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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.

Brain amyloid deposition is an early pathological event in Alzheimer's disease (AD), and abnormally low levels amyloid-β 42 peptide (Aβ 42 ) in cerebrospinal fluid (CSF) can be detected in preclinical AD. To identify the genetic determinants that regulate the rate of CSF Aβ 42 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 Aβ 42 in the gene CBFA2T3 ( CBFA2/RUNX1 translocation partner 3; rs13333659-T; p = 2.24 × 10 -9 ) was identified. Besides displaying abnormal CSF Aβ 42 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 Aβ 42 preceding the onset of clinical symptoms.

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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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.

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 <0.05). SBP between 110 and 120mmHg played a protective role in population aged 62 to 82; while SBP above 162 mmHg would significantly increase the risk in those aged 70 to 86.5. It is also noteworthy that there is a linear association between diastolic blood pressure (DBP) and AD risk in the population aged ≥ 65 years, such that the risk decreased by 3% for per 10 mmHg increase in a specific range of DBP., Conclusion: These findings indicate that BP management strategy for dementia prevention might be tailored according to specific population characteristics., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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 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 ε4 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: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]