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Central immunity components especially microglia in dementia have been well studied and corresponding immunotherapy gradually caught the attention. However, few studies focused on peripheral immunity and dementia. To address the issue, we examined the longitudinal association between incident dementia and peripheral immunity markers encompassing immune cell counts, and their derived ratios including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and lymphocyte-to-monocyte ratio (LMR), utilizing data of 361,653 participants from the UK Biobank (UKB). During a median follow-up of 8.99 years, 4239 participants developed dementia. The results revealed that increased innate immunity markers were associated with higher dementia risk (per SD increment hazard ratio [HR]; 95% confidence interval [CI] 1.14; 1.09-1.19 for neutrophils, 1.16; 1.11-1.20 for NLR and 1.11; 1.07-1.16 for SII), while increased adaptive immunity markers were associated with lower dementia risk (0.93; 0.90-0.97 for lymphocytes and 0.94; 0.90-0.98 for LMR). Our study pinpoints the differential role of innate and adaptive immunity in dementia incidence, which may provide some new perspectives in etiology and therapy of dementia.

Background: Although social networks are deemed as moderators of incident Alzheimer’s disease (AD), few data are available on the mechanism relevant to AD pathology. Objective: We aimed to investigate whether social networks affect metabolism of cerebrospinal fluid (CSF) AD biomarkers during early stage and identify modification effects of genetic factor and subjective cognitive decline (SCD). Methods: We studied participants from the Chinese Alzheimer’s disease Biomarker and Lifestyle (CABLE) database who received cognition assessments and CSF amyloid-β (Aβ1–42 and Aβ1–40) and tau proteins (total-tau [T-tau] and phosphorylated-tau [P-tau]) measurements. The social networks were measured using self-reported questionnaires about social ties. Linear regression models were used. Results: Data were analyzed from 886 cognitively intact individuals aged 61.91 years (SD = 10.51), including 295 preclinical AD participants and 591 healthy controls. Social networks were mostly associated with CSF indicators of AD multi-pathologies (low P-tau/Aβ1–42 and T-tau/Aβ1–42 and high Aβ1–42/Aβ1–40). Significant differences of genetic and cognitive status were observed for CSF indicators, in which associations of social network scores with CSF P-tau and indicators of multi-pathologies appeared stronger in APOE 4 carriers (versus non-carriers) and participants with SCD (versus controls), respectively. Alternatively, more pronounced associations for CSF T-tau (β= –0.005, p

Background and Purpose The present study aimed to compare the efficacy and tolerability of different blood pressure (BP)-lowering strategies.Methods Randomized controlled trials that compared various antihypertensive treatments and stroke outcomes were included. Eligible trials were categorized into three scenarios: single or combination antihypertensive agents against placebos; single or combination agents against other agents; and different BP-lowering targets. The primary efficacy outcome was the risk reduction pertaining to strokes. The tolerability outcome was the withdrawal of drugs, owing to drug-related side effects (PROSPERO registration number CRD42018118454 [20/12/2018]).Results The present study included 93 trials (average follow-up duration, 3.3 years). In the pairwise analysis, angiotensin-converting enzyme inhibitors (ACEis) and beta-blockers (BBs) were inferior to calcium channel blockers (CCBs) (odds ratio [OR], 1.123; 95% confidence interval [CI], 1.008 to 1.252) (OR, 1.261; 95% CI, 1.116 to 1.425) for stroke prevention, BB was inferior to angiotensin II receptor blockers (ARB) (OR, 1.361; 95% CI, 1.142 to 1.622), and diuretics were superior to ACEi (OR, 0.871; 95% CI, 0.771 to 0.984). The combination of ACEi+CCB was superior to ACEi+diuretic (OR, 0.892; 95% CI, 0.823 to 0.966). The network meta-analysis confirmed that diuretics were superior to BB (OR, 1.34; 95% CI, 1.11 to 1.58), ACEi+diuretic (OR, 1.47; 95% CI, 1.02 to 2.08), BB+CCB (OR, 2.05; 95% CI, 1.05 to 3.79), and renin inhibitors (OR, 1.87; 95% CI, 1.25 to 2.75) for stroke prevention. Regarding the tolerability profile, the pairwise analysis revealed that ACEi was inferior to CCB and less tolerable, compared to the other treatments.Conclusions Monotherapy using diuretics, CCB, or ARB, and their combinations could be employed as first-line treatments for stroke prevention in terms of efficacy and tolerability.

Background: Green tea has been widely recognized in ameliorating cognitive impairment and Alzheimer’s disease (AD), especially the progression of cognitive dysfunction. But the underlying mechanism is still unclear. Objective: This study was designed to determine the role of green tea consumption in the association with cerebrospinal fluid (CSF) biomarkers of AD pathology and to ascertain whether specific population backgrounds showed the differences toward these relationships. Methods: Multivariate linear models analyzed the available data on CSF biomarkers and frequency of green tea consumption of 722 cognitively intact participants from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) database, and we additionally detected the interaction effects of tea consumption with APOE ɛ4 status and gender using a two-way analysis of covariance. Results: Frequent green tea consumption was associated with a decreased level of CSF total-tau protein (t-tau) (p = 0.041) but not with the levels of CSF amyloid-β 42 (Aβ42) and CSF phosphorylated tau. The more pronounced associations of green tea consumption with CSF t-tau (p = 0.007) and CSF t-tau/Aβ42 (p = 0.039) were observed in individuals aged 65 years or younger. Additionally, males with frequent green tea consumption had a significantly low level of CSF t-tau/Aβ42 and a modest trend toward decreased CSF t-tau. There were no interaction effects of green tea consumption with APOE ɛ4 and gender. Conclusion: Collectively, our findings consolidated the favorable effects of green tea on the mitigation of AD risk. The constituents of green tea may improve abnormal tau metabolism and are promising targets in interventions and drug therapies.

The relevance between circulating metabolites and vascular events remains controversial and comprehensive studies are lacking. We sought to investigate the prospective associations of plasma metabolomics with risks of incident stroke, ischemic stroke (IS), hemorrhagic stroke (HS), and myocardial infarction (MI). Within the UK Biobank cohort, 249 circulating metabolites were measured in 90 438 participants without baseline vascular diseases. Cox proportional hazards regressions were applied to estimate adjusted hazard ratios (HRs) for per 1 standard deviation increment in metabolites. The least absolute shrinkage and selection operator algorithm was used for selecting metabolite subsets. During a median of 9.0 years of follow-up, we documented 833 incident stroke and 1256 MI cases. Lipid constituents, comprising cholesterol, cholesteryl esters, free cholesterol, phospholipids, and total lipids, in very low- (VLDL), intermediate- (IDL), and low-density lipoprotein (LDL) particles were positively associated with MI risk (HR = 1.12 to 1.36; 95% CI = 1.06 to 1.44), while in high-density lipoprotein (HDL) particles showed inverse associations (HR = 0.68 to 0.81; 95% CI = 0.63 to 0.87). Similar association pattern with MI was also observed for VLDL, IDL, LDL, and HDL particles themselves. In contrast, triglycerides within all lipoproteins, including most HDL particles, were positively associated with MI risk (HR = 1.14 to 1.28; 95% CI = 1.08 to 1.35) and, to a slightly lesser extent, with stroke and IS. Unsaturation of fatty acids and albumin were inversely associated with risks of stroke, IS, and MI. In contrast, the linear association for HS is absent. When combining multiple metabolites, the metabolite risk score captured a drastically elevated risk of all vascular events, about twice that of any single metabolite. Taken together, circulating metabolites showed remarkably widespread associations with incident MI, but substantially weakened associations with risks of stroke and its subtypes. Exhaustive metabolomics profiling may shed light on vascular risk prediction and, in turn, guide pertinent strategies of intervention and treatment.

As a promising diagnostic and prognostic biomarker for Alzheimer's Disease (AD), plasma p-tau181 is robustly differentiated AD dementia from non-AD neurodegenerative diseases. We aimed to discover single nucleotide polymorphisms (SNPs) associated with plasma phosphorylated tau at threonine 181 (p-tau181) levels that affect the risk of developing AD. We carried out a genome-wide association study for plasma p-tau181 levels using participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The thresholds of P 5 × 10

Dementia and cognitive impairment can be attributed to both genetic and modifiable risk factors. Recently, considerable evidence emerged and urgently require standardized evaluation. To address it, we conducted an umbrella review of prospective studies regarding the associations of dementia and cognitive impairment with modifiable factors to evaluate the strength and validity of the existing evidence. We searched PubMed, Embase, CINAHL and Cochrane Database of Systematic Reviews to identify relevant systematic reviews and meta-analyses of prospective studies. Mendelian randomization studies were reviewed to assess the causality for these associations. For each association, we analyzed the summary effect size, 95% confidence interval, 95% prediction interval, heterogeneity, small study effect and excess significance bias. Based on these estimates, the evidence was graded into levels of convincing, highly suggestive, suggestive, or weak. In total, 12015 articles were identified, of which 118 eligible studies yielded 243 unique associations. Convincing evidence was found for associations of dementia and cognitive impairment with early-life education, midlife to late-life plasma glucose, body mass index, atrial fibrillation, benzodiazepine use, and gait speed. Suggestive to highly suggestive evidence was found for associations of dementia and cognitive impairment with midlife to late-life blood pressure, homocysteine, cerebrovascular diseases, hearing impairment, respiratory illness, anemia, smoking, alcohol consumption, diet, sleep, physical activity and social engagement. Among convincing evidence, Mendelian randomization studies verified genetic predicted causal relationships for education and plasma glucose with Alzheimer's disease. Modifiable factors identified in this study, especially those with high-level evidence, should be considered in dementia prevention. Trial registration: PROSPERO CRD42020195729.

As a marker of neuroaxonal injury, neurofilament light (NFL) in blood is robustly elevated in many neurodegenerative conditions. We aimed to discover single nucleotide polymorphisms (SNPs) associated with longitudinal changes in plasma NFL levels that affect the risk of developing neurodegenerative disease and clinical disease progression. 545 eligible non-Hispanic white participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with longitudinal plasma NFL data were included. Three SNPs (rs16840041, p=4.50×10-8; rs2269714, p=4.50×10-8; rs2269715, p=4.83×10-8) in CD1A were in high linkage disequilibrium (LD) and significantly associated with the increase in plasma NFL levels. We demonstrate a promoting effect of rs16840041-A on clinical disease progression (p = 0.006). Moreover, the minor allele (A) of rs16840041 was significantly associated with accelerated decline in [18F] Fluorodeoxyglucose (FDG) (estimate -1.6% per year [95% CI -0.6 to -2.6], p=0.0024). CD1A is a gene involved in longitudinal changes in plasma NFL levels and AD-related phenotypes among non-demented elders. Given the potential effects of these variants, CD1A should be further investigated as a gene of interest in neurodegenerative diseases and as a potential target for monitoring disease trajectories and treating disease.

Funder: ZHANGJIANG LAB, Tianqiao and Chrissy Chen Institute, and the State Key Laboratory of Neurobiology and Frontiers Center for Brain Science of Ministry of Education, Fudan University, Background: Genome-wide association studies have identified more than 30 Alzheimer’s disease (AD) risk genes, although the detailed mechanism through which all these genes are associated with AD pathogenesis remains unknown. We comprehensively evaluate the roles of the variants in top 30 non-APOE AD risk genes, based on whether these variants were associated with altered mRNA transcript levels, as well as brain amyloidosis, tauopathy, and neurodegeneration. Methods: Human brain gene expression data were obtained from the UK Brain Expression Consortium (UKBEC), while other data used in our study were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. We examined the association of AD risk allele carrier status with the levels of gene expression in blood and brain regions and tested the association with brain amyloidosis, tauopathy, and neurodegeneration at baseline, using a multivariable linear regression model. Next, we analyzed the longitudinal effects of these variants on the change rates of pathology using a mixed effect model. Results: Altogether, 27 variants were detected to be associated with the altered expression of 21 nearby genes in blood and brain regions. Eleven variants (especially novel variants in ADAM10, IGHV1-68, and SLC24A4/RIN3) were associated with brain amyloidosis, 7 variants (especially in INPP5D, PTK2B) with brain tauopathy, and 8 variants (especially in ECHDC3, HS3ST1) with brain neurodegeneration. Variants in ADAMTS1, BZRAP1-AS1, CELF1, CD2AP, and SLC24A4/RIN3 participated in more than one cerebral pathological process. Conclusions: Genetic variants might play functional roles and suggest potential mechanisms in AD pathogenesis, which opens doors to uncover novel targets for AD treatment.

Additional file 1.

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 clinical recommendations on AD prevention. Methods: Electronic databases and relevant websites were searched from inception to March 1, 2019. Both observational prospective studies (OPSs) and randomized 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 recommendations were summarized. Findings: 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, among which 104 modifiable factors and 11 interventions were included for the meta-analyses. In the OPSs, 26 risk factors and 8 protective factors were found to significantly modify AD risk by an effect size of over 25%, amongst which eight factors were rated at a moderate-to-high level of evidence. Among the interventions tested in RCTs, physical exercise and the homocysteine lowering treatment were the most promising interventions to reduce AD risk. Finally, 21 recommendations are proposed based on the consolidated evidence, with 'Class I' recommendations targeting 19 factors: ten are with 'Level A' strong evidence (cognitive activity, hyperhomocysteinemia, high BMI in late-life, depression, stress, diabetes, head trauma, hypertension in midlife, orthostatic hypotension, and education) and nine with 'Level B' weaker evidence (obesity in midlife, weight loss in late-life, physical exercise, smoking, sleep, CVD, frailty, atrial fibrillation, and Vitamin C). In contrast, two interventions are not recommended: estrogen replacement therapy (Level A2) and acetylcholinesterase inhibitors (Level B). Interpretation: Our study mapped the current evidence profile and assessed the findings in order to guide future research directions for AD prevention. Evidence-based recommendations are proposed, offering clinicians and stakeholders current guidance for the prevention of AD. Funding Statement: The authors stated: "There was no direct funding source for this study." Declaration of Interest: JTY serves as an associate editor-in-chief for Annals of Translational Medicine, is senior editor for Journal of Alzheimer's Disease. SA has received grants from Europe, Ipsen, and France Alzheimer, served as a consultant for Ipsen, Pierre Fabre, Lilly, Nestle, Sanof, and Servier, and received non-financial support from Biogen, Nutrition Sante, Pfzer, and Icon, and other support from the AMPA Association. SG has received clinical trial support from Lilly and Roche in DIAN-TU, TauRx Therapeutics (TauRx), and Lundbeck; has been a data safety monitoring board (DSMB) member of ADCS, ATRI, API, and Eisai; and has been a scientific adviser to Affiris, BoehringerIngelheim, Lilly, Roche, Servier, Sanofi, Schwabe, Takeda, and TauRx. PSA has received grants from the US Alzheimer’s Association, Janssen, Lilly, the US National Institute on Aging, and Toyama; and consulting fees from Abbott, Abbvie, Amgen, Anavex, AstraZeneca, Biogen Idec, Biotie, Bristol-Myers Squibb, Cardeus, Cohbar, Eisai, Elan, Eli Lilly, Genentech, Ichor, iPerian, Janssen, Lundbeck, Medivation, Merck, NeuroPhage, Novartis, Pfizer, Probiodrug, Roche, Somaxon, and Toyama, outside the submitted work. BV reports grants from Pierre Fabre, Avid, Exonhit, AbbVie, Lilly, Lundbeck, MSD, Otsuka, Regenron, Sanof, Roche, AstraZeneca, LPG Systems, Nestle, and Alzheon, and personal fees from Lilly, Lundbeck, MSD, Otsuka, Roche, Sanof, Biogen, Nestle, Transition Therapeutics, and Takeda. All other authors declare no competing interests. Ethics Approval Statement: The authors followed the recommendations by the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2009 guidelines.

Background: Amyloid-β (Aβ) plaques and tau neurofibrillary tangles are two neuropathological hallmarks of Alzheimer’s disease (AD), which both can be visualized in vivo using PET radiotracers, opening new opportunities to study disease mechanisms. Objective: Our study investigated 11 non-PET factors in 5 categories (including demographic, clinical, genetic, MRI, and cerebrospinal fluid (CSF) features) possibly affecting PET amyloid and tau status to explore the relationships between amyloid and tau pathology, and whether these features had a different association with amyloid and tau status. Methods: We included 372 nondemented elderly from the Alzheimer’s Disease Neuroimaging Initiative cohort. All underwent PET amyloid and tau analysis simultaneously, and were grouped into amyloid/tau quadrants based on previously established abnormality cut points. We examined the associations of above selected features with PET amyloid and tau status using a multivariable logistic regression model, then explored whether there was an obvious correlation between the significant features and PET amyloid or tau levels. Results: Our results demonstrated that PET amyloid and tau status were differently affected by patient features, and CSF biomarker features provided most significant values associating PET findings. CSF Aβ42/40 was the most important factor affecting amyloid PET status, and negatively correlated with amyloid PET levels. CSF pTau could significantly influence both amyloid and tau PET status. Besides CSF pTau and Aβ42, APOE ɛ4 allele status and Mini-Mental State Examination scores also could influence tau PET status, and significantly correlated with tau PET levels. Conclusion: Our results support that tau pathology possibly affected by Aβ-independent factors, implicating the importance of tau pathology in AD pathogenesis.

Introduction Amyloid beta (Aβ) deposition was identified to precede tau pathology and neurodegeneration in familial Alzheimer's disease (AD). But the divergence between sporadic and familial AD limits the extension of these findings to sporadic AD. Methods Longitudinal changes of biomarkers among different stages were assessed using linear mixed‐effects models. The slopes of the models were used to estimate rates of change to calculate the biomarker trajectories in sporadic AD. Results Cerebrospinal fluid (CSF) Aβ was estimated to decline 45.2 years (abnormal: 27.8 years) before dementia, and Aβ deposition seemed to increase 31.7 years (abnormal: 26.7 years) before dementia. It was estimated to take 29.0 years (CSF t‐tau), 12.2 years (memory), 11.6 years (hippocampus), 9.3 years (hypometabolism), and 6.1 years (cognition) to move from normal to dementia. Discussion The trajectory in sporadic AD is led by Aβ accumulation, followed by CSF t‐tau increase, memory deficits, brain atrophy, hypometabolism, and cognitive decline.

Background Accumulating reports have suggested that α-synuclein is involved in the pathogenesis of Alzheimer’s disease (AD). As the cerebrospinal fluid (CSF) α-synuclein has been suggested as a potential biomarker of AD, this study was set out to test whether CSF α-synuclein is associated with other AD biomarkers and could predict neurodegeneration and clinical progression in non-demented elders. Methods The associations between CSF α-synuclein and other AD biomarkers were investigated at baseline in non-demented Chinese elders. The predictive values of CSF α-synuclein for longitudinal neuroimaging change and the conversion risk of non-demented elders were assessed using linear mixed effects models and multivariate Cox proportional hazard models, respectively, in the Alzheimer’s disease Neuroimaging Initiative (ADNI) database. Results The CSF α-synuclein levels correlated with AD-specific biomarkers, CSF total tau and phosphorylated tau levels, in 651 Chinese Han participants (training set). These positive correlations were replicated in the ADNI database (validation set). Using a longitudinal cohort from ADNI, the CSF α-synuclein concentrations were found to increase with disease severity. The CSF α-synuclein had high diagnostic accuracy for AD based on the “ATN” (amyloid, tau, neurodegeneration) system (A + T+ versus A − T − control) (area under the receiver operating characteristic curve, 0.84). Moreover, CSF α-synuclein predicted longitudinal hippocampus atrophy and conversion from MCI to AD dementia. Conclusions CSF α-synuclein is associated with CSF tau levels and could predict neurodegeneration and clinical progression in non-demented elders. This finding indicates that CSF α-synuclein is a potentially useful early biomarker for AD.

We aimed to explore the association between blood pressure, intracranial atherosclerotic stenosis (ICAS) risks and ICAS burden in the Chinese population.A retrospective hospital-based multi-center case-control study with large sample size was conducted. 1055 ICAS patients and 1296 non-ICAS subjects with complete clinical information and intracranial artery evaluation were identified between 2014 and 2019. Cerebral arteries were evaluated by magnetic resonance angiography, and/or computed tomography, and/or digital subtraction angiography. Two or more neurologists were involved in reading and assessment of images. The association between ICAS and burden of ICAS with blood pressure was evaluated with univariate logistic models and multivariate logistic models.With every increase of 10 mmHg in systolic blood pressure, diastolic blood pressure and pulse pressure, the odds of ICAS increased by 32%, 28% and 35% in multivariate analysis, respectively (odds ratio = 1.32, 1.28, and 1.35 respectively, all p 0.001). Similarly, every increment of 10 mmHg in systolic blood pressure and pulse pressure was associated with an increased risk of ICAS burden (each odds ratio = 1.08, p 0.05).Systolic blood pressure, diastolic blood pressure, and pulse pressure were associated with the risk of ICAS in a dose-response manner. Moreover, higher systolic blood pressure and pulse pressure could lead to higher ICAS burdens.

Funder: ZHANGJIANG LAB, Tianqiao and Chrissy Chen Institute, and the State Key Laboratory of Neurobiology and Frontiers Center for Brain Science of Ministry of Education, Fudan University, Background: Models of Alzheimer’s disease (AD) pathophysiology posit that amyloidosis [A] precedes and accelerates tau pathology [T] that leads to neurodegeneration [N]. Besides this A-T-N sequence, other biomarker sequences are possible. This current work investigates and compares the longitudinal trajectories of Alzheimer’s ATN biomarker profiles in non-demented elderly adults from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Methods: Based on the ATN classification system, 262 individuals were identified before dementia diagnosis and accompanied by baseline and follow-up data of ATN biomarkers (CSF Aβ42, p-tau, and FDG-PET). We recorded the conversion processes in ATN biomarkers during follow-up, then analyzed the possible longitudinal trajectories and estimated the conversion rate and temporal evolution of biomarker changes. To evaluate how biomarkers changed over time, we used linear mixed-effects models. Results: During a 6–120-month follow-up period, there were four patterns of longitudinal changes in Alzheimer’s ATN biomarker profiles, from all negative to positive through the course of the disease. The most common pattern is that A pathology biomarker first emerges. As well as the classical A-T-N sequence, other “A-first,” “T-first,” and “N-first” biomarker pathways were found. The N-A-T sequence had the fastest rate of pathological progression (mean 65.00 months), followed by A-T-N (mean 67.07 months), T-A-N (mean 68.85 months), and A-N-T sequences (mean 98.14 months). Conclusions: Our current work presents a comprehensive analysis of longitudinal trajectories of Alzheimer’s ATN biomarkers in non-demented elderly adults. Stratifying disease into subtypes depending on the temporal evolution of biomarkers will benefit the early recognition and treatment.

BackgroundAccumulating reports suggest that α-synuclein is involved in Alzheimer disease (AD) pathogenesis. Cerebrospinal fluid (CSF) α-synuclein could be a potential biomarker of AD. We sought to test whether CSF α-synuclein is associated with other AD biomarkers and could predict neurodegeneration and clinical progression in prodromal AD. MethodsAssociations were investigated between CSF α-synuclein and other AD biomarkers at baseline in prodromal AD stage Chinese elders. The predictive values of CSF α-synuclein in longitudinal change in clinical outcomes and conversion risk of prodromal AD stage subjects were assessed using linear mixed effects models and multivariate Cox proportional hazard models, respectively, in Alzheimer's disease Neuroimaging Initiative (ADNI) database.ResultsAmong individuals in prodromal AD stage, we detected that CSF α-synuclein levels correlated with AD-specific biomarkers CSF total tau and phosphorylated tau levels in 651 Chinese Han participants (training set). These positive correlations were replicated in ADNI database (validation set). Using a longitudinal cohort from ADNI, CSF α-synuclein concentrations increased with disease severity. CSF α-synuclein had high diagnostic accuracy for AD based on the “ATN” system (A+T+) vs controls (A-T-) (area under the receiver operating characteristic curve, 0.84). Moreover, CSF α-synuclein predicted longitudinal hippocampus atrophy and conversion from MCI to AD dementia.ConclusionsCSF α-synuclein is associated with CSF tau levels and could predict neurodegeneration and clinical progression in prodromal AD. This finding indicates CSF α-synuclein is a potentially useful, early biomarker for AD.

α-Synuclein is a 140-amino acid protein produced predominantly by neurons in the brain which plays a role in the regulation of neurotransmitter release, synaptic function, and plasticity, thus making it the focus in understanding the etiology of a group of neurodegenerative diseases. We conducted genome-wide association studies (GWAS) of α-synuclein levels in cerebrospinal fluid (CSF) with 209 non-Hispanic white participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI-1) cohort using a linear regression model to identify novel variants associated with α-synuclein concentration. The minor allele (T) of rs7072338 in the long intergenic non-protein coding RNA 1515 (LINC01515) and the minor allele (T) of rs17794023 in clusterin-associated protein 1 (CLUAP1) were associated with higher CSF α-synuclein levels at genome-wide significance (P = 4.167 × 10–9 and 9.56 × 10–9, respectively). In addition, single nucleotide polymorphisms (SNPs) near amyloid beta precursor protein (APP) (rs1394839) (P = 2.31 × 10–7), Rap guanine nucleotide exchange factor 1 (RAPGEF1) (rs10901091) (P = 8.07 × 10–7), and two intergenic loci on chromosome 2 and 14 (rs11687064 P = 2.50 × 10–7and rs7147386 P = 4.05 × 10–7) were identified as suggestive loci associated with CSF α-synuclein levels. We have identified significantly associated SNPs for CSF α-synuclein. These associations have important implications for a better understanding of α-synuclein regulation and allow researchers to further explore the relationships between these SNPs and α-synuclein-related neurodegenerative disorders.

The ATP-binding cassette transporter A7 (ABCA7) was identified as a known risk factor for Alzheimer's disease (AD). However, the relation between ABCA7 and AD was still inconsistent across these studies. Here, our meta-analysis aimed at confirming the association of ABCA7 with AD. Finally, 16 case-control studies (63747 versus 85833) were retrieved from PubMed and other databases. Three common loci were confirmed to increase the risk of AD (rs3764650: OR = 1.20, 95% CI = 1.16-1.24; rs3752246: OR = 1.13,95% CI = 1.08-1.19; rs4147929: OR = 1.17, 95% CI = 1.10-1.24), but the associations varied among the different races. Furthermore, ABCA7 loss-of-function (LOF) mutations conferred a higher risk for AD than did the above variants (LOF: OR = 1.78, 95% = 1.43-2.22). In conclusion, ABCA7 genetic variants, especially the LOF mutations, were significantly associated with the risk of AD.

// Rui-Chun Lu 1 , Wu Yang 2 , Lin Tan 1 , Fu-Rong Sun 1 , Meng-Shan Tan 1 , Wei Zhang 1 , Hui-Fu Wang 1 and Lan Tan 1 1 Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China 2 International Department, The Affiliated Hospital of Qingdao University, Qingdao, China Correspondence to: Lan Tan, email: dr.tanlan@163.com Keywords: Alzheimer’s disease, polymorphism, association study, HLA-DRB1, meta-analyses Received: April 19, 2017 Accepted: September 20, 2017 Published: October 04, 2017 ABSTRACT Genome-wide association studies (GWAS) have identified one single-nucleotide polymorphism (SNP) rs9271192 within HLA-DRB1 as a risk factor for Alzheimer's disease (AD) in Caucasians. The effect of rs9271192 on AD needed to be verified in other ethnic cohorts. In order to evaluate the association between HLA-DRB1 rs9271192 polymorphism and late-onset AD (LOAD) in the Northern Han Chinese population, we recruited 982 LOAD patients and 1344 sex- and age-matched healthy controls. The results showed that HLA-DRB1 rs9271192 was associated with LOAD (genotype P = 0.015, allele P = 0.04). The results of logistic regression revealed the C allele homozygosity strongly increased the risk of LOAD under a recessive model in the total sample ( P = 0.004, OR =2.069, 95% CI = 1.262–3.434). When these data were stratified by apolipoprotein E ( APOE ) e4 status, the observed association was confined to APOE e4 non-carriers (additive model: P=0.048, OR =1.191, 95% CI =1.001–1.417; recessive model: P < 0.001, OR = 2.601, 95% CI =1.519–4.566). Furthermore, meta-analysis after sensitive analysis confirmed that rs9271192 within HLA-DRB1 increased the risk of LOAD (OR = 1.12, 95% CI = 1.08–1.15). To summarize, the C allele in HLA-DRB1 rs9271192 may be an independent risk factor for LOAD.

Objective MicroRNA (miRNA) processing genes play important roles in the craniofacial development. The aim of this study was to explore the associations between single nucleotide polymorphisms (SNPs) of miRNA processing genes with the risk of non-syndromic orofacial clefts (NSOC). Methods We genotyped 12 potentially functional SNPs from seven miRNA processing genes (GEMIN3, DROSHA, DGCR8, GEMIN4, PIWIL1, XPO5, and DICER) in a case–control study of 602 NSOC cases and 605 controls. Results Two SNPs were associated with the susceptibility of CL/P: rs10719 in DROSHA led to an increased risk of cleft lip with or without palate (CL/P) (GA/AA: p = .024, OR = 1.33, 95% CI = [1.04, 1.70]; GG + GA/AA: p = .037, OR = 1.29, 95% CI = [1.02, 1.63]), while rs493760 in DROSHA (CC/TT: p = .049, OR = 0.58, 95% CI = [0.34, 0.99]) could reduce the risk of CL/P. In addition, rs10719 (A)-rs493760 (C) haplotype contributed to a decreased risk of CL/P (OR = 0.77, 95% CI = [0.63, 0.94]), whereas the rs10719 (G)-rs493760 (C) haplotype contributed to the increased risk of cleft palate only (CPO) (OR = 2.70, 95% CI = [1.15, 6.35]). However, there was no difference observed in these SNPs after the Bonferroni correction. Conclusion Taken together, our results provided the potential evidence that rs10719 and rs493760 might contribute to the risk of CL/P and suggested potential genetic basis and mechanisms of CL/P. The lack of association between these SNPs and CPO might be due to the limited sample size of CPO subgroup.

19 kinds of different ratio of binary mixed molten salt have been formulated, and the formulation of a low melting point binary molten salt has been exploited and its primary thermophysical properties were presented here. The eutectic temperature of the selected binary salt mixture was determined to be 116.9 ℃. Further the decomposition point, specific heat, density, viscosity, thermal conductivity and corrosion were determined respectively. Sensible thermal storage cost of the novel eutectic mixture was found to be lower than that of conventional solar salt and HITEC salt. The performance of the binary salt mixture taken at different stages during the test of 1200-h exposure to constant high temperature was discussed based on the results obtained from long-term thermal stability studies. The results show that thermodynamic properties of the molten salt show perfect repeatability before and after the experiments, and most variations rate of the thermal physical properties is within±10%, which can be considered as an implication that the candidate has good thermal stability. Therefore, this new kind of binary molten salt thermal storage materials is more competitive and promising to be used in solar power generation systems while providing a comprehensive data for its engineering application and theoretical research.

Background: Hypertension is a leading cause of stroke and the significance of blood pressure lowering treatment strategies for prevention of stroke has been well established. Despite the established and widespread use of BP lowering drugs, which one is better for stroke prevention is still debated. This study aimed to determine the most effective and safest blood pressure lowering treatments for stroke prevention among various single and combined therapies. Methods: A systematic search will be performed in PubMed and the Cochrane Library to identify RCTs and meta analyses of different pharmacological interventions for stroke prevention from January 01, 1966 to December 01, 2018. Primary efficacy outcome will be reduction of stroke incidence and safety outcome will be drug-related side effects withdraw. Study quality will be critically appraised based on the seven-point tool for assessing risk of bias by Cochrane collaboration. Pairwise meta-analyses and Bayesian network meta-analyses will be performed for all related outcome measures. We will conduct subgroup analyses and sensitivity analyses to assess the robustness of our findings. Discussion: This network meta-analysis will summarize the direct and indirect evidence aiming to provide a ranking of various blood pressure lowering strategies for prevention of stroke. The results of this meta-analysis may help the physicians in determining the best treatments for their patients in stroke prevention. Trial registration: CRD42018118454.

Introduction We aimed to estimate the frequency of each AT(N) (β-amyloid deposition [A], pathologic tau [T], and neurodegeneration [N]) profile in different clinical diagnosis groups and to describe the longitudinal change in clinical outcomes of individuals in each group. Methods Longitudinal change in clinical outcomes and conversion risk of AT(N) profiles are assessed using linear mixed-effects models and multivariate Cox proportional-hazard models, respectively. Results Participants with A+T+N+ showed faster clinical progression than those with A−T−N− and A+T±N−. Compared with A−T−N−, participants with A+T+N± had an increased risk of conversion from cognitively normal (CN) to incident prodromal stage of Alzheimer's disease (AD), and from MCI to AD dementia. A+T+N+ showed an increased conversion risk when compared with A+T±N−. Discussion The 2018 research framework may provide prognostic information of clinical change and progression. It may also be useful for targeted recruitment of participants with AD into clinical trials.

Objective:To identify genetic loci associated with plasma tau concentrations in healthy elders and individuals with Alzheimer disease.Methods:Four hundred sixty-three non-Hispanic white individuals exceeding quality control criteria were included from the Alzheimer's Disease Neuroimaging Initiative (ADNI-1) cohort. Association of plasma tau with genetic polymorphisms was performed with a linear regression model. Significant associations were validated in an independent replication cohort consisting of 431 healthy elders or individuals with mild cognitive impairment recruited from the University of California, San Francisco Memory and Aging Center.Results:The minor allele (A) of rs242557 in the microtubule-associated protein tau gene (MAPT) was associated with higher plasma tau levels at genome-wide significance (p = 4.85 × 10−9, empiric family-wise error corrected p = 0.0024) in a dose-dependent fashion. This association was also observed in the replication cohort (p = 1.0 × 10−5; joint analysis p = 1.2 × 10−12). Single nucleotide polymorphisms near PARK2 (rs2187213) (p = 6.15 × 10−6), IL2RA (rs7072793, rs7073236) (p = 7.89 × 10−6), and an intergenic locus on 9p21.3 (rs7047280) (p = 8.13 × 10−6) were identified as suggestive loci associated with plasma tau levels.Conclusions:MAPT H1c haplotype (rs242557) has previously been identified as a genetic risk factor for progressive supranuclear palsy and corticobasal degeneration. The current findings suggest that plasma tau concentration could be an endophenotype for identifying risk for 4-repeat tauopathies in older individuals.