratisl Lek Listy 2000; 101: 407-415. 598-602.

4816 A systematic umbrella review and meta-analysis of Alzheimer’s disease therapies

79) Tschanz JT, Corcoran CD, Schwartz S, Treiber K, Gre- in Alzheimer’s disease]. Neurol Neurochir Pol en RC, Norton MC, Mielke MM, Piercy K, Steinberg 2010; 44: 65-79. M, Rabins PV, Leoutsakos JM, Welsh-Bohmer KA, 85) Williams DK, Wang J, Papke RL. Positive allosteric Breitner JC, Lyketsos CG . Progression of cogni- modulators as an approach to nicotinic acetylcholi- tive, functional, and neuropsychiatric symptom ne receptor-targeted therapeutics: advantages and domains in a population cohort with Alzheimer limitations. Biochem Pharmacol 2011; 82: 915-930. dementia: the cache county dementia progres- 86) Pandya A, Yakel JL. Allosteric modulators of the sion study. Am J Geriatr Psychiatry 2011; 19: alpha4beta2 subtype of neuronal nicotinic acetyl- 532-542. choline receptors. Biochem Pharmacol 2011; 82: 80) Bax L, Yu LM, Ikeda N, Tsuruta H, Moons KG. De- 952-958. velopment and validation of MIX: comprehensive 87) Chung JK, Nakajima S, Plitman E, Iwata Y, Uy free software for meta-analysis of causal resear- D, Gerretsen P, Caravaggio F, Chakravarty MM, ch data. BMC Med Res Methodol 2006; 6: 50. Graff-Guerrero A. Beta-Amyloid Burden is not as- 81) Neyeloff JL, Fuchs SC, Moreira LB. Meta-analyses sociated with cognitive impairment in schizophre- and Forest plots using a microsoft excel spread- nia: a systematic review. Am J Geriatr Psychiatry sheet: step-by-step guide focusing on descriptive 2016; 24: 923-939. data analysis. BMC Res Notes 2012; 5: 52. 88) McClam TD, Marano CM, Rosenberg PB, Lyketsos 82) Etminan M, Gill S, Samii A. Effect of non-steroidal CG. Interventions for neuropsychiatric symptoms anti-inflammatory drugs on risk of Alzheimer’s in neurocognitive impairment due to Alzheimer’s disease: systematic review and meta-analysis of disease: a review of the literature. Harv Rev observational studies. Br Med J 2003; 327: 128. Psychiatry 2015; 23: 377-393. 83) Group AR, Martin BK, Szekely C, Brandt J, Piantadosi 89) Group A-FR. Follow-up evaluation of cognitive fun- S, Breitner JC, Craft S, Evans D, Green R, Mullan ction in the randomized Alzheimer’s disease anti-in- M. Cognitive function over time in the Alzhei- flammatory prevention trial and its follow-up study. mer’s Disease Anti-inflammatory Prevention Trial Alzheimers Dement 2015; 11: 216-225 e211. (ADAPT): results of a randomized, controlled trial 90) Ashok A, Rai NK, Raza W, Pandey R, Bandyopa- of naproxen and celecoxib. Arch Neurol 2008; 65: dhyay S. Chronic cerebral hypoperfusion-induced 896-905. impairment of Abeta clearance requires HB-E- 84) Cakala M, Strosznajder JB. [The role of cyclooxy- GF-dependent sequential activation of HIF1alpha genases in neurotoxicity of amyloid beta peptides and MMP9. Neurobiol Dis 2016; 95: 179-193.

4817