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- amyloid beta (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 research 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 enzyme 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 receptor 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 systematic review 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.