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The relationship between depression and Alzheimer's disease (AD) is complex and still not well understood. We aimed to examine the roles of the AD core pathologies in modulating the associations of minimal depressive symptoms (MDSs) with cognitive impairments.A total of 721 participants who had measures of cognition, depressive symptoms, and cerebrospinal fluid AD biomarkers were included from the CABLE (Chinese Alzheimer's Biomarker and LifestylE) study. Causal mediation analyses with 10,000 bootstrapped iterations were conducted to explore the mediation effects of AD pathologies on cognition. The ADNI (Alzheimer's Disease Neuroimaging Initiative) was used 1) to replicate the mediation effects and 2) to examine the longitudinal relationships of MDSs with amyloid pathology and incident AD risk.In CABLE, MDSs were associated with poorer global cognition (p = .006) and higher amyloid burden as indicated by cerebrospinal fluid amyloid markers (p.0001). The influence of MDSs on cognition was partially mediated by amyloid pathology (a maximum of 85%). The mediation effects were replicated in 725 elderly persons without dementia (age, mean ± SD = 73.5 ± 6.9 years; 301 female subjects [42%]) in ADNI, such that the mediation percentage varied from 10% to 30% for general cognition, memory, and executive functions. Longitudinal analyses revealed a bidirectional relationship between MDSs and amyloid pathology (p = .01). MDSs were associated with 83% increased risk of developing AD dementia (hazard ratio = 1.83, p.01).Overall, amyloid pathology might partially mediate and magnify the influences of MDSs on cognitive impairments and AD risk.

It was unclear whether sex hormone-binding globulin (SHBG) was a circulating biomarker of Alzheimer’s disease (AD). We tested the cross-sectional relationships between plasma SHBG and cerebrospinal fluid (CSF) AD biomarkers in 707 non-demented adults. Next, the influences of plasma SHBG on dynamic changes of CSF Aβ42, hippocampus volume, brain metabolism, and cognition were explored in 448 non-demented adults from the Alzheimer’s disease Neuroimaging Initiative (ADNI). Finally, the predictive and diagnostic values of plasma SHBG in AD were explored. A positive correlation was found between SHBG levels in plasma and CSF. Individuals with higher plasma SHBG levels had lower CSF Aβ42 (p < 0.005), after adjusting for age, gender, education, APOE4 allele, and cognitive scores. Though no significant difference of plasma SHBG was observed between mild AD dementia and healthy normal, plasma SHBG could contribute to accelerated rates of CSF Aβ42 decrease (p < 0.0005), decline in brain metabolism (p < 0.05), and hippocampus atrophy (p < 0.01), cognitive decline (p < 0.01), as well as higher risk of AD dementia (p < 0.05). These findings indicated plasma SHBG could be a prodromal biomarker to predict disease progression in AD.

White matter hyperintensities (WMH) is mainly caused by cerebrovascular injury and may also increase the possibilities of progression to Alzheimer's disease. The present study aims to determine whether plasma neurofilament light (NFL) protein levels could predict the progression of WMH volume in elderly persons without dementia. The present study enrolled 1029 non-dementia participants from the Alzheimer's Disease Neuroimaging Initiative in which all had measurements of plasma NFL and WMH at baseline and 589 had longitudinal measurements during follow-up. Spearman correlation analyses and regression models were used to assess cross-sectional and longitudinal associations between plasma NFL and WMH. Plasma NFL concentration had a moderately strong correlation with WMH at baseline (r = 0.17, p < 0.001). Longitudinal analyses showed that higher baseline plasma NFL concentration was associated with accelerated progression of WMH (β=0.015, p = 0.007). Furthermore, higher change rates of plasma NFL could predict faster progression of WMH in the future (β=0.581, p = 0.002). The results of the study suggest that plasma NFL level might be used as a noninvasive biomarker to track variation trend in WMH in elderly persons without dementia.

Cognitive impairment is a debilitating manifestation in Parkinson’s disease (PD). We sought to investigate predictors of PD-CI (PD with cognitive impairment). We systematically searched PubMed and Cochrane Library for prospective cohort studies and pooled estimates via random-effects models. Primary analyses for all types of cognitive impairments and subgroup analyses by separate outcomes were conducted. A total of 28,009 studies were identified, of which 57 studies with 31 factors were included in the meta-analysis. In the primary analysis, 13 factors were associated with PD-CI, comprising advanced age [relative risk (RR) = 1.07, 95% confidence interval (CI) = 1.03–1.12], age at onset (RR = 4.43, 95% CI = 1.87–10.54), postural-instability-gait disorder (RR = 3.76, 95% CI = 1.36–10.40), higher Hoehn and Yahr stage (RR = 1.83, 95% CI = 1.35–2.47), higher UPDRS III score (RR = 1.04, 95% CI = 1.01–1.08), rapid eye movement sleep behavior disorder (RR = 3.72, 95% CI = 1.20–11.54), hallucinations (RR = 3.09, 95% CI = 1.61–5.93), orthostatic hypotension (RR = 2.98, 95% CI = 1.41–6.28), anxiety (RR = 2.59, 95% CI = 1.18–5.68), APOE e2 (RR = 6.47, 95% CI = 1.29–32.53), APOE e4 (RR = 3.04, 95% CI = 1.88–4.91), electroencephalogram theta power > median (RR = 2.93, 95% CI = 1.61–5.33), and alpha power

A subgroup of overweight/obese individuals, who had favorable metabolic profiles, was termed as metabolically healthy overweight/obese (MHO). Several studies suggested that MHO individuals were not at increased risk of cardiovascular disease and all-course mortality. However, whether MHO is associated with excess risk of Alzheimer’s disease (AD) in elders remains unclear. To explore the risk of AD among MHO phenotype and investigate whether MHO associates with neurodegenerative biomarkers of AD, we assessed body mass index-metabolic status phenotypes of 1199 longitudinal elders from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort using the Adult Treatment Panel-III (ATP- III) criteria. MHO subjects were at a significantly decreased risk for AD (adjusted HR=0.73, 95% CI: 0.54-0.97) compared with metabolically healthy normal weight (MHNW) subjects. In multivariable linear regression models, the cross-sectional associations of MHO with cerebrospinal fluid (CSF) biomarkers, brain Aβ load, and cortical structure were explored. MHO was positively correlated with CSF-Aβ (β=0.746, P=0.015), hippocampal volume (β=0.181, P=0.011), and whole brain volume (β=0.133, P=0.004). The MHO phenotype of the elder conferred a decreased risk of AD and its role may be driven by Aβ.

Triggering receptor expressed on myeloid cells-1 (TREM1) has been reported to associate with Alzheimer’s disease (AD) pathology. Recently, TREM1 variant rs2234246A was reported to regulate TREM-1 protein and mRNA levels. We explored the effect of rs2234246 on AD specific biomarker (amyloid-β PET) to look into the role of this TREM1 locus in AD pathogenesis. We calculated the association of the TREM1 locus with amyloid deposition at baseline and follow-up using both multiple linear models and mixed effect models respectively in 522 the Alzheimer’s Disease Neuroimaging Initiative (ADNI) subjects. We also analyzed the association of TREM1 with this marker in subregions during the AD process. In the pooled sample, TREM1 rs2234246A was associated with the levels of mean standard uptake volume ratios (SUVRs) at baseline (p = 0.02) and the length of follow-up (p = 0.04) in the cross-sectional analysis and longitudinal study. Subgroup analyses showed no correlation between rs2234246A and amyloid deposition in the cognitively normal (CN) group. In the mild cognitive impairment (MCI) group, TREM1 rs2234246A reached significance at baseline (p = 0.04) and the length of follow-up (p = 0.04). In the AD group, TREM1 rs2234246A was associated with mean SUVR at baseline (p

Hippocampal atrophy rate has been correlated with cognitive decline and its genetic modifiers are still unclear. Here we firstly performed a genome-wide association study (GWAS) to identify genetic loci that regulate hippocampal atrophy rate. Six hundred and two non-Hispanic Caucasian elders without dementia were included from the Alzheimer's Disease Neuroimaging Initiative cohort. Three single nucleotide polymorphisms (SNPs) (rs4420638, rs56131196, rs157582) in the TOMM40-APOC1 region were associated with hippocampal atrophy rate at genome-wide significance and 3 additional SNPs (in TOMM40 and near MIR302F gene) reached a suggestive level of significance. Strong linkage disequilibrium between rs4420638 and rs56131196 was found. The minor allele of rs4420638 (G) and the minor allele of rs157582 (T) showed associations with lower Mini-mental State Examination score, higher Alzheimer Disease Assessment Scale-cognitive subscale 11 score and smaller entorhinal volume using both baseline and longitudinal measurements, as well as with accelerated cognitive decline. Moreover, rs56131196 (P = 1.96 × 10-454) and rs157582 (P = 9.70 × 10-434) were risk loci for Alzheimer's disease. Collectively, rs4420638, rs56131196 and rs157582 were found to be associated with hippocampal atrophy rate. Besides, they were also identified as genetic loci for cognitive decline.

Brain amyloid deposition is an early pathological event in Alzheimer’s disease (AD), and abnormally low levels amyloid-β42 peptide (Aβ42) in cerebrospinal fluid (CSF) can be detected in preclinical AD. To identify the genetic determinants that regulate the rate of CSF Aβ42 decline among non-demented elders, we conducted a genome-wide association study involved 321 non-demented elders from Alzheimer’s Disease Neuroimaging Initiative (ADNI) 1/GO/2 cohorts restricted to non-Hispanic Caucasians. A novel genome-wide significant association of higher annualized percent decline of CSF Aβ42 in the gene CBFA2T3 (CBFA2/RUNX1 translocation partner 3; rs13333659-T; p = 2.24 × 10−9) was identified. Besides displaying abnormal CSF Aβ42 levels, rs13333659-T carriers were more likely to exhibit a greater longitudinal cognitive decline (p = 0.029, β = 0.097) and hippocampal atrophy (p = 0.029, β = −0.160) in the non-demented elders, especially for the participants who were amyloid-positive at baseline. These findings suggest rs13333659 in CBFA2T3 as a risk locus to modulate the decline rate of CSF Aβ42 preceding the onset of clinical symptoms.

Background Reduced 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) brain metabolism was recognized as a biomarker of neurodegeneration in the recently proposed ATN framework for Alzheimer’s disease (AD) biological definition. However, accumulating evidence suggested it is an independent biomarker, which is denoted as “F” in the very study. Methods A total of 551 A+T+ individuals from the Alzheimer’s Disease Neuroimaging Initiative database were recruited and then further divided into four groups based on the biomarker positivity as 132 A+T+N−F−, 102 A+T+N−F+, 113 A+T+N+F−, and 204 A+T+N+F+. Frequency distributions of the groups were compared, as well as the clinical progression [measured by the longitudinal changes in cognition and brain structure, and mild cognitive impairment (MCI) to AD dementia conversion] between every pair of F+ and F− groups. Results The prevalence of A+T+N+F+ profile was 66.24% in clinically diagnosed AD dementia patients; similarly, the majority of individuals with reduced FDG-PET were AD dementia subjects. Among the 551 individuals that included, 537 had at least one follow-up (varied from 1 to 8 years). Individuals in F+ groups performed worse and dropped faster in Mini-Mental State Examination scale and had faster shrinking middle temporal lobe than those in F− groups (all p

Age-related hearing loss (ARHL) has been considered as a promising modifiable risk factor for cognitive impairment and dementia. Nonetheless, it is still unclear whether age-related hearing loss associates with neurodegenerative biomarkers of Alzheimer’s disease (AD). Participants with ARHL were selected from the established Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. In multivariable models, the cross-sectional and longitudinal associations of ARHL with CSF β-amyloid (Aβ) and tau measurements, brain Aβ load, and cortical structural measures were explored. ARHL was associated with higher CSF levels of tau (p < 0.001) or ptau181 (p < 0.05) at baseline as well as faster elevation rates of these two types of biomarkers (p < 0.05). Although the baseline volume/thickness of hippocampus (p < 0.05) and entorhinal cortex (p < 0.0005) were higher in individuals with ARHL, these two regions (p < 0.01 for hippocampus, p < 0.05 for entorhinal cortex) displayed significantly accelerated atrophy in individuals with ARHL. No association of ARHL with CSF or brain Aβ levels was found. Subgroup analyses indicated that the above effects of ARHL were more significant in non-demented stage. Age-related hearing loss was associated with elevated cerebrospinal fluid tau levels and atrophy of entorhinal cortex.

Background The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism emerged as a risk factor for Alzheimer's disease (AD). However, little was known about its effects on the process of potential AD. Objective To explore the effects of the Val66Met polymorphism on cognition, cerebrospinal fluid (CSF), and neuroimaging markers in non-demented elderly individuals. Methods A total of 1,081 adults without dementia (375 healthy subjects and 706 individuals with mild cognitive impairment) were recruited from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to test the influence of BDNF Val66Met polymorphism on cognitive impairment, brain structure atrophy, and change in the levels of CSF biomarkers. Moreover, we also conducted our study in abnormal amyloid-β (A+) subgroup and normal amyloid-β (A-) subgroup, as well as in APOEɛ4 carriers and non-carriers. Results The BDNF Val66Met polymorphism had significant association with atrophy of the entorhinal cortex and Mini-Mental State Examination (MMSE) scores in the non-demented elderly and A + subgroup, while no association was found in A-subgroup. What is more, there was a significant effect of interaction between BDNF Val66Met and amyloid-β load in MMSE. In addition, significant associations of BDNF Val66Met with the entorhinal cortex and ventricular volumes were found among APOEɛ4 non-carriers, but not APOEɛ4 carriers. Conclusions The BDNF Val66Met polymorphism is associated with cognitive impairment and brain atrophy among the non-demented elderly, APOEɛ4 non-carriers and A + subgroup, implying the potential of the Val66Met polymorphism as an important genetic factor for AD-related neurodegeneration.

Early-onset neonatal sepsis (EONS), a bacterial infection that occurs within 72 h after birth, is associated with high likelihood of neonatal mortality. Latamoxef, a semi-synthetic oxacephem antibiotic developed in 1980s, has been brought back into empirical EONS treatment in recent years. In the preliminary work, we established a population pharmacokinetics (PPK) model for latamoxef in Chinese neonates. Moreover, in order to better guide clinical treatment, we conducted dose simulation and found that ascending administration frequency could improve the target rate of 70% of patients having a free antimicrobial drug concentration exceeding the MIC during 70% of the dosing interval (70% fT > MIC). Accordingly, this study is aimed to compare the 70% fT > MIC, efficacy and safety between conventional regimen and PPK model regimen for rational use of latamoxef in EONS treatment. A single-blind, multicenter randomized controlled trial (RCT) for latamoxef will be conducted in Chinese EONS patients. Neonates (≤3 days of age, expected number = 114) admitted to the hospital with the diagnosis of EONS and fulfilling inclusion and exclusion criteria will be randomized (ratio of 1:1) to either a conventional regimen (30 mg/kg q12h) or model regimen (20 mg/kg q8h) latamoxef treatment group for at least 3 days. Primary outcome measure will be 70% fT > MIC and secondary outcome indicators will be the latamoxef treatment failure, duration of antibiotic therapy, changes of white blood cell count (WBC), C-reactive protein (CRP) and procalcitonin (PCT), blood culture results during administration and incidence of adverse event (AE)s. Assessments will be made at baseline, initial stage of latamoxef treatment (18–72 h) and before the end of latamoxef treatment. Ethical approval of our clinical trial has been granted by the ethics committee of the Beijing Children’s Hospital (ID: 2020-13-1). Written informed consent will be obtained from the parents of the participants. This trial is registered in the Chinese Clinical Trial Registry (ChiCTR 2000040064).It is hoped that our study will provide a clinical basis for the rational clinical use of latamoxef in EONS treatment.

BackgroundSex-related difference in Alzheimer’s disease (AD) has been proposed, and apolipoprotein E (ApoE) isoforms have been suggested to be involved in the pathogenesis of AD.ObjectiveWe aimed to explore whether cerebrospinal fluid (CSF) ApoE is associated with AD biomarkers and whether the associations are different (between sexes).MethodsData of 309 participants [92 with normal cognition, 148 with mild cognitive impairment (MCI), and 69 with AD dementia] from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were cross-sectionally evaluated with the multiple linear regression model and longitudinally with the multivariate linear mixed-effects model for the associations of CSF ApoE with AD biomarkers. Sex–ApoE interaction was used to estimate whether sex moderates the associations of CSF ApoE and AD biomarkers.ResultsSignificant interactions between CSF ApoE and sex on AD biomarkers were observed [amyloid-β (Aβ):p= 0.0169 and phosphorylated-tau (p-tau):p= 0.0453]. In women, baseline CSF ApoE levels were significantly associated with baseline Aβ (p= 0.0135) and total-tau (t-tau) (p< 0.0001) as well as longitudinal changes of the biomarkers (Aβ:p= 0.0104; t-tau:p= 0.0110). In men, baseline CSF ApoE levels were only correlated with baseline p-tau (p< 0.0001) and t-tau (p< 0.0001) and did not aggravate AD biomarkers longitudinally.ConclusionThe associations between CSF ApoE and AD biomarkers were sex-specific. Elevated CSF ApoE was associated with longitudinal changes of AD biomarkers in women, which indicates that CSF ApoE might be involved in the pathogenesis of AD pathology in a sex-specific way.

The microtubule-associated protein tau gene (MAPT) rs242557 variant is associated with multiple tauopathies and dementia. This study investigated whether it was correlated with brain tau-PET uptake in non-demented elders. Ninety non-demented elders were identified from the Alzheimer's Disease Neuroimaging Initiative cohort. We compared standardized uptake value ratios (SUVRs) of tau-PET tracer 18F-AV-1451 between rs242557 variant carriers and non-carriers in 25 regions of interest (ROIs). The minor allele A was associated with increased hippocampus 18F-AV-1451 uptake in non-demented elders (left: β = 0.111, Bonferroni corrected p = 0.035; right: β = 0.103, Bonferroni corrected p = 0.031). Aβ-positive participants (left: β = 0.206, Bonferroni corrected p = 0.029; right: β = 0.198, Bonferroni corrected p = 0.035) and APOE e4 non-carriers (left: β = 0.140, Bonferroni corrected p = 0.006; right: β = 0.134, Bonferroni corrected p = 0.004) exhibited approximately the same findings in hippocampus. Considering no obvious associations in other regions, we confirmed the significant correlation of MAPT rs242557 risk variant with increased hippocampus tau deposition in non-demented elders. With higher magnitude signals in the hippocampus that is more likely to be uniquely affected in AD, the tau PET ligand 18F-AV-1451 seemed to possess a specific binding property for AD-like tau pathology.

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.

Progranulin (PGRN) is a secreted pleiotropic glycoprotein associated with the development of common neurodegenerative diseases. Understanding the pathophysiological role of PGRN may help uncover biological underpinnings. We performed a genome-wide association study to determine the genetic regulators of cerebrospinal fluid (CSF) PGRN levels. Common variants in region of FAM171A2 were associated with lower CSF PGRN levels (rs708384, P = 3.95 × 10−12). This was replicated in another independent cohort. The rs708384 was associated with increased risk of Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia and could modify the expression of the FAM171A2 gene. FAM171A2 was considerably expressed in the vascular endothelium and microglia, which are rich in PGRN. The in vitro study further confirmed that the rs708384 mutation up-regulated the expression of FAM171A2, which caused a decrease in the PGRN level. Collectively, genetic, molecular, and bioinformatic findings suggested that FAM171A2 is a key player in regulating PGRN production.

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.

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.

The microtubule-associated protein tau gene (MAPT) rs242557 variant is associated with multiple tauopathies and dementia. This study investigated whether it was correlated with brain tau-PET uptake in non-demented elders. Ninety non-demented elders were identified from the Alzheimer's Disease Neuroimaging Initiative cohort. We compared standardized uptake value ratios (SUVRs) of tau-PET tracer 18F-AV-1451 between rs242557 variant carriers and non-carriers in 25 regions of interest (ROIs). The minor allele A was associated with increased hippocampus 18F-AV-1451 uptake in non-demented elders (left: β = 0.111, Bonferroni corrected p = 0.035; right: β = 0.103, Bonferroni corrected p = 0.031). Aβ-positive participants (left: β = 0.206, Bonferroni corrected p = 0.029; right: β = 0.198, Bonferroni corrected p = 0.035) and APOE e4 non-carriers (left: β = 0.140, Bonferroni corrected p = 0.006; right: β = 0.134, Bonferroni corrected p = 0.004) exhibited approximately the same findings in hippocampus. Considering no obvious associations in other regions, we confirmed the significant correlation of MAPT rs242557 risk variant with increased hippocampus tau deposition in non-demented elders. With higher magnitude signals in the hippocampus that is more likely to be uniquely affected in AD, the tau PET ligand 18F-AV-1451 seemed to possess a specific binding property for AD-like tau pathology.

Background Plasma neurofilament light (NFL) is a promising biomarker for Alzheimer disease (AD), which increases in the early stage of AD and is associated with the progression of AD. We performed a genome-wide association study (GWAS) of plasma NFL in Alzheimer’s Disease Neuroimaging Initiative 1 (ADNI-1) cohort to identify novel variants associated with AD. Methods This study included 179 cognitively healthy controls (HC), 176 patients with mild cognitive impairment (MCI), and 172 patients with AD. All subjects were restricted to non-Hispanic Caucasian derived from the ADNI cohort and met all quality control (QC) criteria. Association of plasma NFL with the genetic variants was assessed using PLINK with an additive genetic model, i.e.dose-dependent effect of the minor alleles. The influence of a genetic variant associated with plasma NFL (rs7943454) on brain structure was further assessed using PLINK with a linear regression model. Results The minor allele (T) of rs7943454 in leucine zipper protein 2 gene (LUZP2) was associated with higher plasma NFL at suggestive levels (P = 1.39 × 10− 6) in a dose-dependent fashion. In contrast, the minor allele (G) of rs640476 near GABRB2 was associated with lower plasma NFL at suggestive levels (P = 6.71 × 10− 6) in a dose-dependent effect in all diagnostic groups except the MCI group. Furthermore, the minor allele (T) of rs7943454 within LUZP2 increased the onset risk of AD (odds ratio = 1.547, confidence interval 95% = 1.018–2.351) and was associated with atrophy of right middle temporal gyrus in the whole cohort in the longitudinal study (P = 0.0234). Conclusion GWAS found the associations of two single nucleotide polymorphisms (rs7943454 and rs640476) with plasma NFL at suggestive levels. Rs7943454 in LUZP2 was associated with the onset risk of AD and atrophy of right middle temporal gyrusin the whole cohort. Using an endophenotype-based approach, we identified rs7943454 as a new AD risk locus. Electronic supplementary material The online version of this article (10.1186/s12920-018-0364-8) contains supplementary material, which is available to authorized users.

Background The activity of cerebrospinal fluid (CSF) β-site APP cleaving enzyme (BACE) is a potential diagnostic biomarker for Alzheimer disease (AD). Methods A total of 340 non-Hispanic Caucasian participants from the Alzheimer’s Disease Neuroimaging Initiative cohort (ADNI) database were included in this study with quality-controlled CSF BACE and genotype data. Association of CSF BACE with the genetic variants of single nucleotide polymorphisms (SNPs) was assessed using PLINK under the additive genetic model. The P values of all SNPs for CSF BACE were adjusted for multiple comparisons. Results One SNP (rs1481950) in the ATP6V1H gene reached genome-wide significance for associations with CSF BACE (P = 4.88 × 10− 9). The minor allele (G) of rs1481950 was associated with higher CSF BACE activity. Although seven SNPs in SNX31, RORA, CDH23, RGS20, LRRC4C, MAPK6PS1 and LOC105378355 did not reach genome-wide significance (P

BACKGROUND As cognitive function declines with age, identifying factors affecting the trajectory of cognitive decline is an indispensable step toward developing intervention strategies to improve the quality of the elderly life. OBJECTIVE We performed a genome-wide association study (GWAS) focusing on memory function to explore single nucleotide polymorphisms (SNPs) associated with the rate of memory decline. METHODS Seven hundred and nine eligible non-Hispanic Caucasians from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were included for analysis after quality control. GWAS was performed with linear regression. We subsequently tested whether the associations remained significant in subgroup analysis and also examined the impact of SNPs on the longitudinal changes in other neuropsychological measures and amyloid pathology. RESULTS We identified rs13374761-A in SLAMF1 gene associated with less memory decline (MAF = 0.071, β= 0.0103, p = 4.14×10-8). Subgroup analysis showed stability of results across groups with different diagnosis at baseline. Rs13374761-A also had protective effects on global cognition (p = 0.024), episodic memory (p = 0.024), and semantic memory (p = 0.042), and exerts protection against a decrease in CSF Aβ42 concentration (p = 0.0463) and an increase in Aβ loading in cerebral cortex (p = 0.00666) among minor allele carriers. CONCLUSION A novel variant in gene SLAMF1 affects the rate of memory decline in the aged population. Given the protective effect of this variant, SLAMF1 should be further investigated as a potential preventive and therapeutic target for monitoring cognition trajectories.

Introduction Plasma markers have been reported to be associated with brain amyloid burden, tau pathology, or neurodegeneration. We aimed to evaluate whether plasma biomarker profiles could predict Alzheimer's disease (AD) pathology and clinical progression in older adults without dementia. Methods Cross‐sectional and longitudinal data of participants enrolled in this study were from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Plasma amyloid beta (Aβ)1‐42/Aβ1‐40 ratio was selected as the marker for amyloid pathology, p‐tau181 for tau pathology, and neurofilament light for neurodegeneration. Cut‐offs for these plasma markers were calculated with well‐established positron emission tomography and structural imaging biomarkers as reference. Older adults without dementia were categorized into eight groups at baseline by plasma amyloid/tau/neurodegeneration (A/T/N) cut‐offs. Clinical progression was analyzed using linear mixed‐effects models and Cox proportional hazard models. Results A total of 183 participants (97 cognitively normal [CN] subjects and 86 patients with mild cognitive impairment [MCI]; mean age 72.6 years, and 48.1% men) were included. Participants with A+ had significantly higher proportions of apolipoprotein E (APOE) gene ɛ4 carriers than those with A–. Brain atrophy was observed in all groups of CN, whereas cognition decline was obvious in the A+T+N+ group. Compared to A–T–N–, MCI patients with A+T+N+ had faster cognition worsening and faster brain atrophy. In the whole cohort, A+T+N+ and A+T+N– participants were at higher risk of clinical progression. Discussion Plasma A/T/N biomarker profiles may predict AD pathology and clinical progression, indicating a potential role for plasma biomarkers in clinical trials. More research is warranted to develop a robust plasma AD framework.

Background Neurofilament light chain (NFL) as a potential biomarker of neurodegenerative diseases has been studied in a number of studies. Thus, a comprehensive meta-analysis is warranted to assess NFL performance in neurodegenerative diseases. Objective To assess the performance of NFL in blood and cerebrospinal fluid (CSF) as a biomarker for neurodegenerative diseases. Methods A total of 36 studies with comparison of NFL level between individuals with neurodegenerative diseases and controls were retrieved from PubMed, Web of Science and Science Direct, and the ratio of means method and delta method based on the random-effect model were used to analyze the differentiation of NFL between patients and controls. Results Differentiation of CSF NFL between patients with neurodegenerative diseases and controls showed significant results. Although a few studies on blood NFL available were included in the meta-analysis, the results still showed a distinct possibility that NFL could be a potential biomarker for neurodegenerative diseases. NFL levels were increased significantly in dementias, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, and Huntington's disease. By contrast, NFL levels were not increased in Parkinson's disease (PD), although they were increased significantly in PD-related disorders (multiple system atrophy and progressive supranuclear palsy). Conclusions In our study, in addition to PD, NFL was suggested to be a global diagnostic biomarker for neurodegenerative diseases. Moreover, it could be used in differential diagnosis of PD and PD-related disorders. However, it was worth noting that NFL was not appropriate for diagnosis or differential diagnosis without clinical symptoms and other auxiliary examinations.

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.

Background: rs9357347 located at the triggering receptor expressed on myeloid cells (TREM) gene cluster could increase TREM2 and TREM-like transcript 1 (TREML1) brain gene expression, which is considered to play a protective role against Alzheimer's disease (AD). Objectives: To investigate the role of rs9357347 in AD pathogenesis by exploring the effects of rs9357347 on AD specific biomarkers. Methods: This study analyzed the association of rs9357347 with AD-related cerebrospinal fluid (CSF) and neuroimaging markers from 201 cognitively normal (CN) older adults, 349 elders with mild cognitive impairment (MCI), and 172 elders with AD dementia from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We next analyzed the association in 259 amyloid-β positive (Aβ+) elders and 117 amyloid-β negative (Aβ-) elders (Aβ+: CSF Aβ1-42 ≤ 192 pg/ml; Aβ-: CSF Aβ1-42 > 192 pg/ml). Associations were tested using multiple linear regression models at baseline. Furthermore, multiple mixed-effects models were used in a longitudinal study which lasted 4 years. Results: At baseline, we found that rs9357347 had association with CSF Aβ1-42 in CN group (β = 0.357, P = 0.009). In AD group, rs9357347 was associated with total tau (T-tau) level (β = -0.436, P = 0.007). Moreover, the strong influence exerted by rs9357347 on T-tau was also seen in Aβ+ group (β = -0.202, P = 0.036). In the longitudinal study, rs9357347 was also found to be associated with Aβ1-42 in CN group (β = 0.329, P = 0.023). In AD group, the mutation of rs9357347 was associated with slower accumulation of T-tau (β = -0.472, P = 0.002) and tau phosphorylated at threonine 181 [P-tau 181 (β = -0.330, P = 0.019)]. Furthermore, the obvious influence exerted by rs9357347 on T-tau was also seen in Aβ+ group (β = -0.241, P = 0.013). Conclusion: This study suggested that rs9357347 reduced the risk of AD by modulating both amyloid-β pathology and neuronal degeneration.

A potential role for ABI3 gene has been suggested in the risk of Alzheimer's disease (AD), but the detailed mechanism before typical AD onset was unclear. In this study, we investigated the associations of ABI3 common variants with cerebrospinal fluid biomarkers and cognitive function scores among non-demented elderly from the ADNI database. We found that, in the progressive mild cognitive impairment group, rs5978930 was associated with total tau levels and rs16947151 was associated with cognitive function scores at baseline and over time, suggesting that ABI3 variants may be associated with cognitive decline and may influence AD onset through tau pathology.

A coding missense mutation (rs3747742) in triggering receptor expressed on myeloid cell-like 2 (TREML2) has been recently proposed as an important protective factor against Alzheimer’s disease (AD). However, the link between TREML2 and AD pathology remains unclear. Therefore, we explored the association of TREML2 rs3747742 with cognitive function, neuroimaging biomarkers and cerebrospinal fluid (CSF) biomarkers related to AD, including CSF total-tau (T-tau), phosphor-tau (P-tau), and amyloid-β (Aβ1-42). As for cognitive function, related cognitive scores of Clinical Dementia Rating Sum of Boxes (CDRSB), Alzheimer’s Disease Assessment Scale-cognitive section 11 (ADAS-cog 11), Mini-Mental State Examination (MMSE), and Rey Auditory-Verbal Learning Test (RAVLT) were extracted. We used a multiple linear regression model to examine the association of TREML2 rs3747742 with the baseline variables. Furthermore, we also calculated the change rate of above variables influenced by TREML2 rs3747742 via applying a mixed-effects model over a 4-year follow-up. In this analysis, a total of 1,306 individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database were included. Finally, we observed that only in AD patients, but not in normal controls or mild cognitive impairment (MCI) individuals, TREML2 rs3747742 exhibited a strong association with CSF total-tau levels at baseline (β = -22.1210, p = 0.0166) and 4-year follow-up (β = -0.3961, p = 0.0115). Furthermore, no associations were found with CSF Aβ1-42 levels, P-tau levels, neuroimaging biomarkers and cognitive function neither for baseline variables nor for longitudinal data. Thus, this study indicated that TREML2 mediated the risk of AD through influencing AD-related neurodegeneration (abnormal T-tau levels) but not P-tau levels and Aβ pathology.

It is widely believed that light-to-moderate alcohol intake may protect against dementia while excessive drinking may instead increase the risk. Nonetheless, these findings need cautious interpretations due to varying methodologies and lack of standard definition, which hindered our transferring into preventative practice. The objective of this study is to investigate the potential dose–response association between alcohol consumption and risk of dementia. A systematic search was conducted in electronic databases to identify relevant studies. Risk estimates were combined using a random-effect model. Eleven studies with 73,330 participants and 4586 cases for all-cause dementia (ACD), five studies with 52,715 participants and 1267 cases for Alzheimer’s dementia (AD) and four studies with 49,535 participants and 542 cases for vascular dementia were included. We observed a nonlinear association between alcohol consumption and ACD risk (p nonlinearity

Background Early-life environment is related to childhood brain development and cognitive function in later life. However, the associations of early-life risk factors with dementia and cognitive impairment were still controversial. Objective Our study aims to investigate early-life risk factors for dementia and cognitive impairment. Methods PubMed and Cochrane Library were searched to identify prospective cohort and retrospective case-control studies exploring early-life factors for dementia and cognitive impairment. Pooled effect estimates for each factor were calculated by random-effect model. Results Thirty-seven studies with 46,727 participants were included. The pooled results indicated significant associations of dementia with food deficiency (OR = 2.05, 95% CI = 1. 22-3.44), low education level (RR = 1.80, 95% CI = 1.60-2.02), and shorter leg length (OR = 1.19, 95% CI = 1.07-1.32). Other potential risk factors identified in the systematic review include rural residence, number of siblings, history of head trauma, early parental death or re-marriage, and poor learning ability. Conclusion Early-life factors, including education level, leg length, history of childhood head trauma, family-related factors and learning ability, were associated with the risk of dementia and cognitive impairment in later life. Further high-quality longitudinal studies are needed to verify the causality between early-life risk factors and dementia and cognitive impairment.

Objective:The aim of this study is to assess the association between midlife risk factors and dementia.Methods:PubMed and Cochrane library were systematically searched on May 24, 2018, to retrieve prospective cohort studies. The summary Relative Risk (RR) and 95% Confidence Interval (CI) were calculated by the random-effect model to explore the association between midlife risk factors and dementia. Sensitivity analysis and meta-regression were conducted to explore the source of heterogeneity. Publication bias was examined using Begg's and Egger's tests.Results:Thirty-four prospective cohort studies were included, among which 24 were eligible for metaanalysis. A total of 159,594 non-demented adults were enrolled at baseline before 65 years and 13,540 people were diagnosed with dementia after follow-up. The pooled results revealed that five factors could significantly increase the dementia risk by 41 to 78%, including obesity (RR, 1.78; 95% CI: 1.31-2.41), diabetes mellitus (RR, 1.69; 95% CI: 1.38-2.07), current smoking (RR, 1.61; 95%, CI: 1.32-1.95), hypercholesterolemia (RR, 1.57; 95% CI: 1.19-2.07), and hypertension (borderline blood pressure RR, 1.41; 95% CI: 1.23-1.62 and high Systolic Blood Pressure (SBP) RR, 1.72; 95% CI: 1.25-2.37). However, the sensitivity analyses found that the results of hypercholesterolemia and high SBP were not reliable, which need to be confirmed by more high-quality studies. No influences due to publication bias were revealed. In the systematic review, another three factors (hyperhomocysteinemia, psychological stress, and heavy drinking) were found to be associated with elevated dementia risk. In addition, physical exercise, a healthy diet, and hormone therapy in middle age were associated with the reduction of dementia risk.Conclusions:Middle-aged people with obesity, diabetes, hypertension, or hypercholesterolemia, and current smokers in midlife are at higher risk of developing dementia later in life.

Background Cognitive impairment is a common and devastating manifestation in Parkinson's disease (PD). We aimed to identify modifiable risk factors for PD with cognitive impairment. Methods We systematically searched PubMed and the Cochrane Library from June 1937 to September 2018 and included prospective cohort studies with random-effects model used to combine estimates. Primary analyses for all types of cognitive impairments and subgroup analyses for separate outcomes were conducted. Results A total of 31,298 articles were identified, of which 32 articles with 18 factors met the inclusion criteria for meta-analysis. In the primary analysis, 9 modifiable risk factors were found to increase the risk of PD with cognitive impairment, including postural-instability-gait disorder (relative risk = 3.76, 95% confidence interval = 1.36-10.40), hallucinations (relative risk = 3.09, 95% confidence interval = 1.61-5.93), orthostatic hypotension (relative risk = 2.98, 95% confidence interval = 1.41-6.28), cerebrovascular disease (relative risk = 1.52, 95% confidence interval = 1.01-2.28), diabetes mellitus (relative risk = 1.47, 95% confidence interval = 1.13-1.92), obesity (relative risk = 1.38, 95% confidence interval = 1.15-1.65), cardiac disease (relative risk = 1.35, 95% confidence interval = 1.17-1.56), alcohol consumption (relative risk = 1.32, 95% confidence interval = 1.15-1.52), and smoking (relative risk = 1.31, 95% confidence interval = 1.14-1.50). In the subgroup analysis, postural-instability-gait disorder subtype, orthostatic hypotension and hallucinations may increase the risk of dementia in PD. A total of 37 articles were included in the systematic review, in which 9 risk factors and 1 protective factor were additionally associated in single studies with the risk of PD with cognitive impairment, and 5 factors were associated with specific cognition domains. Conclusions Effective interventions in the management of PD symptoms, comorbidities, and lifestyles may be promising to reduce PD with cognitive impairment risk. © 2019 International Parkinson and Movement Disorder Society.

Background The conclusions about risk factors for rapid cognitive decline (RCD) in Alzheimer's disease (AD) and mild cognitive impairment (MCI) remain contradictory. Objective To explore the factors predicting RCD in AD and MCI. Methods We searched the PubMed, EMBASE, and the Cochrane Library from inception to May 27, 2017 for studies investigating factors associated with faster cognitive progression in AD and MCI. Effect sizes were meta-analyzed using fixed-effects and random-effects models. Results Fifty-three studies with 14,330 patients (12,396 AD and 1,934 MCI) were included in the systematic review. The following factors were identified to increase the risk of RCD in AD: Apolipoprotein E4 (ApoE4) (SMD [95% CI]: 0.52 [0.06,0.98]), early age at onset (SMD [95% CI]: -0.42 [-0.71, -0.13]), high level of education (RR = 2.05, 95% CI = 1.26 to 3.33), early appearance of extrapyramidal signs (RR = 2.18; 95% CI = 1.30 to 3.67), and neuropsychiatric conditions including hallucination (RR = 2.01, 95% CI = 1.40 to 2.87), strolling (RR = 1.99, 95% CI = 1.38 to 2.86), agitation (RR = 1.66, 95% CI = 1.23 to 2.24), and psychosis (RR = 1.42, 95% CI = 1.07 to 1.89). Instead, advanced age (≥75 years) (RR = 0.96, 95% CI = 0.93 to 0.99), diabetes (RR = 0.57; 95% CI = 0.35 to 0.93), and multidrug therapy (RR = 0.61, 95% CI = 0.60 to 0.62) would lower the risk of RCD. Furthermore, systematic research also reviewed seven risk factors associated with RCD in MCI. Conclusion ApoE4, early onset, early appearance of extrapyramidal signs, high education level, and neuropsychiatric conditions might increase the risk of RCD while older age, diabetes, and multidrug therapy were the protective factors for AD.

BACKGROUND A number of epidemiological studies have revealed a controversial correlation between Blood Pressure (BP) and the risk of dementia, hindering translation of research into preventative practice. OBJECTIVE To meta-analyze the dose-response relationship of dementia and its subtypes to BP. METHOD Relevant studies were identified via a systematic retrieval analysis in electronic databases from inception to May 1, 2017. Linear and non-linear dose-response meta-analyses were conducted to evaluate the effects of BP on dementia risk. RESULTS Twenty-three studies from 17 articles with 830631 participants and 4384 cases for all dementia, 17 studies from 12 articles with 1707445 participants and 3481 cases for Alzheimer's disease (AD) and 11 studies from 8 articles with 1693690 participants and 1067 cases for Vascular Dementia (VD) were included. We identified that the associations between BP and dementia varied with population characteristics. A nonlinear relationship was found between systolic blood pressure (SBP) and all dementia risk in population-aged ≥ 65 years (pnonlinearity

Recent studies found the variants in Alzheimer's disease (AD) risk gene PLD3 were associated with cognitive function, but its detailed mechanism before typical AD onset was unknown. Our current study examined the impact of PLD3 common variant rs11667768 on cerebrospinal fluid (CSF) total-tau and phosphorylated-tau levels and structural MRI from the ADNI database. We found rs11667768 was significantly associated with CSF total-tau levels and hippocampal volumes at baseline and six-year follow-up in the total non-demented elderly group and the mild cognitive impairment subgroup, indicating a potential role of PLD3 common variants in influencing cognitive function through changing CSF total-tau levels and hippocampal volumes.

Background Neuropsychiatric symptoms (NPS) are being increasingly recognized as common serious problems in Alzheimer’s disease (AD). However, published data on the prevalence of NPS in persons with AD are conflicting. This meta-analysis aimed to estimate the prevalence of NPS in persons with AD. Methods Studies published from 1964 to September 30, 2014, were identified from PubMed and Embase database, reference lists and conference abstracts. We calculated prevalence rates and conducted meta-regression analysis with random-effects model, according to study characteristics, population demographics or condition information. Results We identified 48 eligible articles, which provided data for 12 NPS reported in Neuropsychiatric Inventory (NPI). The most frequent NPS was apathy, with an overall prevalence of 49% (95% CI 41–57%), followed by depression, aggression, anxiety and sleep disorder, the pooled prevalence estimates of which were 42% (95% CI 37–46%), 40% (95% CI 33–46%), 39% (95% CI 32–46%) and 39% (95% CI 30–47%), respectively. The less prevalent NPS were irritability (36%, 31–41%), appetite disorder (34%, 27–41%), aberrant motor behavior (32%, 25–38%), delusion (31%, 27–35%), disinhibition (17%, 12–21%) and hallucination (16%, 13–18%). Least common was euphoria, with an overall prevalence of 7% (95% CI 5–9%). Limitations Several aspects, such as the quality of included studies were not always optimal and there was significant heterogeneity of prevalence estimate across studies. Conclusions NPS were observed to be highly prevalent in AD patients. Disease duration, age, education level, population origin and the severity of cognitive impairment had influence on the prevalence of some NPS.

BACKGROUND Vascular dementia (VaD) is the second most common type of dementia. So far, little is known about the contribution of genetic polymorphisms to the risk of VaD. Many candidate genetic polymorphisms have been examined in a large number of studies. However, due to the conflicting results, the genetics of VaD is still behind the shadow. OBJECTIVE We conducted a comprehensive meta-analysis on associations between genetic polymorphisms of any gene and VaD to investigate the genetics of VaD. METHOD We sought the published studies of associations between any genetic polymorphism and VaD and critically appraised them. We assessed the effects of genetic models by calculating pooled odds ratios (ORs), investigating the origin of heterogeneity by subgroup analysis, and testing the robustness by random effect model and sensitivity analysis. RESULTS 69 studies with 4,462 cases and 11,583 controls were included. We identified APOE ɛ2/ɛ3/ɛ4 and additional four genetic polymorphisms including MTHFR C677T, PON1 L55M, TGF-β1 +29C/T, and TNF-α -850C/T associated with VaD. Tested by random effect model and sensitivity analysis, the pooled results show nice robustness. CONCLUSIONS Our comprehensive meta-analysis highlighted the genetic contribution to sporadic VaD. Because of the small amount of data on associations between genetic polymorphisms, except for APOE, and VaD, more studies are needed to test the existing genetic polymorphisms and detect other related genetic variants.

Educational level has been regarded as one of the most widely accepted risk factors in the epidemiological studies for dementia, despite with discordant qualitative results. However, the dose-response relation between education and incident dementia was still unknown. To quantitatively evaluate the association between exposure level to high and low education and risk of dementia, we searched PubMed, EMBASE, and the Cochrane Library up to November 2014 and references of retrieved literatures. Specific prospective cohort studies, in which educational attainment was categorized into at least three levels, were included. Newcastle-Ottawa scale was used to assess the quality of included studies. Fifteen prospective cohort studies with 55655 for low education and eight prospective cohort studies with 20172 for high education were included. In the qualitative analysis, both low and high education showed a dose-response trend with risk of dementia and Alzheimer's disease (AD). In the quantitative analysis, the dementia risk was reduced by 7 % for per year increase in education (RR, 0.93; 95 % CI, 0.92-0.94; p for overall trend = 0.000; p for nonlinearity = 0.0643). Nonetheless, we did not find statistically significant association between per year decrease in education and dementia (RR, 1.03; 95 % CI, 0.96-1.10; p for overall trend = 0.283; p for nonlinearity = 0.0041) or AD (RR, 1.03; 95 % CI, 0.97-1.10; p for overall trend = 0.357; p for nonlinearity = 0.0022). Both low and high education showed a trend of dose-response relation with risk of dementia and AD. The dementia risk was reduced by 7 % for per year increase in education.

The endoplasmic reticulum (ER) serves many crucial cellular functions. However, when misfolded or unfolded proteins accumulated in the ER, the stress of ER will be induced. Meanwhile, the intracellular signaling network, which is called unfolded protein response, will also be activated to cope with. Those unfolded proteins can be recognized by three kinds of stress sensors which are IRE1, PERK, and ATF6. Based on lots of medical reports, ER stress in postmortem brains from Alzheimer's disease (AD) patients, animals, and vitro models have indicated that ER dysfunction might work as an important part in causing AD. In this review, we demonstrated that the effect of ER stress contributed to the pathogenesis of AD. ER stress associates almost the whole brain pathology processes which can be observed in AD, such as gene mutation of presenilin1, the abnormal clipped mRNA of presenilin2, β-amyloid production, tau phosphorylation, and cell death. The status of ER stress and unfolded protein response in the pathogenesis of AD also suggests they can be used as potential therapeutic agents.

The triggering receptor expressed on myeloid cells 2 (TREM2) gene has been reported to increase the risk of Alzheimer's disease (AD). The soluble TREM2 protein (sTREM2) in cerebrospinal fluid (CSF) was also associated with AD. However, the role of sTREM2 in AD and its genetic modifiers remain unclear. We carried out a genome-wide association study for CSF sTREM2 levels using participants from the Alzheimer's Disease Neuroimaging Initiative and validated the significant association in an independent cohort from Chinese Alzheimer's Biomarker and LifestylE study. rs7232 in membrane spanning 4-domains A6A (MS4A6A) gene was associated with CSF sTREM2 levels at genome-wide significance (p = 1.42 × 10−15). The locus influences CSF sTREM2 levels especially in nondemented individuals. And the association was replicable in the validation cohort from Chinese Alzheimer's Biomarker and LifestylE study (p = 0.0106). Besides, the expressions of MS4A6A and TREM2 were correlated in brain regions (p

Background: Cerebrospinal fluid (CSF) neurofilament light (NFL) is a general biomarker for axonal damage. Methods: This genome-wide association study (GWAS) consisted of 169 mild cognitive impairment (MCI) subjects and 94 cognitively normal (CN) subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Analyses of associations between CSF NFL and genetic polymorphisms were performed using an additive genetic model. The novel single nucleotide polymorphisms (SNPs) identified by GWAS were further examined for their correlation with other AD-related phenotypes at baseline and during follow-up using multiple linear regression model and mixed effects model respectively. Survival analysis was performed to evaluate the respective risks of progression from CN to prodromal AD and from MCI to AD among populations with different genotypes. Results: Two novel SNPs (rs465401 and rs460420), both near the ADAMTS1 gene on chromosome 21, showed genome-wide significant associations with CSF NFL. The minor allele (A) of rs465401 was also associated with higher CSF total tau (t-tau) levels, lower amyloid-β (Aβ) levels as well as greater longitudinal change in both Aβ and t-tau among the CN group. Furthermore, the Cox proportional hazards models showed increased risks for prodromal AD among the cognitive normal AA homozygotes. Conclusions: We found that two SNPs (rs465401 and rs460420) were associated with CSF NFL in non-demented elders. The associations identified in this study may make the SNPs and ADAMTS1 ideal candidates for future genetic studies on aging and neurodegenerative disorders.

Background: ATP-binding cassette transporter A7 (ABCA7) rs3764650 has been identified to be a susceptibility locus for Alzheimer’s disease (AD), but its role in cerebrospinal fluid (CSF) proteins was still unclear. Methods: The associations of rs3764650 with CSF Aβ 1–42 , t-tau and p-tau were analyzed in non-dementia AD, including preclinical and prodromal AD from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Results: Finally, GG + GT genotypes significantly decreased CSF Aβ1–42 level, but did not alter CSF t-tau and p-tau levels in non-dementia AD at baseline, which was further confirmed in longitudinal studies. Conclusions: Our findings supported that ABCA7 modified AD risk by altering Aβ deposition rather than tau pathology.

Background: Fluorodeoxyglucose f18 positron emission tomography (18F-FDG PET) is regarded as the only functional neuroimaging biomarker for degeneration which can be used to increase the certainty of Alzheimer’s disease (AD) pathophysiological process in research settings or as an optional clinical tool where available. Although a decline in FDG metabolism was confirmed in some regions known to be associated with AD, there was little known about the genetic association of FDG metabolism in AD cohorts. In this study, we present the first genome-wide association study (GWAS) analysis of brain FDG metabolism. Methods: A total of 222 individuals were included from the Alzheimer’s Disease Neuroimaging Initiative 1 (ADNI-1) cohort. All subjects were restricted to non-Hispanic Caucasians and met all quality control (QC) criteria. Associations of 18F-FDG with the genetic variants were assessed using PLINK 1.07 under the additive genetic model. Genome-wide associations were visualized using a software program R 3.2.3. Results: One significant SNP rs12444565 in RNA-binding Fox1 ( RBFOX1 ) was found to have a strong association with 18F-FDG (P=6.06×10 −8 ). Rs235141, rs79037, rs12526331 and rs12529764 were identified as four suggestive loci associated with 18F-FDG. Conclusions: Our study results suggest that a genome-wide significant SNP (rs12444565) in the RBFOX1 , and four suggestive loci (rs235141, rs79037, rs12526331 and rs12529764) are associated with 18F-FDG.

Recently, 19 susceptibility loci for Alzheimer's disease (AD) had been identified through AD genome-wide association studies (GWAS) meta-analysis. However, how they influence the pathogenesis of AD still remains largely unknown. We studied those loci with six MRI measures, abnormal glucose metabolism, and β-amyloid (Aβ) deposition on neuroimaging in a large cohort from Alzheimer's Disease Neuroimaging Initiative (ADNI) database in order to provide clues of the mechanisms through which these genetic variants might be acting. As a result, single nucleotide polymorphisms (SNPs) at rs983392 within MS4A6A and rs11218343 within SOLR1 were both associated with the percentage of increase in the volume of left inferior temporal regions in the follow-up study. Meanwhile, rs11218343 at SORL1 and rs6733839 at BIN1 was associated with rate of volume change of left parahippocampal and right inferior parietal, respectively. Moreover, rs6656401 at CR1 and rs983392 at MS4A6A were both associated with smaller volume of right middle temporal at baseline. However, in addition to the APOE locus, we did not detect any influence on glucose metabolism and Aβ deposition. APOE e4 allele was associated with almost all measures. Altogether, five loci (rs6656401 at CR1, rs983392within MS4A6A, rs11218343 at SORL1, rs6733839 at BIN1, and APOE e4) have been detected to be associated with one or a few established AD-related neuroimaging measures.