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The Efficacy and Safety of Alzheimer's Disease Therapies: An Updated Umbrella Review.
Fan, F, Liu, H, Shi, X, Ai, Y, Liu, Q, Cheng, Y
Journal of Alzheimer's disease : JAD. 2022;(3):1195-1204
Abstract
BACKGROUND Evidence summaries for efficacy and safety of frequently employed treatments of Alzheimer's disease (AD) are sparse. OBJECTIVE We aimed to perform an updated umbrella review to identify an efficacious and safe treatment for AD patients. METHODS We conducted a search for meta-analyses and systematic reviews on the Embase, PubMed, The Cochrane Library, and Web of Science to address this knowledge gap. We examined the cognitive functions, behavioral symptoms, global clinical assessment, and Activities of Daily Living as efficacy endpoints, and the incidence of adverse events as safety profiles. RESULTS Sixteen eligible papers including 149 studies were included in the umbrella review. The results showed that AChE inhibitors (donepezil, galantamine, rivastigmine, Huperzine A), Ginkgo biloba, and cerebrolysin appear to be beneficial for cognitive, global performances, and activities of daily living in patients with AD. Furthermore, anti-Aβ agents are unlikely to have an important effect on slowing cognitive or functional impairment in mild to moderate AD. CONCLUSION Our study demonstrated that AChE inhibitors, Ginkgo biloba, and cerebrolysin are the optimum cognitive and activities of daily living medication for patients with AD.
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Effects of vitamin E supplementation on the risk and progression of AD: a systematic review and meta-analysis.
Wang, W, Li, J, Zhang, H, Wang, X, Zhang, X
Nutritional neuroscience. 2021;(1):13-22
Abstract
Objective: The association between vitamin E supplementation and Alzheimer's disease (AD) was controversial because of conflicting data in the literature. This study was designed to systematically evaluate evidence about the efficacy of vitamin E supplementation not only on the risk but also on the progression of AD. Design: Five electronic databases were searched for studies published up to June 2017. Articles reporting vitamin E supplementation and AD were included, and the random-effect model was performed for the meta-analysis about the relationship between vitamin E supplementation and AD. Results: Five cohort studies and three randomized controlled trial (RCT) studies (total n = 14,262) involving 1313 cases about vitamin E effects on the risk of AD and 244 cases about effects on progression of AD. The pooled RR for vitamin E supplemental and risk of AD was 0.81 [95% CI: 0.50-1.33, I 2 = 69.2%]. Suitable data could not be extracted to do meta-analysis as there was no unified standard of outcome measure for studies on AD progression. We carefully analyzed and evaluated the authenticity and accuracy of every single trial, while reliable evidence could not be obtained. Conclusions: From what we do, neither the synthetic data on risk of AD nor the critical review on progression of AD could provide enough evidence on our research. Thus, we cannot draw a specific conclusion on the association or correlation between Vitamin E and AD.
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Lipid lowering and Alzheimer disease risk: A mendelian randomization study.
Williams, DM, Finan, C, Schmidt, AF, Burgess, S, Hingorani, AD
Annals of neurology. 2020;(1):30-39
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Abstract
OBJECTIVE To examine whether genetic variation affecting the expression or function of lipid-lowering drug targets is associated with Alzheimer disease (AD) risk, to evaluate the potential impact of long-term exposure to corresponding therapeutics. METHODS We conducted Mendelian randomization analyses using variants in genes that encode the protein targets of several approved lipid-lowering drug classes: HMGCR (encoding the target for statins), PCSK9 (encoding the target for PCSK9 inhibitors, eg, evolocumab and alirocumab), NPC1L1 (encoding the target for ezetimibe), and APOB (encoding the target of mipomersen). Variants were weighted by associations with low-density lipoprotein cholesterol (LDL-C) using data from lipid genetics consortia (n up to 295,826). We meta-analyzed Mendelian randomization estimates for regional variants weighted by LDL-C on AD risk from 2 large samples (total n = 24,718 cases, 56,685 controls). RESULTS Models for HMGCR, APOB, and NPC1L1 did not suggest that the use of related lipid-lowering drug classes would affect AD risk. In contrast, genetically instrumented exposure to PCSK9 inhibitors was predicted to increase AD risk in both of the AD samples (combined odds ratio per standard deviation lower LDL-C inducible by the drug target = 1.45, 95% confidence interval = 1.23-1.69). This risk increase was opposite to, although more modest than, the degree of protection from coronary artery disease predicted by these same methods for PCSK9 inhibition. INTERPRETATION We did not identify genetic support for the repurposing of statins, ezetimibe, or mipomersen for AD prevention. Notwithstanding caveats to this genetic evidence, pharmacovigilance for AD risk among users of PCSK9 inhibitors may be warranted. ANN NEUROL 2020;87:30-39.
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Effectiveness of omega-3 fatty acid supplementation in patients with Alzheimer disease: A systematic review and meta-analysis.
Araya-Quintanilla, F, Gutiérrez-Espinoza, H, Sánchez-Montoya, U, Muñoz-Yañez, MJ, Baeza-Vergara, A, Petersen-Yanjarí, M, Fernández-Lecaros, L
Neurologia. 2020;(2):105-114
Abstract
INTRODUCTION Alzheimer disease (AD) is a neurodegenerative disease characterised by progressive dementia associated with global cognitive dysfunction. METHODS We conducted a systematic review and meta-analysis of clinical trials evaluating omega-3 supplementation in patients with AD. OBJECTIVE To determine if there is scientific evidence of the effectiveness of omega-3 supplementation in improving cognitive function in patients with AD. SEARCH STRATEGY We included only randomised controlled trials (RCTs) from the following databases: Medline, Cochrane Central, Cinahl, and LILACS. An electronic search was also conducted using Google Scholar. STUDY SELECTION Six articles met the eligibility criteria. The risk of bias was assessed following the Cochrane method. CONCLUSION There is no consistent evidence to support the effectiveness of omega-3 supplementation in improving cognitive function in AD patients in the short and medium term.
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Postmenopausal hormone therapy and Alzheimer's disease, dementia, and Parkinson's disease: A systematic review and time-response meta-analysis.
Wu, M, Li, M, Yuan, J, Liang, S, Chen, Z, Ye, M, Ryan, PM, Clark, C, Tan, SC, Rahmani, J, et al
Pharmacological research. 2020;:104693
Abstract
Hormone therapy continues to be a favourable option in the management of menopausal symptomatology, but the associated risk-benefit ratios with respect to neurodegenerative diseases remain controversial. The study aim was to determine the relation between menopausal hormone therapy and Alzheimer's disease, dementia, and Parkinson's disease in human subjects. A literature search was performed in PubMed/Medline, Cochrane collaboration, and Scopus databases from onset of the database to September 2019. Random-effects model was used to estimate pooled odd ratio (OR) and 95 % confidence intervals (CI). Subgroup analysis was performed based on the type and formulation of hormone. In addition, the time-response effect of this relationship was also assessed based on duration of hormone therapy. Associations between hormone therapy and Alzheimer's disease, dementia, and Parkinson's disease in menopausal women were reported in 28 studies. Pooled results with random effect model showed a significant association between hormone therapy and Alzheimer's disease (OR 1.08, 95 % CI 1.03-1.14, I2: 69 %). This relationship was more pronounced in patients receiving the combined estrogen-progestogen formulation. Moreover, a significant non-linear time-response association between hormone therapy and Alzheimer's disease was also identified (Coef1 = 0.0477, p1<0.001; Coef2 = -0.0932, p2<0.001). Similarly, pooled analysis revealed a significant association between hormone therapy and all-cause dementia (OR 1.16, 95 % CI 1.02-1.31, I2: 19 %). Interestingly, no comparable relationship was uncovered between hormone therapy as a whole and Parkinson's disease (OR 1.14, 95 % CI 0.95-1.38, I2: 65 %); however, sub-group analysis revealed a significant relationship between the disease and progestogen (OR 3.41, 95 % CI 1.23-9.46) or combined estrogen-progestogen formulation use (OR 1.49, 95 % CI 1.34-1.65). Indeed, this association was also found to be driven by duration of exposure (Coef1 = 0.0626, p1 = 0.04). This study reveals a significant direct relationship between the use of certain hormonal therapies and Alzheimer's disease, all-cause dementia, and Parkinson's disease in menopausal women. However, the association appears to shift in direct after five years in the context of Alzheimer's disease, adding further weight to the critical window or timing hypothesis of neurodegeneration and neuroprotection.
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Elevated serum TC and LDL-C levels in Alzheimer's disease and mild cognitive impairment: A meta-analysis study.
Liu, Y, Zhong, X, Shen, J, Jiao, L, Tong, J, Zhao, W, Du, K, Gong, S, Liu, M, Wei, M
Brain research. 2020;:146554
Abstract
Serum lipid levels such as triglyceride and cholesterol has been reported to play an important role in the pathophysiological process of Alzheimer disease (AD) and mild cognitive impairment (MCI). However, it still remains controversial in different studies. Here, we performed a meta-analysis to assess the importance of serum levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) in AD and MCI patients. PubMed, China National Knowledge Infrastructure (CNKI) system database were used to identify 17 studies (10 AD-only + 4 MCI-only + 3 shared AD/MCI), including 2333 cases and 3615 healthy controls (HC). We found that compared with HC, both the serum TC levels [SMD = 0.58; 95%CI (0.25, 0.90); P = 0.001) and the serum LDL-C levels [SMD = 0.7780; 95%CI (0.3940, 1.1521); P = 0.000] were higher in cognitive impairment population (including AD and MCI) than those in HC, respectively. Furthermore, we analyzed the serum TC and LDL-C levels in AD and MCI patients. We found that the serum TC levels [SMD = 0.76; 95% CI (0.13, 1.40); P = 0.019]1 and the LDL-C levels [SMD = 1.40; 95% CI (0.70, 2.10; P = 0.000] were increased in AD patients. In the MCI patients, the serum TC levels [SMD = 0.30; 95%CI (0.01, 0.59); P = 0.041] had a significantly upward trend, while the LDL-C levels had no significant change, compared with HC subjects. However, there is no significant changes in HDL-C and TG levels in AD or MCI patients. Therefore, our results suggested that the elevated TC and LDL-C levels may be a potential risk factor for cognitive impairment.
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Evidence-based prevention of Alzheimer's disease: systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials.
Yu, JT, Xu, W, Tan, CC, Andrieu, S, Suckling, J, Evangelou, E, Pan, A, Zhang, C, Jia, J, Feng, L, et al
Journal of neurology, neurosurgery, and psychiatry. 2020;(11):1201-1209
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BACKGROUND Evidence on preventing Alzheimer's disease (AD) is challenging to interpret due to varying study designs with heterogeneous endpoints and credibility. We completed a systematic review and meta-analysis of current evidence with prospective designs to propose evidence-based suggestions on AD prevention. METHODS Electronic databases and relevant websites were searched from inception to 1 March 2019. Both observational prospective studies (OPSs) and randomised controlled trials (RCTs) were included. The multivariable-adjusted effect estimates were pooled by random-effects models, with credibility assessment according to its risk of bias, inconsistency and imprecision. Levels of evidence and classes of suggestions were summarised. RESULTS A total of 44 676 reports were identified, and 243 OPSs and 153 RCTs were eligible for analysis after exclusion based on pre-decided criteria, from which 104 modifiable factors and 11 interventions were included in the meta-analyses. Twenty-one suggestions are proposed based on the consolidated evidence, with Class I suggestions targeting 19 factors: 10 with Level A strong evidence (education, cognitive activity, high body mass index in latelife, hyperhomocysteinaemia, depression, stress, diabetes, head trauma, hypertension in midlife and orthostatic hypotension) and 9 with Level B weaker evidence (obesity in midlife, weight loss in late life, physical exercise, smoking, sleep, cerebrovascular disease, frailty, atrial fibrillation and vitamin C). In contrast, two interventions are not recommended: oestrogen replacement therapy (Level A2) and acetylcholinesterase inhibitors (Level B). INTERPRETATION Evidence-based suggestions are proposed, offering clinicians and stakeholders current guidance for the prevention of AD.
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A systematic review and meta-analysis of the associations of vitamin D receptor genetic variants with two types of most common neurodegenerative disorders.
Geng, J, Zhang, J, Yao, F, Liu, X, Liu, J, Huang, Y
Aging clinical and experimental research. 2020;(1):21-27
Abstract
BACKGROUND Whether vitamin D receptor (VDR) genetic variants influence individual susceptibility to neurodegenerative disorders remains controversial. AIMS This meta-analysis was conducted to analyze correlations of VDR genetic variants with two types of most common neurodegenerative disorders, Parkinson's disease (PD) and Alzheimer's disease (AD). METHODS Systematic literature research of PubMed and Embase was performed to identify eligible articles. Q test and I2 statistic were employed to decide whether pooled analyses would be performed with random-effect models (REMs) or fixed-effect models (FEMs). All statistical analyses were conducted with Review Manager. RESULTS Totally sixteen studies were enrolled for analyses. Among these eligible studies, ten studies were about PD (2356 cases and 2815 controls) and six studies were about AD (1256 cases and 1205 controls). Pooled overall analyses suggested that VDR rs7975232 (additive model: p = 0.03, OR = 1.19, 95% CI 1.01-1.39) and rs2228570 (recessive model: p < 0.008, OR = 1.26, 95% CI 1.06-1.50; allele model: p < 0.001, OR = 0.80, 95% CI 0.71-0.91) variants were significantly correlated with PD, and VDR rs731236 (dominant model: p = 0.003, OR = 0.70, 95% CI 0.56-0.89; additive model: p = 0.02, OR = 1.32, 95% CI 1.06-1.66; allele model: p = 0.02, OR = 0.82, 95% CI 0.69-0.96) variant was significantly correlated with AD. Further subgroup analyses by ethnicity revealed that the positive results were mainly driven by the Asians, whereas no significant associations were observed in Caucasians. CONCLUSION Our meta-analysis suggested that VDR rs7975232 and rs2228570 variants might serve as genetic biomarkers of PD, whereas VDR rs731236 variant might serve as a genetic biomarker of AD.
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Vitamin D deficiency as a risk factor for dementia and Alzheimer's disease: an updated meta-analysis.
Chai, B, Gao, F, Wu, R, Dong, T, Gu, C, Lin, Q, Zhang, Y
BMC neurology. 2019;(1):284
Abstract
BACKGROUND We aimed to comprehensively explore the associations between serum 25(OH)D deficiency and risk of dementia and Alzheimer's disease(AD). METHODS We systematically searched Pubmed, the Cochrane Library, Embase and the reference lists of pertinent review articles for relevant articles published from database inception up until January 2019. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with random effects models using the Stata 12.0 statistical software package. RESULTS Twelve prospective cohort studies and four cross-sectional studies were included in this meta-analysis. The pooled HRs of dementia and AD, respectively, were 1.32 (95%CI: 1.16, 1.52) and 1.34 (95%CI: 1.13, 1.60) for vitamin D deficiency (< 20 ng/ml). In the subgroup analyses, the pooled HRs of dementia and AD, respectively, were 1.48 (95%CI: 1.19, 1.85) and 1.51 (95%CI: 1.04, 2.18) for moderate vitamin D deficiency (10-20 ng/ml) and 1.20 (95%CI: 0.99, 1.44) and 1.36 (95%CI: 1.01, 1.84) for severe vitamin D deficiency (< 10 ng/ml). CONCLUSION There are significant associations between vitamin D deficiency and both dementia and AD. There are stronger associations between severe vitamin D deficiency (< 10 ng/ml) and both dementia and AD compared to moderate vitamin D deficiency (10-20 ng/ml).
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Vitamin D concentration and risk of Alzheimer disease: A meta-analysis of prospective cohort studies.
Yang, K, Chen, J, Li, X, Zhou, Y
Medicine. 2019;(35):e16804
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BACKGROUND Considerable controversy exists on the association between serum vitamin D concentrations and Alzheimer disease (AD) risk. This study aimed to synthesize the association of serum vitamin D concentrations with AD in adults. METHODS PubMed, Embase, and Cochrane library databases were searched for prospective cohort studies with data on serum vitamin D concentrations and AD risk. RESULT The studies that reported the adjusted relative risks (RRs) with 95% confidence intervals (CIs) of AD associated with serum vitamin D concentrations were included and subjected to subgroup analyses. Six prospective cohort studies with 1607 AD cases and 21,692 individuals were included in the meta-analysis. In 4 cohort studies with information about serum vitamin D concentrations <25 and 25 to 50 nmol/L, the random effects summary estimate did not show an increased risk of AD after adjustment for the established risk factors, while 3 cohort studies reported the RRs for incident AD per standard deviation (SD) decrease in serum vitamin D concentration and the random effects summary estimate did not show an increased risk of AD after adjustment for the established risk factors. CONCLUSIONS The current meta-analysis indicated that serum vitamin D deficiency (<25 nmol/L) or insufficiency (25-50 nmol/L) was not statistically significant and associated with the risk of AD.