Associations between cardiometabolic multimorbidity and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact adults: the CABLE study.

BACKGROUND: Cardiometabolic multimorbidity is associated with an increased risk of dementia, but the pathogenic mechanisms linking them remain largely undefined. We aimed to assess the associations of cardiometabolic multimorbidity with cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathology to enhance our understanding of the underlying mechanisms linking cardiometabolic multimorbidity and AD. METHODS: This study included 1464 cognitively intact participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database. Cardiometabolic diseases (CMD) are a group of interrelated disorders such as hypertension, diabetes, heart diseases (HD), and stroke. Based on the CMD status, participants were categorized as CMD-free, single CMD, or CMD multimorbidity. CMD multimorbidity is defined as the coexistence of two or more CMDs. The associations of cardiometabolic multimorbidity and CSF biomarkers were examined using multivariable linear regression models with demographic characteristics, the APOE ε4 allele, and lifestyle factors as covariates. Subgroup analyses stratified by age, sex, and APOE ε4 status were also performed. RESULTS: A total of 1464 individuals (mean age, 61.80 years; age range, 40-89 years) were included. The markers of phosphorylated tau-related processes (CSF P-tau181: ß = 0.165, P = 0.037) and neuronal injury (CSF T-tau: ß = 0.065, P = 0.033) were significantly increased in subjects with CMD multimorbidity (versus CMD-free), but not in those with single CMD. The association between CMD multimorbidity with CSF T-tau levels remained significant after controlling for Aß42 levels. Additionally, significantly elevated tau-related biomarkers were observed in patients with specific CMD combinations (i.e., hypertension and diabetes, hypertension and HD), especially in long disease courses. CONCLUSIONS: The presence of cardiometabolic multimorbidity was associated with tau phosphorylation and neuronal injury in cognitively normal populations. CMD multimorbidity might be a potential independent target to alleviate tau-related pathologies that can cause cognitive impairment.

Associations between multimorbidity burden and Alzheimer's pathology in older adults without dementia: the CABLE study.

Studies have shown that multimorbidity may be associated with the Alzheimer's disease (AD) stages, but it has not been fully characterized in patients without dementia. A total of 1402 Han Chinese older adults without dementia from Chinese Alzheimer's Biomarker and LifestylE (CABLE) study were included and grouped according to their multimorbidity patterns, defined by the number of chronic disorders and cluster analysis. Multivariable linear regression models were used to detect the associations with AD-related cerebrospinal fluid (CSF) biomarkers. Multimorbidity and severe multimorbidity (≥4 chronic conditions) were significantly associated with CSF amyloid and tau levels (pFDR < 0.05). Metabolic patterns were significantly associated with higher levels of CSF Aß40 (ß = 0.159, pFDR = 0.036) and tau (P-tau: ß = 0.132, pFDR = 0.035; T-tau: ß = 0.126, pFDR = 0.035). The above associations were only significant in the cognitively normal (CN) group. Multimorbidity was associated with brain AD pathology before any symptomatic evidence of cognitive impairment. Identifying such high-risk groups might allow tailored interventions for AD prevention.

Cerebral Small Vessel Disease Burden Predicts Neurodegeneration and Clinical Progression in Prodromal Alzheimer's Disease.

BACKGROUND: Cerebral small vessel disease (CSVD) has been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). OBJECTIVE: This study aimed to comprehensively investigated the associations of CSVD burden with cognition and AD pathologies. METHODS: A total of 546 non-demented participants (mean age, 72.1 years, range, 55-89; 47.4% female) were included. The longitudinal neuropathological and clinical correlates of CSVD burden were assessed using linear mixed-effects and Cox proportional-hazard models. Partial least squares structural equation model (PLS-SEM) was used to assess the direct and indirect effects of CSVD burden on cognition. RESULTS: We found that higher CSVD burden was associated with worse cognition (MMSE, ß= -0.239, p = 0.006; MoCA, ß= -0.493, p = 0.013), lower cerebrospinal fluid (CSF) Aß level (ß= -0.276, p < 0.001) and increased amyloid burden (ß= 0.048, p = 0.002). In longitudinal, CSVD burden contributed to accelerated rates of hippocampus atrophy, cognitive decline, and higher risk of AD dementia. Furthermore, as the results of PLS-SEM, we observed both significant direct and indirect impact of advanced age (direct, ß= -0.206, p < 0.001; indirect, ß= -0.002, p = 0.043) and CSVD burden (direct, ß= -0.096, p = 0.018; indirect, ß= -0.005, p = 0.040) on cognition by Aß-p-tau-tau pathway. CONCLUSION: CSVD burden could be a prodromal predictor for clinical and pathological progression. Simultaneously, we found that the effects were mediated by the one-direction-only sequence of pathological biomarker changes starting with Aß, through abnormal p-tau, and neurodegeneration.

Associations of Lung Function Decline with Risks of Cognitive Impairment and Dementia: A Meta-Analysis and Systematic Review.

BACKGROUND: There are controversies surrounding the effects of lung function decline on cognitive impairment and dementia. OBJECTIVE: We conducted a meta-analysis and systematic review to explore the associations of lung function decline with the risks of cognitive impairment and dementia. METHODS: The PubMed, EMBASE, and the Cochrane Library were searched to identify prospective studies published from database inception through January 10, 2023. We pooled relative risk (RR) and 95% confidence intervals (CI) using random-effects models. The Egger test, funnel plots, meta-regression, sensitivity, and subgroup analyses were conducted to detect publication bias and investigate the source of heterogeneity. RESULTS: Thirty-three articles with a total of 8,816,992 participants were subjected to meta-analysis. Poorer pulmonary function was associated with an increased risk of dementia (FEV: RR = 1.25 [95% CI, 1.17-1.33]; FVC: RR = 1.40 [95% CI, 1.16-1.69]; PEF: RR = 1.84 [95% CI, 1.37-2.46]). The results of the subgroup analyses were similar to the primary results. Individuals with lung diseases had a higher combined risk of dementia and cognitive impairment (RR = 1.39 [95% CI, 1.20-1.61]). Lung disease conferred an elevated risk of cognitive impairment (RR = 1.37 [95% CI, 1.14-1.65]). The relationship between lung disease and an increased risk of dementia was only shown in total study participants (RR = 1.32 [95% CI, 1.11-1.57]), but not in the participants with Alzheimer's disease (RR = 1.39 [95% CI, 1.00-1.93]) or vascular dementia (RR = 2.11 [95% CI, 0.57-7.83]). CONCLUSION: Lung function decline was significantly associated with higher risks of cognitive impairment and dementia. These findings might provide implications for the prevention of cognitive disorders and the promotion of brain health.

Association between Kidney Function and the Burden of Cerebral Small Vessel Disease: An Updated Meta-Analysis and Systematic Review.

INTRODUCTION: Due to anatomical and functional similarities in microvascular beds, the brain and kidney share distinctive susceptibilities to vascular injury and common risk factors of small vessel disease. The aim of this updated meta-analysis is to explore the association between kidney function and the burden of cerebral small vessel disease (CSVD). METHODS: PubMed, EMBASE, and Cochrane Library were systematically searched for observational studies that explored the association between the indicators of kidney function and CSVD neuroimaging markers. The highest-adjusted risk estimates and their 95% confidence intervals (CIs) were aggregated using random-effect models. RESULTS: Twelve longitudinal studies and 51 cross-sectional studies with 57,030 subjects met the inclusion criteria of systematic review, of which 52 were included in quantitative synthesis. According to the pooled results, we found that low estimated glomerular filtration rate (eGFR <60 mL/min/1.73 m2) was associated with cerebral microbleeds (odds ratio (OR) = 1.55, 95% CI = 1.26-1.90), white matter hyperintensities (OR = 1.40, 95% CI = 1.05-1.86), and lacunar infarctions (OR = 1.50, 95% CI = 1.18-1.92), but not with severe perivascular spaces (OR = 1.20, 95% CI = 0.77-1.88). Likewise, patients with proteinuria (OR = 1.75, 95% CI = 1.47-2.09) or elevated serum cystatin C (OR = 1.51, 95% CI = 1.25-1.83) also had an increased risk of CSVD. CONCLUSION: The association between kidney function and CSVD has been comprehensively updated through this study, that kidney insufficiency manifested as low eGFR, proteinuria, and elevated serum cystatin C was independently associated with CSVD burden.

Residential greenness and risk of incident dementia: A prospective study of 375,342 participants.

INTRODUCTION: Incorporation of greenspace may be a novel environmental policy that might result in positive health effects; hence, this study aimed to investigate the association between residential greenness and dementia incidence. The effects of particulate air pollution on mediating dementia were also determined. METHODS: A prospective cohort study involving 375,342 UK biobank participants was conducted, in which Cox regression models were used to determine the association of greenspace exposure with the risks of all-cause dementia (ACD), Alzheimer's disease (AD) and vascular dementia (VD). Sociodemographic variables, lifestyle or dietary characteristics and apolipoprotein E4 status were controlled using two levels of adjusted models. Mediation analyses were performed to determine the mediation effects of PMs. RESULTS: The results indicated that there were 4929 ACD, 2132 AD, and 1184 VD incidents throughout the 8-year study. In the multi-adjusted model, each interquartile increment in greenspace (buffer 300m) conferred the lower risks of ACD (HR = 0.968, 95% confidence intervals [CI]: 0.938-1.000]) and VD (HR = 0.926, 95% CI: 0.867-0.989). The fourth greenspace quartile conferred also reduced risks of ACD (HR = 0.891, 95% CI: 0.804-0.989) and VD (HR = 0.778, 95% CI: 0.630-0.960) in reference to the first quartile. With regard to 1000m catchment, each interquartile increment conferred a 5.0% (95% CI: 1.8-8.1) lower risk of ACD, and the fourth greenspace quartile conferred a 10.9% (95% CI: 0.9-19.8) lower risk of ACD compared to the first quartile. The protective effect of greenness might be mediated based on the reduction of PM2.5 and PM10 (Pindirect effect<0.05). CONCLUSIONS: Increasing greenness reduces the risk of dementia. This study suggests that greenspace is an environmental strategy that helps prevent dementia.

Association between multimorbidity status and incident dementia: a prospective cohort study of 245,483 participants.

Multimorbidity (the presence of two or more long-term conditions [LTCs]) was suggested to exacerbate the neuronal injuries. The impact of multimorbidity on dementia has not been fully elucidated. We aimed to investigate the association between multimorbidity and dementia risk. We used the prospective data from 245,483 UK Biobank participants during a 9-year follow-up. Multimorbidity status was evaluated based on the LTC counts and multimorbidity patterns. Cox regression models adjusted for potential confounders were used to examine the associations of multimorbidity status with all-cause dementia (ACD), Alzheimer's disease (AD) and vascular dementia (VD). Participants with multimorbidity at baseline had higher risks of ACD and VD, and the risks were elevated with the increase of LTC counts (ACD: hazard ratios [HR] = 1.15, 95% confidence intervals [CI] = 1.01-1.31 with 2 LTCs; HR = 1.18, CI = 1.01-1.39 with 3 LTCs; HR = 1.65, CI = 1.44-1.88 with ≥4 LTCs; VD: HR = 1. 66, CI = 1.24-2.21 with 2 LTCs; HR = 2.10, CI = 1.53-2.88 with 3 LTCs; HR = 3.17, CI = 2.43-4.13 with ≥4 LTCs). Participants with ≥4 LTCs also had a higher risk of AD (HR = 1.34, CI = 1.08-1.66]. Participants with the cardio-cerebrovascular/respiratory/metabolic/musculoskeletal/depressive multimorbidity were 1.46, 1.28, and 2.50 times more likely to develop ACD (HR = 1.46, 95% CI = 1.28-1.67), AD (HR = 1.28, CI = 1.04-1.58), and VD (HR = 2.50, CI = 1.90-3.27), respectively. Those with tumor/genitourinary/digestive disorders had a 11% higher hazard of ACD (HR = 1.11, CI = 1.00-1.24) and a 73% elevated risk of VD (HR = 1.73, CI = 1.37-2.18). The prevention of LTC accumulation and the identification of specific multimorbidity patterns might be beneficial to the prevention of dementia and its subtypes, AD as well as VD.

Association between air pollution and CSF sTREM2 in cognitively normal older adults: The CABLE study.

OBJECTIVES: Ambient air pollution aggravates the process of Alzheimer's disease (AD) pathology. Currently, the exact inflammatory mechanisms underlying these links from clinical research remain largely unclear. METHODS: This study included 1,131 cognitively intact individuals from the Chinese Alzheimer's Biomarker and LifestylE database with data provided on cerebrospinal fluid (CSF) AD biomarkers (amyloid beta-peptide 42 [Aß42], total tau [t-tau], and phosphorylated tau [p-tau]), neuroinflammatory (CSF sTREM2), and systemic inflammatory markers (high sensitivity C-reactive protein and peripheral immune cells). The 2-year averaged levels of ambient fine particulate matter with diameter <2.5 µm (PM2.5 ), nitrogen dioxide (NO2 ), and ozone (O3 ) were estimated at each participant's residence. Multiple-adjusted models were approached to detect associations of air pollution with inflammatory markers and AD-related proteins. RESULTS: Ambient 2-year averaged exposure of PM2.5 was associated with changes of neuroinflammatory markers, that is, CSF sTREM2 (ß = -0.116, p = 0.0002). Similar results were found for O3 exposure among the elderly (ß = -0.111, p = 0.0280) or urban population (ß = -0.090, p = 0.0144). No significant evidence supported NO2 related to CSF sTREM2. For potentially causal associations with accumulated AD pathologies, the total effects of PM2.5 on CSF amyloid-related protein (CSF Aß42 and p-tau/Aß42) were partly mediated by CSF sTREM2, with proportions of 14.22% and 47.15%, respectively. Additional analyses found inverse associations between peripheral inflammatory markers with PM2.5 and NO2 , but a positive correlation with O3 . INTERPRETATION: These findings demonstrated a strong link between PM2.5 exposure and microglial dysfunction. Furthermore, CSF sTREM2 as a key mediator modulated the influences of PM2.5 exposure on AD amyloid pathologies.

The Association Between Osteoarthritis with Risk of Dementia and Cognitive Impairment: A Meta-Analysis and Systematic Review.

BACKGROUND: The relationship between osteoarthritis (OA) and risk of dementia and cognitive impairment (CIM) has long been debated; however, uncertainties still persist. OBJECTIVE: The aim of our present meta-analysis and systematic review was to roundly illuminate the association between OA and the risk of dementia and CIM. METHODS: We identified relevant studies by searching PubMed, Embase, and Web of Science up to October 2021. The relative risk (RR) or odds ratio (OR) with 95% confidence interval (CI) were aggregated using random-effects methods. Credibility of each meta-analysis was assessed. Meta-regression and subgroup analyses were conducted. Publication bias was explored using funnel plot. RESULTS: Of 21,925 identified literatures, 8 were eligible for inclusion in the systematic review and 19 observational studies involving 724,351 individuals were included in the meta-analysis. The risk of developing dementia and CIM among OA patients was demonstrated in 11 prospective studies (RR = 1.42, 95% CI = 1.07-1.86, I2 = 98.9%, p < 0.001), 2 retrospective cohort studies (RR = 1.35, 95% CI = 1.19-1.52, I2 = 61.0%, p = 0.109), 3 retrospective case-control studies (OR = 1.21, 95% CI = 0.96-1.53, I2 = 95.2%, p < 0.001), and 4 cross-sectional studies (OR = 1.51, 95% CI = 1.09-2.09, I2 = 75.8%, p = 0.006). Meta-regression analyses did not find any valid moderators. Heterogeneity in subgroup analyses for population age, OA location, year of publication, outcome type, adjusted for BMI, depression, and comorbidity decreased to zero. No significant evidence of publication bias was found. CONCLUSION: OA associated with an increased risk of dementia and CIM. Effective interventions in OA patients may decrease new incidence of dementia or CIM.

Application of the Amyloid/Tau/Neurodegeneration Framework in Cognitively Intact Adults: The CABLE Study.

OBJECTIVES: The amyloid/tau/neurodegeneration (AT[N]) framework has conceptualized the Alzheimer's disease (AD) continuum as a continuum of disease with evidence of amyloid-related pathologies independent of clinical manifestation. Based on this framework, it is necessary to reveal the distribution and risk factors of AD continuum in the cognitively intact population among different cohorts and races, including the northern Chinese Han population. METHODS: This study classified cognitively intact Chinese Alzheimer's Biomarker and LifestylE (CABLE) participants through the AT(N) scheme. Gaussian mixture models were used to identify the cutoff values of cerebrospinal fluid biomarkers, which distinguished AD continuum ( A + T-N-, A + T + N-, A + T-N + and A + T + N +) from 1,005 participants (mean age 61 years; 40% female). Multivariable logistic regressions and Cochran-Armitage trend tests were used to test neuropsychological performance and risk factors for AD continuum. RESULTS: Approximately one-third of individuals (33.7%) belonged to the AD continuum. Four potential modifiable risk factors, including hypertension, thyroid diseases, social isolation, and minimal depression symptoms, were identified for the AD continuum (OR ranging 1.68-6.90). A trend toward higher prevalence of the AD continuum was associated with a larger number of risk factors (p for trend <0.0001). The risk of AD continuum increased by approximately twofold for each additional modifiable risk factor (OR 1.9, 95% CI 1.65-2.24, p < 0.0001). INTERPRETATION: This study revealed the distribution and potential risk factors of the AD continuum in a cognitively intact Han population in northern China, which filled the gap in the area about the performance of the AT(N) framework in the Asian population. ANN NEUROL 2022;92:439-450.

Tea consumption and risk of incident dementia: A prospective cohort study of 377 592 UK Biobank participants.

As a widely consumed beverage, tea boasts diverse health benefits. Herein, we aimed to investigate the association between tea consumption and dementia risk. We conducted a prospective cohort study with 377 592 UK Biobank participants during a 9-year follow-up. Cox regression models adjusted for age, sex, ethnicity, Townsend deprivation index, education, body mass index, lifestyle factors, dietary factors and apolipoprotein E4 status were used to examine the association of tea consumption with dementia risk. Subgroup analyses stratified by age, sex and forms of dementia (Alzheimer's disease [AD] and vascular dementia [VD]) were performed. Moreover, the restricted cubic splines were used to calculate the nonlinear relationship between daily dosage of tea and dementia risk. After adjustment for all covariates, tea drinkers were 16% (95% confidence interval: 8-23) less likely to develop dementia compared with non-drinkers. Moderate consumption (1-6 cups/day) of tea exerted significant protective effects. Subgroup analyses showed that mid-aged participants or males benefited more from tea consumption. Moreover, moderate drinkers had a 16-19% lower hazard of AD and a 25-29% lower hazard of VD. Furthermore, a U-shaped association between tea consumption and dementia risk was shown (Pnon-linearity = 7E-04), and the consumption of around three cups per day showed the strongest protective effect. Within 3 cups/day, drinking one extra cup of tea per day brought a 6% reduction of incidence. In conclusion, moderate consumption of tea was significantly associated with a reduced risk of dementia, suggesting that tea consumption could be a modifiable lifestyle factor for dementia.

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

BACKGROUND: Inflammation plays a role in occurrence and progression of Alzheimer's disease (AD). Whether peripheral immune cells are involved in major pathological processes including amyloid-ß plaques and tau tangles is still controversial. OBJECTIVE: We aimed to examine whether peripheral immune cells counts were associated with early changes in cerebrospinal fluid (CSF) biomarkers of AD pathology in cognitively intact older adults. METHODS: This study included 738 objective cognitive normal participants from the Chinese Alzheimer's Biomarker and Lifestyle (CABLE) database. Group comparisons of peripheral immune cells counts were tested by analysis of covariance. Multiple linear regression models were used to examine the associations of peripheral immune cells counts with CSF AD biomarkers. RESULTS: In preclinical AD, peripheral lymphocytes and eosinophils changed dynamically along with disease progression. Consistently, regression analysis showed that lymphocytes and eosinophils were associated with Aß pathology. There were no interaction effects of peripheral immune cells counts with APOE ɛ4, gender, age, and educate. Eosinophil to lymphocyte ratio were also significantly associated with Aß-related biomarkers. CONCLUSION: Our findings showed the relationship between peripheral immune cells and Aß pathological biomarkers, which indicated that peripheral immune might play a role in progression of AD pathology.

Association of Subjective Cognitive Decline with Cerebrospinal Fluid Biomarkers of Alzheimer's Disease Pathology in Cognitively Intact Older Adults: The CABLE Study.

BACKGROUND: Subjective cognitive decline (SCD) might occur at the early stages of dementia. Individuals with SCD have an increased risk of subsequent objective cognitive decline and greater rates of progression to dementia. OBJECTIVE: We aimed to explore the associations between SCD and cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathology in cognitively normal individuals. METHODS: A total of 1,099 cognitively normal elders with available data on CSF biomarkers of AD pathology (Aß42, P-tau, and T-tau) were included in our analysis. Linear regression was used to examine the associations of SCD status and SCD severity with CSF biomarkers. Additionally, a review was conducted to discuss the associations between SCD and CSF biomarkers of AD pathology. RESULTS: After adjustments for covariates, SCD and SCD severity showed significant associations with CSF Aß42 (SCD: ß= -0.0003, p = 0.0263; SCD severity: ß= -0.0004, p = 0.0046), CSF T-tau/Aß42 ratio (SCD: ß= 0.1080, p = 0.0064; SCD severity: ß= 0.1129, p = 0.0009) and CSF P-tau/Aß42 ratio (SCD: ß= 0.0167, p = 0.0103; SCD severity: ß= 0.0193, p = 0.0006) rather than T-tau and P-tau compared with cognitively normal individuals. In the review, a total of 28 studies were finally included after reviewing 174 articles. CSF Aß42 was lower in SCD than cognitively normal (CN) individuals, but higher than those with objective cognitive decline. However, CSF tau pathology showed no difference between SCD and CN. CONCLUSION: The results indicated that pathophysiological changes in CSF Aß pathology occurred in individuals with SCD, which provide new insights into early intervention of AD.

Late-Life Obesity Associated with Tau Pathology in Cognitively Normal Individuals: The CABLE Study.

BACKGROUND: Existed evidence suggests that midlife obesity increases the risk of Alzheimer's disease (AD), while there is an inverse association between AD and obesity in late life. However, the underlying metabolic changes of AD pathological proteins attributed to obesity in two life stages were not clear. OBJECTIVE: To investigate the associations of obesity types and obesity indices with AD biomarkers in cerebrospinal fluid (CSF) in different life stages. METHODS: We recruited 1,051 cognitively normal individuals (61.94±10.29 years, 59.66%male) from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study with CSF detections for amyloid-ß 42 (Aß42), total-tau (T-tau), and phosphorylated tau (P-tau). We utilized body mass index, waist circumference, waist-to-height ratio, and metabolic risk factors to determine human obesity types. Multiple linear models and interaction analyses were run to assess the impacts of obesity on AD biomarkers. RESULTS: The metabolically unhealthy obesity or healthy obesity might exert a reduced tau pathology burden (p < 0.05). Individuals with overweight, general obesity, and central obesity presented lower levels of tau-related proteins in CSF than normal controls (p < 0.05). Specially, for late-life individuals, higher levels of obesity indices were associated with a lower load of tau pathology as measured by CSF T-tau and T-tau/Aß42 (p < 0.05). No similar significant associations were observed in midlife. CONCLUSION: Collectively, late-life general and central obesity seems to be associated with the reduced load of tau pathology, which further consolidates the favorable influence of obesity in specific life courses for AD prevention.

Associations of Sleep Characteristics with Cerebrospinal Fluid sTREM2 in Cognitively Normal Older Adults: the CABLE Study.

As brain insults, sleep disorders could enhance microglial activation and aggravate neuroinflammation. Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) serves as a readout for TREM2-associated microglial responses. We aimed to study the association of sleep characteristics with CSF sTREM2 in cognitively normal (CN) older adults. Linear and non-linear regression analyses were conducted in 830 participants with measurements of sleep characteristics and CSF sTREM2, after adjusting for age, sex, education, the Chinese-Modified Mini-Mental State Examination (CM-MMSE) scores, and APOE4 status. These analyses were also performed in amyloid-negative (A -) and amyloid-positive (A +) individuals. Linear relationships between sleep characteristics and CSF sTREM2 were found. In all the participants, sleep efficiency score in Pittsburgh Sleep Quality Index (PSQI) (p = 0.037) showed a positive linear association with CSF sTREM2. In A + individuals, the grade of PSQI total score (p = 0.011) as well as subjective sleep quality score (p = 0.048) and sleep efficiency score (p < 0.001) in PSQI were positively associated with CSF sTREM2. Besides, several U-shaped relationships were revealed of sleep-time measures, such as insufficient or excessive nocturnal sleep duration, with CSF sTREM2 in A + individuals (the optimal model: bedtime 22:21 p.m., time to fall asleep 22:52 p.m., nocturnal sleep duration 7.36 h). In A - individuals, the above relationships were not found. Poor self-reported sleep characteristics and sleep indicators were associated with higher CSF sTREM2, suggesting that sleep might play an important role in the regulation of TREM2-associated microglial activity.

White matter hyperintensities and risks of cognitive impairment and dementia: A systematic review and meta-analysis of 36 prospective studies.

BACKGROUND: White matter hyperintensities of presumed vascular origin (WMH) are one of the imaging features of cerebral small vessel disease. Controversies persist about the effects of WMH on cognitive dysfunction. This meta-analysis aimed to identify the associations of WMH with risks of cognitive impairment and dementia. METHODS: We searched PubMed, EMBASE and Cochrane Library for prospective studies. Primary analyses of cognitive dysfunction and sub-analyses of specific outcomes and study characteristics were conducted using random-effect models. RESULTS: Thirty-six prospective studies with 19,040 participants were included. WMH at baseline conferred a 14 % elevated risk of cognitive impairment and all-cause dementia (ACD). WMH also conferred 25 % elevated risk of Alzheimer's disease and 73 % elevated risk of vascular dementia. Risk effects of high-grade WMH and continually increasing WMH (in volume or severity) on ACD were revealed. Periventricular WMH conferred a 1.51-fold excess risk for dementia. CONCLUSIONS: WMH were associated with increased risk of cognitive dysfunction and could become a neuroimaging indicator of dementia.

Association of Occupational Factors and Dementia or Cognitive Impairment: A Systematic Review and Meta-Analysis.

BACKGROUND: Several existing studies have reported that occupational factors might play an important part in cognitive function with aging. OBJECTIVE: We aim to explore the associations between modifiable occupational factors and risk of dementia or mild cognitive impairment (MCI). METHODS: Adopting random-effect models, this study conducted primary analyses for all occupational factors and subgroup analyses for the effect of occupation type based on prospective cohort and case-control studies searched from PubMed and EMBASE databases up to March 2020. RESULTS: Among the 38,111 identified literatures, 9 studies on occupation type, 4 studies on work complexity, and 30 studies on occupational exposure were included. In terms of occupation type, mental work conferred a 44% reduced risk (95% CI = 0.34-0.94, I²â€Š= 85.00%, p < 0.01) for MCI. In terms of work complexity, higher work complexity conferred a 5% reduced risk (95% CI = 0.91-1.00, I²â€Š= 57.00%, p < 0.01) for dementia. In terms of occupational exposure, high strain and passive job in the longest-held job conferred a 1.21- and 1.15-fold excess risk (95% CI = 1.05-1.39 I²â€Š= 62.00%, p < 0.05; 95% CI = 1.05-1.26 I²â€Š= 31.00%, p = 0.23; respectively) of cognitive decline. Besides, magnetic field exposure conferred a 1.26-fold excess risk (95% CI = 1.01-1.57, I²â€Š= 69.00%, p < 0.01) for dementia. CONCLUSION: Novel prevention strategies based on occupational factors may hold promise against dementia and MCI.

Association of body mass index with risk of cognitive impairment and dementia: A systematic review and meta-analysis of prospective studies.

Controversies persist about the associations of body mass index (BMI) with risk of cognitive impairment and dementia. This study aimed to evaluate these associations from various aspects, in which Embase, PubMed and Cochrane databases were searched to identify prospective studies up to May 2019. Random-effects meta-analyses and dose-response meta-analysis were conducted, involving twenty-nine of 20,083 identified literatures. Meta-analysis showed that midlife underweight, obesity and late-life underweight conferred 1.39-, 1.31- and 1.64-fold excess risk for cognitive impairment and dementia, while late-life overweight and obesity conferred 21% and 25% reduced risk. In dose-response meta-analysis, all cause dementia (ACD), Alzheimer's disease (AD) and vascular dementia (VaD) risk in midlife was significantly elevated when BMI surpassed 29, 30 and 32 kg/m2. AD risk in late-life was decreased when BMI was under 27 kg/m2, while this protection for VaD was absent when BMI surpassed 39 kg/m2. Higher BMI produced opposite exerted opposite effects on dementia in mid- and late-age population. Firstly reported, a dose-response relationship further supports the guideline from the standpoint of dementia prevention.

Fasting blood glucose and cerebrospinal fluid Alzheimer's biomarkers in non-diabetic cognitively normal elders: the CABLE study.

It is unclear how blood glucose levels mediate the pathology of Alzheimer's disease (AD). This study aimed to investigate whether fasting blood glucose (FBG) levels are associated with cerebrospinal fluid (CSF) biomarkers preferentially affected by AD in non-diabetic cognitively normal elders. A total of 499 non-diabetic cognitively normal elders were from the Chinese Alzheimer's Biomarker and LifestyLE (CABLE) study. We detected the associations of FBG with individual CSF measures using multiple linear regression models controlling for age, sex, educational level, and apolipoprotein E (APOE) ε4 genotype. Fasting blood glucose level was positively correlated with CSF Aß42 level (ß = 0.045, p = 0.010), CSF Aß42/Aß40 ratio (ß = 0.005, p < 0.001), Aß42/P-tau ratio (ß = 0.282, p = 0.013), and Aß42/T-tau ratio (ß = 0.050, p = 0.040). Interaction analysis indicated that gender affected the correlations of FBG level with CSF Aß40 (p < 0.001) and Aß42/Aß40 ratio (p < 0.001). This study raises additional questions about the role of blood glucose in the predisposition to AD and supports the possibility of targeting these processes in pre-symptomatic AD trials in non-diabetic elders.