A gene-environment interplay between omega-3 supplementation and APOE ε4 provides insights for Alzheimer's disease precise prevention amongst high-genetic-risk population.

BACKGROUND AND PURPOSE: The present study aimed to explore whether and how omega-3 (ω-3) supplementation could interact with genetic factors to modulate cognitive functions, amyloid pathologies, and Alzheimer's disease (AD) risk. METHODS: A total of 1,670 non-demented participants (mean age 73 years, 47% females, 41% APOE ε4 carriers) were followed up for 10 years. Hierarchical regressions, linear mixed-effects models, and Cox proportional hazards models were used to examine the interaction effects of ω-3 supplementation with APOE ε4 and polygenic hazard scores, after adjusting for age, gender, education, cognitive diagnosis, insomnia, depression, anxiety, and cardiovascular risk score. RESULTS: Individuals who progress to AD during the follow-up tend to take a shorter duration of ω-3 at baseline than those stable, for whom the difference remained significant only amongst APOE ε4 carriers (p < 0.01). The interaction term (APOE ε4 × ω-3) accounted for a significant amount of variance in cognition and cerebral amyloid burden. Long-term ω-3 use protected cognition (especially memory function) and lowered amyloid burden and AD risk only amongst APOE ε4 carriers. Mediation analysis suggested that amyloid pathologies, brain reserve capacities, and brain metabolism mediated the relationships of ω-3 use with memory and global cognition for APOE ε4 (+) carriers. Similar interaction and mediation effects were also indicated amongst high-risk subjects defined by polygenic hazard scores. CONCLUSIONS: Long-term ω-3 intake may have a role in AD prevention in genetically at-risk populations.

Dynamic changes of CSF clusterin levels across the Alzheimer's disease continuum.

BACKGROUND: Clusterin is a multifunctional protein, which is associated with the pathogenesis and the development of Alzheimer's disease (AD). Compared with normal controls, inconsistent results have yielded in previous studies for concentration of cerebrospinal fluid (CSF) clusterin in AD patients. We explored CSF clusterin levels in different pathological processes of AD. METHODS: Following the National Institute on Aging-Alzheimer's Association (NIA-AA) criteria, we employed on the levels of CSF Aß42(A), phosphorylated-Tau (T), and total-tau (N). Based on previously published cutoffs and the close correlation between CSF p-tau and t-tau, 276 participants from the publicly available ADNI database with CSF biomarkers were divided into four groups: A-(TN)- (normal Aß42 and normal p-tau and t-tau; n = 50), A+(TN)- (abnormal Aß42 and normal p-tau and t-tau; n = 39), A+(TN) + (abnormal Aß42 and abnormal p-tau or t-tau; n = 147), A-(TN) + (normal Aß42 and abnormal p-tau or t-tau; n = 40). To assess CSF clusterin levels in AD continuum, intergroup differences in four groups were compared. Pairwise comparisons were conducted as appropriate followed by Bonferroni post hoc analyses. To further study the relationships between CSF clusterin levels and AD core pathological biomarkers, we employed multiple linear regression method in subgroups. RESULTS: Compared with the A-(TN)- group, CSF clusterin levels were decreased in A+ (TN)- group (P = 0.002 after Bonferroni correction), but increased in the A+(TN) + group and the A-(TN) + group (both P <  0.001 after Bonferroni correction). Moreover, we found CSF clusterin levels are positively associated with CSF Aß42 (ß = 0.040, P <  0. 001), CSF p-tau (ß = 0.325, P <  0.001) and CSF t-tau (ß = 0.346, P <  0.001). CONCLUSIONS: Our results indicated that there are differences levels of CSF clusterin in different stages of AD pathology. The CSF clusterin level decreased at the early stage are related to abnormal Aß pathology; and the increased levels are associated with tau pathology and neurodegeneration.

Metabolically healthy obesity and lipids may be protective factors for pathological changes of alzheimer's disease in cognitively normal adults.

The associations between obesity and Alzheimer's disease (AD) at different ages have been debated. Recent evidence implied the protective effects of metabolically healthy obesity on AD. We hypothesized that obesity and lipids could mitigate the detrimental impacts of AD pathological changes among metabolically healthy individuals in late life. In this study, a total of 604 metabolically healthy participants with normal cognition were included from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database. Multiple linear regression models were used to test the associations of body mass index (BMI) or lipids with cerebrospinal fluid (CSF) biomarkers after adjustment for age, gender, education, and Apolipoprotein E-ɛ4 (APOE-ɛ4). The results showed the lower CSF levels of total tau protein (t-tau: p = .0048) and phosphorylated tau protein (p-tau: p = .0035) in obese participants than in non-obese participants, even after correcting for covariates. Moreover in late life, higher BMI was associated with decreased CSF t-tau (ß: -0.15, p = .0145) and p-tau (ß: -0.17, p = .0052). As for lipids, higher levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were associated with decreased CSF t-tau (TC: ß: -0.16, p = .0115; LDL-C: ß: -0.16, p = .0082) and p-tau (TC: ß: -0.15, p = .0177; LDL-C: ß: -0.14, p = .0225) in obese participants. Furthermore, these associations were only significant in participants with late-life obesity and APOE-ɛ4 non-carriers. Overall, in a cognitively normal population, we found metabolically healthy obesity and lipids in late life might be protective factors for neurodegenerative changes.

Anaemia and cerebrospinal fluid biomarkers of Alzheimer's pathology in cognitively normal elders: the CABLE study.

BACKGROUND: Anaemia has been reported to be associated with cognitive decline and Alzheimer's disease (AD), but the associations between anaemia and cerebrospinal fluid (CSF) AD biomarkers are still unknown. This study aimed to investigate the associations between anaemia and CSF AD biomarkers. METHODS: Participants were included from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study. The associations of anaemia and its severity with CSF AD biomarkers including ß-amyloid 1-42 (Aß42), total tau (t-tau) and phosphorylated tau (p-tau) were analysed by multiple linear regression models. Adjusted for age, gender, educational levels, APOE ε4 alleles, comorbidities (history of coronary heart disease, history of stroke, hypertension, diabetes mellitus, dyslipidaemia) and glomerular filtration rate. RESULTS: A total of 646 cognitively normal older adults, consisting of 117 anaemia patients and 529 non-anaemia individuals, were included in this study. Anaemia patients had lower levels of CSF Aß42 than individuals without anaemia (p = 0.035). Besides, participants with more severe anaemia had lower CSF Aß42 levels (p = 0.045). No significant association of anaemia with CSF t-tau and p-tau levels was found. CONCLUSION: Cross-sectionally, anaemia was associated with lower CSF Aß42 levels. These findings consolidated the causal close relationship between anaemia and AD.

Sleep problems and risk of all-cause cognitive decline or dementia: an updated systematic review and meta-analysis.

OBJECTIVES: To conduct an updated systematic review and meta-analysis of association between sleep and all-cause cognitive disorders. METHODS: PubMed and EMBASE were searched from inception to 18 February 2019. Cohort studies exploring longitudinal associations of sleep with cognitive decline or dementia were included. The multivariable-adjusted effect estimates were pooled by random-effects models, with credibility assessment. The robust error meta-regression model was used to conduct the dose-response meta-analysis for sleep duration. RESULTS: 11 155 reports were searched and 51 eligible cohorts with 15 sleep problems were included for our meta-analyses. Ten types of sleep conditions or parameters, including six (insomnia, fragmentation, daytime dysfunction, prolonged latency, rapid eye movement sleep behaviour disorder and excessive time in bed) with moderate-to-high levels of evidence, were linked to higher risk of all-cause cognitive disorders. Furthermore, a U-shaped relationship was revealed for the associations with sleep duration. CONCLUSIONS: Sleep management might serve as a promising target for dementia prevention.

Association of peripheral neutrophil count with intracranial atherosclerotic stenosis.

BACKGROUND: Inflammation plays an important role in atherosclerosis but the contribution of neutrophils to this process is unclear. We sought to assess whether neutrophil count is associated with intracranial atherosclerotic stenosis (ICAS). METHODS: A total of 2847 individuals were included in our study, including 1363 with acute ischemic stroke and 1484 normal controls without stroke. The presence of ICAS was confirmed by magnetic resonance angiography. The association between neutrophil count and ICAS was evaluated by multivariable logistic regression analysis. RESULTS: Among 2847 individuals included in this study, individuals with ICAS had higher neutrophil counts than those without ICAS in groups with and without stroke (P <  0.0001 for stroke group, P = 0.0097 for group without stroke). The multivariable logistic regression analysis showed that the third and fourth quartiles were independent predictors of ICAS in all the subjects (Q3: OR 1.81, 95% CI 1.39-2.37, Q4: OR 2.29, 95% CI 1.70-3.10) and patients in the fourth quartile had a higher risk for the occurrence of ICAS in stroke group (Q4: OR 2.82, 95% CI 1.79-4.48). However, there was no significant association between neutrophil count and ICAS in the group without stroke. CONCLUSIONS: The levels of circulating neutrophils were associated with the presence of ICAS. Our findings suggest that neutrophils may play a role in the pathogenesis of stroke related to ICAS and emphasize the need to develop proper strategies to control neutrophil response for the treatment of ICAS.

Models for predicting risk of dementia: a systematic review.

BACKGROUND: Information from well-established dementia risk models can guide targeted intervention to prevent dementia, in addition to the main purpose of quantifying the probability of developing dementia in the future. METHODS: We conducted a systematic review of published studies on existing dementia risk models. The models were assessed by sensitivity, specificity and area under the curve (AUC) from receiver operating characteristic analysis. RESULTS: Of 8462 studies reviewed, 61 articles describing dementia risk models were identified, with the majority of the articles modelling late life risk (n=39), followed by those modelling prediction of mild cognitive impairment to Alzheimer's disease (n=15), mid-life risk (n=4) and patients with diabetes (n=3). Age, sex, education, Mini Mental State Examination, the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological assessment battery, Alzheimer's Disease Assessment Scale-cognitive subscale, body mass index, alcohol intake and genetic variables are the most common predictors included in the models. Most risk models had moderate-to-high predictive ability (AUC>0.70). The highest AUC value (0.932) was produced from a risk model developed for patients with mild cognitive impairment. CONCLUSION: The predictive ability of existing dementia risk models is acceptable. Population-specific dementia risk models are necessary for populations and subpopulations with different characteristics.

Inflammatory markers in Alzheimer's disease and mild cognitive impairment: a meta-analysis and systematic review of 170 studies.

OBJECTIVE: Inflammation plays a crucial role in the pathogenesis of mild cognitive impairment (MCI) and Alzheimer's disease (AD). Our study aimed to analyse previous inconsistent results of inflammatory markers in AD and MCI quantitatively. METHODS: Studies reporting concentrations of peripheral or cerebrospinal fluid (CSF) markers were included, and eligible data on AD, MCI and control were extracted. Pooled Hedges's g was adopted to illustrate comparisons, and various confounding factors were used to explore sources of heterogeneity. RESULTS: A total of 170 studies were included in the meta-analysis and systematic review, which demonstrated increased peripheral levels of high-sensitivity C reactive protein (Hedges's g 0.281, p<0.05), interleukin-6 (IL-6) (0.429, p<0.005), soluble tumour necrosis factor receptor 1 (sTNFR1) (0.763, p<0.05), soluble tumour necrosis factor receptor 2 (sTNFR2) (0.354, p<0.005), alpha1-antichymotrypsin (α1-ACT) (1.217, p<0.005), IL-1ß (0.615, p<0.05) and soluble CD40 ligand (0.868, p<0.005), and CSF levels of IL-10 (0.434, p<0.05), monocyte chemoattractant protein-1 (MCP-1) (0.798, p<0.005), transforming growth factor-beta 1 (1.009, p<0.05), soluble triggering receptor expressed on myeloid cells2 (sTREM2) (0.587, p<0.001), YKL-40 (0.849, p<0.001), α1-ACT (0.638, p<0.001), nerve growth factor (5.475, p<0.005) and visinin-like protein-1 (VILIP-1) (0.677, p<0.005), in AD compared with the control. Higher levels of sTNFR2 (0.265, p<0.05), IL-6 (0.129, p<0.05) and MCP-1 (0.779, p<0.05) and lower levels of IL-8 (-1.293, p<0.05) in the periphery, as well as elevated concentrations of YKL-40 (0.373, p<0.05), VILIP-1 (0.534, p<0.005) and sTREM2 (0.695, p<0.05) in CSF, were shown in MCI compared with the control. Additionally, increased peripheral sTNFR1 (0.582, p<0.05) and sTNFR2 (0.254, p<0.05) levels were observed in AD compared with MCI. CONCLUSION: Significantly altered levels of inflammatory markers were verified in comparison between AD, MCI and control, supporting the notion that AD and MCI are accompanied by inflammatory responses in both the periphery and CSF.

Modifiable risk factors for cognitive impairment in Parkinson's disease: A systematic review and meta-analysis of prospective cohort studies.

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.

Dietary Components and Nutritional Strategies for Dementia Prevention in the Elderly.

BACKGROUND: For decades, evidence from observational studies and randomized controlled trials has converged to suggest associations of dietary components, foods, and dietary patterns with dementia. With population aging and a projected exponential expansion of people living with dementia, formulating nutritional strategies for dementia prevention has become a research hotspot. OBJECTIVE: This review aimed to summarize available data on the roles of specific dietary components, food groups, and dietary patterns in dementia prevention among the elderly. METHODS: Database search was carried out using PubMed, the Cochrane Library, EMBASE, and Medline. RESULTS: Polyphenols, folate, vitamin D, omega-3 fatty acids, and ß-carotene might decrease the risk of dementia. Consumption of green leafy vegetables, green tea, fish, and fruits is recommended. However, saturated fat, a diet rich in both dietary copper and saturated fat, aluminum from drinking water, and heavy drinking might increase dementia risk. Healthy dietary patterns, especially the Mediterranean diet, were proven to bring more cognitive benefits than single dietary components. CONCLUSION: We discussed and summarized the evidence on the roles of dietary components and patterns in dementia prevention among the elderly and found that some factors were closely associated with dementia risk in elderly. This may pave the way for the identification of dietary components and patterns as new therapeutic targets for dementia prevention in the elderly population.

Heart fatty acid-binding protein is associated with phosphorylated tau and longitudinal cognitive changes.

Background: Perturbation of lipid metabolism is associated with Alzheimer's disease (AD). Heart fatty acid-binding protein (HFABP) is an adipokine playing an important role in lipid metabolism regulation. Materials and methods: Two datasets separately enrolled 303 and 197 participants. First, we examine the associations of cerebrospinal fluid (CSF) HFABP levels with cognitive measures [including Mini-Mental State Examination (MMSE), Clinical Dementia Rating sum of boxes (CDRSB), and the cognitive section of Alzheimer's Disease Assessment Scale] and AD biomarkers (CSF amyloid beta and tau levels). Second, we examine the longitudinal associations of baseline CSF HFABP levels and the variability of HFABP with cognitive measures and AD biomarkers. Structural equation models explored the mediation effects of AD pathologies on cognition. Results: We found a significant relationship between CSF HFABP level and P-tau (dataset 1: ß = 2.04, p < 0.001; dataset 2: ß = 1.51, p < 0.001). We found significant associations of CSF HFABP with longitudinal cognitive measures (dataset 1: ADAS13, ß = 0.09, p = 0.008; CDRSB, ß = 0.10, p = 0.003; MMSE, ß = -0.15, p < 0.001; dataset 2: ADAS13, ß = 0.07, p = 0.004; CDRSB, ß = 0.07, p = 0.005; MMSE, ß = -0.09, p < 0.001) in longitudinal analysis. The variability of HFABP was associated with CSF P-tau (dataset 2: ß = 3.62, p = 0.003). Structural equation modeling indicated that tau pathology mediated the relationship between HFABP and cognition. Conclusion: Our findings demonstrated that HFABP was significantly associated with longitudinal cognitive changes, which might be partially mediated by tau pathology.

A Multi-Dimensional Comparison of Alzheimer's Disease Neurodegenerative Biomarkers.

BACKGROUND: In the 2018 AT(N) framework, neurodegenerative (N) biomarkers plays an essential role in the research and staging of Alzheimer's disease (AD); however, the different choice of N may result in discordances. OBJECTIVE: We aimed to compare different potential N biomarkers. METHODS: We examined these N biomarkers among 1,238 participants from Alzheimer's Disease Neuroimaging Initiative (ADNI) in their 1) diagnostic utility, 2) cross-sectional and longitudinal correlations between different N biomarkers and clinical variables, and 3) the conversion risk of different N profiles. RESULTS: Six neurodegenerative biomarkers changed significantly from preclinical AD, through prodromal AD to AD dementia stage, thus they were chosen as the candidate N biomarkers: hippocampal volume (HV), 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET), cerebrospinal fluid (CSF), total tau (T-tau), plasma neurofilament light chain (NFL), CSF NFL, and CSF neurogranin (Ng). Results indicated that FDG-PET not only had the greatest diagnostic utility in differentiating AD from controls (area under the curve: FDG-PET, 0.922), but also had the strongest association with cognitive scores. Furthermore, FDG-PET positive group showed the fastest memory decline (hazard ratio: FDG-PET, 3.45), which was also true even in the presence of amyloid-ß pathology. Moreover, we observed great discordances between three valuable N biomarkers (FDG-PET, HV, and T-tau). CONCLUSION: These results underline the importance of using FDG-PET as N in terms of cognitive decline and AD conversion, followed by HV, and could be a great complement to the AT(N) framework.

Efficacy and Safety of Probiotics for the Treatment of Alzheimer's Disease, Mild Cognitive Impairment, and Parkinson's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Alzheimer's disease (AD) and Parkinson's disease (PD) are two of the most common neurodegenerative diseases, and mild cognitive impairment (MCI) is considered a prodromal stage of clinical AD. Animal studies have shown that probiotics can improve cognitive function and mitigate inflammatory response, however, results from randomized controlled trials in humans are still unclear. OBJECTIVES: A systematic review and meta-analysis was conducted to evaluate the efficacy and safety of probiotic therapy on cognitive function, oxidative stress, and gastrointestinal function in patients with AD, MCI, and PD. METHODS: We searched the electronic databases such as PubMed, EMBASE, Cochrane Library until October 2020 for the eligible randomized controlled trials, as well as the unpublished and ongoing trials. Our primary endpoints were cognitive function, inflammatory and oxidative stress biomarkers, gastrointestinal function, and adverse events. RESULTS: After screening 2,459 titles and abstracts about AD or MCI, we selected 6 eligible studies (n = 499 patients). After screening 1,923 titles and abstracts about PD, we selected 5 eligible studies (n = 342 patients). Compared with the control group, treatment with probiotics improved the cognitive function of patients with AD in the intervention group (P = 0.023). Cognitive function also improved in MCI patients (P = 0.000). Inflammation-related indicators: Malondialdehyde (MDA) was significantly reduced (P = 0.000); and hs-CRP decreased (P = 0.003). Lipid-related indicators: VLDL decreased (P = 0.026); triglyceride decreased (P = 0.009); and insulin resistance level improved: decreased Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) (P = 0.019). CONCLUSION: Our analyses suggest that probiotics can improve cognitive and gastrointestinal symptoms in patients with AD, MCI, and PD, which is possibly through reducing inflammatory response and improving lipid metabolism. The safety has also been proven. However, more RCTs with rigorous study design are needed to support our findings. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, Identifier: CRD42021231502.

Neuroinflammation modulates the association of PGRN with cerebral amyloid-ß burden.

Progranulin (PGRN) and neuroinflammatory markers increased over the course of Alzheimer's disease (AD). We aimed to determine whether neuroinflammation could modulate the association of PGRN with amyloid pathologies. Baseline cerebrospinal fluid (CSF) PGRN and AD pathologies were measured for 965 participants, among whom 228 had measurements of CSF neuroinflammatory markers. Causal mediation analyses with 10,000 bootstrapped iterations were conducted to explore the mediation effects within the framework of A/T/N biomarker profile. Increased levels of CSF PGRN and inflammatory markers (sTNFR1, sTNFR2, TGF-ß1, ICAM1, and VCAM1) were associated with T- or N-positive (TN+) profile, irrespective of the amyloid pathology. In TN+ group, CSF PGRN was associated with increased levels of these inflammatory markers and CSF amyloid-ß1-42 (p < 0.01). The neuroinflammatory markers significantly modulated (proportion: 20%~60%) the relationship of amyloid burden with CSF PGRN, which could predict slower cognitive decline and lower AD risk in the TN+ group. The abovementioned associations became non-significant in the TN- group. These findings revealed a close relationship between neuroinflammation and CSF PGRN in contributing to AD pathogenesis, and also highlighted the specific roles of PGRN in neurodegenerative conditions. Future experiments are warranted to verify the causal relationship.

Insomnia Moderates the Relationship Between Amyloid-ß and Cognitive Decline in Late-Life Adults without Dementia.

BACKGROUND: It is suggested that not all individuals with elevated Aß will develop dementia or cognitive impairment. Environment or lifestyle might modulate the association of amyloid pathology with cognition. Insomnia is a risk factor of cognitive disorders including Alzheimer's disease. OBJECTIVE: To investigate if insomnia moderated the relationship between amyloid-ß (Aß) and longitudinal cognitive performance in non-demented elders. METHODS: A total of 385 Alzheimer's Disease Neuroimaging Initiative participants (mean age = 73 years, 48% females) who completed 4 + neuropsychological evaluations and a [18F] florbetapir positron emission tomography scan were followed up to 8 years. Linear mixed-effects regression models were used to examine the interactions effect between insomnia and Aß on longitudinal cognitive sores, including four domains (memory [MEM], executive function [EF], language [LAN], and visuospatial function [VS]). RESULTS: The Aß-positive status (A+) but not insomnia independently predicted faster cognitive decline in all domains. Furthermore, the relationship between Aß and cognitive decline was moderated by insomnia (MEM: χ2 = 4.05, p = 0.044, EF: χ2 = 4.38, p = 0.036, LAN: χ2 = 4.56, p = 0.033, and VS: χ2 = 4.12, p = 0.042). Individuals with both elevated Aß and insomnia experienced faster cognitive decline than those with only elevated Aß or insomnia. CONCLUSION: These data reinforced the values of insomnia management in preventing dementia, possibly by interacting Aß metabolism. Future efforts are warranted to determine whether sleep improvement will postpone the onset of dementia, specifically among populations in stages of preclinical or prodromal AD.

Predictors of cognitive impairment in Parkinson's disease: a systematic review and meta-analysis of prospective cohort studies.

INTRODUCTION: Cognitive impairment is a debilitating manifestation in Parkinson's disease (PD). We sought to investigate predictors of PD-CI (PD with cognitive impairment). METHODS: 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. RESULTS: 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 ε2 (RR = 6.47, 95% CI = 1.29-32.53), APOE ε4 (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 < median (RR = 1.77, 95% CI = 1.07-2.92). In the subgroup analysis, MAPT H1/H1 genotype increased the risk of dementia in PD. Sixty-four studies were included in the systematic review, of which 12 factors were additionally correlated with PD-CI using single studies. CONCLUSIONS: Advanced age, genetic variation in APOE and MAPT, gait disturbance, motor assessments, non-motor symptoms, and electroencephalogram may be promising predictors for PD-CI.

The Proportion of APOE4 Carriers Among Non-Demented Individuals: A Pooled Analysis of 389,000 Community-Dwellers.

BACKGROUND: The apolipoprotein E epsilon 4 (APOE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). Its carriage percentage in non-demented population varies across geographic regions and ethnic groups. OBJECTIVE: To estimate the proportion of APOE4 (2/4, 3/4, or 4/4) carriers in non-demented community-dwellers. METHODS: PubMed, EMBASE, and China National Knowledge Infrastructure were searched from inception to April 20, 2020. Community-based studies that reported APOE polymorphisms with a sample of≥500 non-demented participants were included. Random-effects models were used to pool the results. Meta-regression and subgroup analyses were performed to test the source of heterogeneity and stratified effects. Age-standardized pooled proportion estimates (ASPPE) were calculated by direct standardization method. RESULTS: A total of 121 studies were included, with a pooled sample of  389,000 community-dwellers from 38 countries. The global average proportion of APOE4 carriers was 23.9% (age-standardized proportion: 26.3%; 2.1% for APOE4/4, 20.6% for APOE3/4 and 2.3% for APOE2/4), and varied significantly with geographical regions (from 19.3% to 30.0%) and ethnic groups (from 19.1% to 37.5%). The proportion was highest in Africa, followed by Europe, North America, Oceania, and lowest in South America and Asia (p < 0.0001). With respect to ethnicity, it was highest in Africans, followed by Caucasians, and was lowest in Hispanics/Latinos and Chinese (p < 0.0001). CONCLUSION: APOE4 carriers are common in communities, especially in Africans and Caucasians. Developing precision medicine strategies in this specific high-risk population is highly warranted in the future.

Social Networks and Cerebrospinal Fluid Biomarkers of Alzheimer's Disease Pathology in Cognitively Intact Older Adults: The CABLE Study.

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-ß (Aß1-42 and Aß1-40) 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/Aß1-42 and T-tau/Aß1-42 and high Aß1-42/Aß1-40). 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 (ß= -0.005, p < 0.001), Aß1-42/Aß1-40 (ß= 0.481, p = 0.001), and T-tau/Aß1-42 (ß= -0.047, p < 0.001) were noted in preclinical AD stage than controls. CONCLUSION: These findings consolidated strong links between social networks and AD risks. Social networks as a modifiable lifestyle probably affected metabolisms of multiple AD pathologies, especially among at-risk populations.

Associations of Alcohol Consumption with Cerebrospinal Fluid Biomarkers of Alzheimer's Disease Pathology in Cognitively Intact Older Adults: The CABLE Study.

BACKGROUND: The relationship between alcohol consumption and Alzheimer's disease (AD) pathology is unclear. Amyloid-ß (Aß) and tau biomarkers in cerebrospinal fluid (CSF) have been proven valuable in establishing prognosis in pre-clinical AD. OBJECTIVE: We sought to examine the associations between alcohol consumption and CSF AD biomarkers in cognitive intact subjects. METHODS: A total of 806 cognitively intact participants who had measurements of CSF Aß, pTau, and total Tau proteins and drinking characteristics were included from the Chinese Alzheimer's Biomarker and Lifestyle (CABLE) study. Linear and logistic regression analyses were utilized to explore the associations of alcohol consumption with CSF AD biomarkers. We examined the interaction effects of age, gender, and apolipoprotein epsilon (APOE) ɛ4 status on the relationships between the frequency of drinking and CSF biomarkers. RESULTS: The multiple linear regression analyses revealed significant differences in CSF AD biomarkers between infrequent drinking (< 1 times/week) and frequent drinking groups (≥1 times/week). Participants in frequent drinking group had higher CSF p-tau/Aß42 and tTau/Aß42. Frequent drinking was significantly associated with greater pTau and tTau abnormalities compared to the infrequent drinking group in older (> 65 years) participants. CONCLUSION: The present study showed significant associations between drinking frequency and CSF AD biomarkers in cognitively intact older adults. Alcohol consumption may have an influence on AD by modulating amyloid deposition and tau phosphorylation in the preclinical stage.