Echocardiographic measures of the left heart and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact adults: The CABLE study.

INTRODUCTION: This study delineated the interrelationships between subclinical alterations in the left heart, cerebrospinal fluid (CSF), Alzheimer's disease (AD) biomarkers, and cognition. METHODS: Multiple linear regressions were conducted in 1244 cognitively normal participants (mean age = 65.5; 43% female) who underwent echocardiography (left atrial [LA] and left ventricular [LV] morphologic or functional parameters) and CSF AD biomarkers measurements. Mediating effects of AD pathologies were examined. Differences in cardiac parameters across ATN categories were tested using analysis of variance (ANOVA) and logistic regressions. RESULTS: LA or LV enlargement (characterized by increased diameters and volumes) and LV hypertrophy (increased interventricular septal or posterior wall thickness and ventricular mass) were associated with higher CSF phosphorylated (p)-tau and total (t)-tau levels, and poorer cognition. Tau pathologies mediated the heart-cognition relationships. Cardiac parameters were higher in stage 2 and suspected non-Alzheimer's pathology groups than controls. DISCUSSION: These findings suggested close associations of subclinical cardiac changes with tau pathologies and cognition. HIGHLIGHTS: Various subclinical alterations in the left heart related to poorer cognition. Subclinical cardiac changes related to tau pathologies in cognitively normal adults. Tau pathologies mediated the heart-cognition relationships. Subclinical cardiac changes related to the AD continuum, especially to stage 2. The accumulation of cardiac alterations magnified their damage to the brain.

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.

Tau pathologies mediate the association of blood pressure with cognitive impairment in adults without dementia: The CABLE study.

INTRODUCTION: This study delineated the interrelationships among blood pressure (BP), cerebrospinal fluid (CSF) core biomarkers of Alzheimer's disease (AD), and cognition. METHODS: The linear regression analyses were conducted in 1546 non-demented participants (mean age of 61.58 years, range 40 to 89 years; 40% female; average days of BP measurement, 9.10 days). Mediation analyses with 10,000 bootstrapped iterations were used to explore the mediation effects. RESULTS: A clear age-related pattern of BP was delineated. Mid-life hypertension (especially systolic BP), late-life lower diastolic BP, as well as mid- and late-life higher pulse pressure were associated with cognitive impairment and tau-related biomarkers. BP variability was associated only with cognition but not with CSF biomarkers. Overall, the associations between BP and cognition were partially mediated (proportion: 11% to 30%) by tau pathologies, independently of amyloid pathology. DISCUSSION: Tau pathologies might play important roles in the relationship between BP and cognition, with significant age- and BP-type dependences.

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 characteristics and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact older adults: The CABLE study.

INTRODUCTION: This study tested the self-reported sleep characteristics associated with cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers in cognitively intact older adults. METHODS: The linear and non-linear regression analyses were conducted in 736 cognitively normal participants (mean [standard deviation; SD] age, 62.3 [10.5] years, range 40 to 88 years, 59% female) who had measurements of cerebrospinal fluid (CSF) amyloid beta (Aß) and tTau proteins and sleep characteristics, after adjusting for age, gender, education, apolipoprotein E gene (APOE) ε4 status, and general cognition. RESULTS: Greater daytime sleepiness was associated with higher CSF indicators of amyloid deposition in female patients. No significant associations were revealed for CSF tTau proteins after Bonferroni correction. A U-shaped relationship was revealed for nocturnal sleep habits, such that those with insufficient or excessive nocturnal sleep duration had greater CSF biomarkers of amyloid deposition (the reflection range: bedtime: around 10:00 p.m. and sleep duration: 6.0 to 6.5 hours). DISCUSSION: These findings consolidated the close relationship between sleep and AD.

[Effects of Scalp Acupuncture on Serum NSE and S-100ß Concentrations and Postoperative Cogni- tive Function of Elderly Patients Undergoing Hip Replacement].

OBJECTIVE: To explore the effect of Scalp acupuncture on serum neuron specific enolase (NSE) and S-100ß concentrations, and incidence rates of postoperative delirium (POD) and postoperative cognitive function (POCD) of elderly patients undergoing hip replacement. METHODS: Eighty-four patients undergoing scheduled hip replacement under combined spinal-epidural anesthesia (CSEA) were assigned to the control group (group C) and the scalp acupuncture group (group S) according to random digit table, 42 cases in each group. In group S, scalp acupuncture was additionally performed according to International Standardized Scheme for Scalp Acupuncture. Scalp acupuncture was performed during the operation from the MS1 middle line of forehead [1 cun before Shenting (GV24), including Shenting (GV24)] and MS5 middle line of vertex [from Baihui (DU20) to Qianding (DU21), including Baihui (DU20) and Qianding (DU21)]. The operation time and post-operative length of stay were observed. The midazolam dosage, hemorrhage amount, fluid transfusion amount, urine amount, use rates of ephedrine and atropine during the operation were also observed and compared between the two groups. The occurrence rate of POD and POCD at post-operative day 3 (T1), week 1 (T2), month 3 (T3), and month 6 (T4) were measured. Eighteen patients were randomly selected to collect blood from internal jugular vein before anesthesia t0), immediately after ending the surgery (t1), 6 h after operation (t2), 24 h after operation (t3), and 48 h after operation (t4), respectively. Serum levels of NSE and S-100ß were correspondingly measured. RESULTS: There was no statistical difference in the operation time, midazolam dosage used during the operation, hemorrhage amount, fluid transfusion amount, urine amount, use rates of ephedrine and atropine (P > 0.05). Compared with group C, the post-operative length of stay was shortened in group S (P < 0.05). The incidence rate of POD and that of POCD at each time point were lower in group S (P < 0.05). The expression level of NSE decreased at t2, t3, and t4, and the expression level of S100ß also decreased at t1, t2, t3, and t4(P < 0.05). There was no statistical difference in expression levels of NSE or S100ß between the two groups at other time points (P > 0.05). CONCLUSION: Scalp acupuncture could attenuate central nervous system lesion and improve POCD of elderly patients undergoing hip replacement.

[Effects of parecoxib sodium analgesia on serum concentrations of neuron-specific enolase and S-100ß and postoperative cognitive function of elderly patients undergoing acute replacement of femoral head].

OBJECTIVE: To explore the effects of parecoxib sodium analgesia on serum concentrations of neuron-specific enolase (NSE) and S-100ß and postoperative cognitive function of elderly patients undergoing acute replacement of femoral head. METHODS: After the approval of institutional review board and the provision of informed consent, 80 patients over 70 years old, undergoing acute replacement of femoral head under combined spinal and epidural anesthesia and midazolam sedation at Qingdao Municipal Hospital and Qingdao Hiser Medical Center from January 2011 to May 2012, were randomly assigned into control group (group C, n = 40) and parecoxib group (group P, n = 40). In group P, parecoxib sodium 20/40 mg (based on weight 50 kg) was administered via an intravenous injection after admission with 12 hours intervals for six times. In group C, morphine 2/4 mg was given initially. Additional morphine 2 mg was given to maintain the pain visual analog scale (VAS) of 3 points or less in both groups. Primary observation indices: (1) postoperative time and additional amount of morphine; (2) rate of postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) at 3 days, 1 week, 3 months and 6 months postoperation (T1-T4); (3) se rum levels of NSE and S-100ß were measured at the timepoints of before analgesia (t0), before anesthesia (t1), end of surgery (t2) and 6 hours, 24 hours, 48 hours postoperation (t3-t5); (4) other serious complications. RESULTS: Compared with group C, the additional amount of morphine, postoperative time, rate of POD and POCD at T1-T4, the level of NSE at t2-t5 and S-100ß at t1-t5 were lower in group P (P < 0.05). No other serious complications were observed. CONCLUSIONS: Parecoxib sodium analgesia reduces the rate of POD and POCD in elderly patients with neuroprotective effects.

Daytime dysfunction may be associated with postoperative delirium in patients undergoing total hip/knee replacement: The PNDABLE study.

PURPOSE: Postoperative delirium (POD) is a usual complication after total hip/knee replacement, which may be affected by sleep characteristics. However, up to now, preoperative sleep characteristics have not been evaluated as risk factors of POD. The relationship between self-reported sleep characteristics and POD in patients has been investigated in this study. PATIENTS AND METHODS: We recruited 495 cognitively intact individuals in the final analysis from the Perioperative Neurocognitive Disorder and Biomarker Lifestyle study. Sleep characteristics were tested by the Pittsburgh Sleep Quality Index (PSQI). Mini-mental state examination was applied to assess preoperative mental status of patients. Postoperatively, we used confusion assessment method and memorial delirium assessment scale to evaluate the incidence of POD and POD severity, respectively. The cerebrospinal fluid (CSF) levels of T-tau, P-tau, Aß40, and Aß42 were detected by enzyme-linked immune-sorbent assay before the operation. Logistic regression, multiple linear regression, and mediation effects were performed to analyze the relationship between self-reported sleep characteristics and POD. RESULTS: POD was detected in 11.31% (56/495) of the patients, with logistic regression analysis showing that daytime dysfunction, P-tau, and T-tau were risk factors of POD, and Aß42 was a protective factor of POD. Multiple linear regression analysis confirmed that daytime dysfunction was positively correlated with P-tau in patients with POD. Meanwhile, compared to the patients with no postoperative delirium, the CSF levels of P- and T-tau were higher in patients with POD. Furthermore, mediation analysis showed that it was probable that daytime dysfunction mediated POD through P-tau (proportion: 12.90%) partially. CONCLUSION: Daytime dysfunction is a risk factor of POD preoperatively. To sum up, CSF P-tau protein might partially mediate the influence of daytime dysfunction on POD. CLINICAL TRIAL REGISTRATION: This study was registered at Chinese Clinical Trial Registry (ChiCTR2000033439).

Habitual tea consumption and postoperative delirium after total hip/knee arthroplasty in elderly patients: The PNDABLE study.

PURPOSE: To clarify the effects of habitual tea consumption on postoperative delirium (POD) in elderly patients undergoing total hip/knee arthroplasty. PATIENTS AND METHODS: A prospective cohort study was carried out at Qingdao Municipal Hospital Affiliated to Qingdao University between June 2020 and June 2021. A total of 332 patients aged 65-85 years undergoing total hip/knee arthroplasty under combined spinal and epidural anesthesia were enrolled from the Perioperative Neurocognitive Disorder and Biomarker Lifestyle (PNDABLE) study in the final analysis, consisting of 168 patients with habitual tea consumption and 164 patients with infrequent tea consumption. The primary endpoint was the effects of habitual tea consumption on POD and the incidence of POD, which was assessed by the Confusion Assessment Method (CAM) twice daily during the first 7 postoperative days, and POD severity was measured by the Memorial Delirium Assessment Scale (MDAS). The secondary endpoints were the concentrations of caffeine and tea polyphenols in plasma and cerebrospinal fluid (CSF), which were detected by the enzyme-linked immunosorbent assay. RESULTS: POD occurred in 61 of 332 patients (18.37%), among whom 19 had habitual tea consumption (5.72%) and 42 had infrequent tea consumption (12.65%). Habitual tea consumption (odds ratio [OR] = 0.370, 95% confidence interval [CI]: 0.205-0.670, P = .001) was significantly associated with POD in the logistic analysis, and then after adjusting for age and American Society of Anesthesiologists (ASA) physical status (OR = 0.353, 95% CI: 0.190-0.655, P = .001). Furthermore, caffeine in T0 plasma (OR = 0.834, 95% CI: 0.752-0.924, P = .001), T1 plasma (OR = 0.818, 95% CI: 0.738-0.908, P < .001), and CSF (OR = 0.899, 95% CI: 0.820-0.984, P = .022) and tea polyphenols in T0 plasma (OR = 0.541, 95% CI: 0.416-0.704, P < .001), T1 plasma (OR = 0.477, 95% CI: 0.359-0.633, P < .001), and CSF (OR = 0.526, 95% CI: 0.397-0.696, P < .001) were associated with POD after adjusting for age and ASA physical status. CONCLUSION: Habitual tea consumption may be associated with a lower incidence of POD in elderly patients.

Association between Life's Simple 7 and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact adults: the CABLE study.

INTRODUCTION: This study sought to explore the association between Life's Simple 7 (LS7) and cerebrospinal fluid (CSF) Alzheimer's disease (AD) pathological biomarkers in the cognitively normal northern Chinese population. METHODS: From the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study, 1106 cognitively normal participants were enrolled. The mean age was 62.34 years, and 39.6% were female. LS7 scores were summed with each metric assigned 0, 1, or 2 scores. The multiple linear regression models were used to investigate the association between LS7 scores and CSF AD biomarkers. RESULTS: We found that LS7 scores were significantly associated with CSF AD pathologies, including Aß42/40 (ß = 0.034, P = .041), p-tau181 (ß = - 0.043, P = .006), and t-tau (ß = - 0.044, P = .003). In subscales, the biological metrics (blood pressure, cholesterol, glucose) were significantly related to CSF tau-related biomarkers. These associations were observed in the APOE ε4 allele non-carriers, yet not in carriers. The relationship of behavior metrics was found in the middle age and males. CONCLUSION: Improving LS7 scores might do a favor to alleviate the pathology of AD in the preclinical stage, especially among the APOE ε4 allele non-carriers.

Tau Pathologies Mediate the Association of Cigarette Smoking with Cognitive Impairment in Older Adults Without Dementia: The CABLE Study.

BACKGROUND: Although cigarette smoking is an important modifiable factor of cognitive impairment, the roles of the Alzheimer's disease (AD) core pathologies in modulating this process have not been fully delineated. OBJECTIVE: This study aimed to explore associations of cigarette smoking with cognition and cerebrospinal fluid (CSF) AD biomarkers. METHODS: A total of 1,079 non-demented participants were included from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study. Associations of cigarette smoking with cognition and CSF AD biomarkers were explored by multiple linear regression models. The mediation analyses with 10,000 bootstrapped iterations were conducted to explore the mediation effects. RESULTS: Heavy cigarette smokers (pack-years > 20) had poorer global cognition as well as higher levels of CSF p-tau and t-tau compared with the non-smokers (p < 0.01). Time-dose effect analysis among smokers also suggested that both cognitive impairment and tau pathologies markedly deteriorated with greater cumulative cigarette exposure, independently of the Aß pathology (p < 0.01). In addition, smokers with older age or APOEɛ4 showed more obvious influences on CSF tau pathologies but not on cognition. Overall, the influence of smoking on cognition was partially mediated by tau pathologies (estimated proportion: 12%), which still remained in late-life (10% ∼11%) and increased in APOEɛ4 carriers (18% ∼24%). Encouragingly, long-term smoking cessation mitigated both cognitive impairment and tau pathologies (p < 0.05). CONCLUSION: Cigarette smoking was associated with both cognitive impairment and tau pathologies, which were accompanied by time-dose effects. Tau pathology might be a key mediator for influences of cigarette smoking on cognitive impairments.

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.

[Effects of acupuncture pre-conditioning on apoptosis in hippocampal neurons following ischemia-reperfusion injury in aged rats].

OBJECTIVE: To investigate the effects of acupuncture pre-conditioning on apoptosis in hippocampal neurons following ischemia-reperfusion injury in aged rats. METHODS: A total of 120 senile male Wistar rats aged 19 - 21 months (corresponding to 60-year-old human being) weighting 550 - 710 g were randomly divided into 4 groups (n = 30 each). Cerebral ischemic group: 4-vessel-block was conducted for 4 minutes to establish cerebral ischemic models; Acupuncture pre-conditioning group: electroacupuncture was applied at acupoint Baihui (GV20) with a frequency of 15 Hz and 2 mA for 30 minutes once daily for 5 days. Then the rats received 4-vessel-block for 4 minutes; Sham-operation group: 4 vessels were exposed; Sham-acupuncture group: only electroacupuncture for 5 days without operation. The rats were sacrificed at the end of predetermined duration of reperfusion 12 h, 1, 2, 3 and 7 d respectively. The brains were immediately harvested and hippocampal CA1 region was isolated for (1) light and electron microscopic examinations of hippocampal neurons; (2) detection of apoptotic neurons (TUNEL); (3) determination of caspase-3 protein expression with SABC (streptavidin-biotin-peroxidase complex) immuno-histochemical technique. RESULTS: There were apoptotic neurons in all groups. The numbers of apoptotic neurons and positive neurons of caspase-3 significantly increased in the acupuncture pre-conditioning and cerebral ischemic groups versus the sham-acupuncture and sham-operation groups (P < 0.01). And the numbers of apoptotic neurons and positive neurons of caspase-3 significantly decreased in the acupuncture pre-conditioning group versus the cerebral ischemic group (P < 0.01). CONCLUSION: Acupuncture pre-conditioning can decrease the neuronal apoptosis after ischemia-reperfusion injury through a lowered expression of caspase-3 protein in senile rats.

Risk factors for subjective cognitive decline: the CABLE study.

Increasing evidences supported that subjective cognitive decline (SCD) might be a potential first symptomatic manifestation of Alzheimer's disease (AD). The rapidly growing number of SCD individuals who seek medical help and advice also makes it urgent to develop more precise strategy for SCD. Therefore, this study aimed to explore the risk factors for SCD. Logistics and linear regression models were performed to investigate 41 factors for SCD in 1165 participants without objective cognitive impairment. Cochran-Armitage trend test was used to confirm the constant trend toward higher prevalence of SCD with an increasing number of risk factors. A high overall prevalence of SCD was found in total participants (42%). Eight factors were eventually identified as risk factors for SCD, including four stable factors associated with both SCD statues and severity (older age, thyroid diseases, minimal anxiety symptoms, and day time dysfunction; odds ratio (OR) ranging from 1.74 to 2.29) as well as four suggestive factors associated with either SCD statues or severity (female sex, anemia, lack of physical exercises, and living alone; OR ranging from 1.30 to 2.29). The prevalence of SCD gradually increased with the number of risk factors clustering increased in individuals (p for trend <0.001). Five of these eight factors were further proved among individuals with SCD-plus features. These findings revealed several risk factors for SCD, providing some new clues for formulating priority strategies for early prevention of SCD.

Associations of healthy lifestyles with cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact older adults: the CABLE study.

OBJECTIVE: We aimed to investigate the associations between healthy lifestyles and Alzheimer's disease (AD) biomarkers in cerebrospinal fluid (CSF). METHODS: A total of 1108 cognitively intact individuals from Chinese Alzheimer's Biomarker and LifestylE (CABLE) study were examined to evaluate the associations of AD biomarkers with healthy lifestyle factors, including no current smoking, no harmful drinking, absence of social isolation, and regular physical activity. The participants were categorized into groups of favorable, intermediate, and unfavorable lifestyles according to the lifestyle factors. The associations between overall lifestyle and CSF biomarkers were also analyzed. RESULTS: Among cognitively intact older adults, those having more social engagement had lower CSF tau (p = 0.009) and p-tau (p < 0.001) than those who had social isolation. Regular physical activity was associated with higher CSF Aß42 (p = 0.013) and lower levels of CSF tau (p = 0.036) and p-tau (p = 0.007). However, no significant associations were found of smoking status or alcohol intake with CSF biomarkers. When the overall lifestyle of the participants was evaluated by all the four lifestyle factors, favorable lifestyle profiles were related to lower levels of CSF tau (p < 0.001) and p-tau (p < 0.001). CONCLUSIONS: These findings suggest that healthy lifestyles had a beneficial effect on AD pathology among cognitively intact elders.

Association between methylation of BIN1 promoter in peripheral blood and preclinical Alzheimer's disease.

The bridging integrator 1 (BIN1) gene is the second most important susceptibility gene for late-onset Alzheimer's disease (LOAD) after apolipoprotein E (APOE) gene. To explore whether the BIN1 methylation in peripheral blood changed in the early stage of LOAD, we included 814 participants (484 cognitively normal participants [CN] and 330 participants with subjective cognitive decline [SCD]) from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database. Then we tested associations of methylation of BIN1 promoter in peripheral blood with the susceptibility for preclinical AD or early changes of cerebrospinal fluid (CSF) AD-related biomarkers. Results showed that SCD participants with significant AD biological characteristics had lower methylation levels of BIN1 promoter, even after correcting for covariates. Hypomethylation of BIN1 promoter were associated with decreased CSF Aß42 (p = 0.0008), as well as increased p-tau/Aß42 (p = 0.0001) and t-tau/Aß42 (p < 0.0001) in total participants. Subgroup analysis showed that the above associations only remained in the SCD subgroup. In addition, hypomethylation of BIN1 promoter was also accompanied by increased CSF p-tau (p = 0.0028) and t-tau (p = 0.0130) in the SCD subgroup, which was independent of CSF Aß42. Finally, above associations were still significant after correcting single nucleotide polymorphic sites (SNPs) and interaction of APOE ɛ4 status. Our study is the first to find a robust association between hypomethylation of BIN1 promoter in peripheral blood and preclinical AD. This provides new evidence for the involvement of BIN1 in AD, and may contribute to the discovery of new therapeutic targets for AD.

Sleep Characteristics and Cerebrospinal Fluid Progranulin in Older Adults: The CABLE Study.

Cerebrospinal fluid (CSF) progranulin (PGRN) is related to various neurodegeneration diseases. And sleep problems can cause abnormality in protein metabolism in vivo. We aim to explore the potential associations between the self-reported sleep characteristics and CSF PGRN in cognitively intact older adults. Our study recruited 747 participants (mean (standard deviation (SD)) age, 61.99 (10.52) years, 329 (42.89%) females) who had normal cognition from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study with CSF PGRN and sleep characteristics measured. The multiple linear regression and nonlinear regression adjusted for age, gender, education, and apolipoprotein E-epsilon 4 gene (APOE4) status were used to assess the associations between sleep characteristics and PGRN. Interaction effects were explored between APOE4 status and sleep characteristics on CSF PGRN level. Sleep disturbances indicated lower CSF PGRN (ß = - 0.0186, p = 0.0160). For detailed items in sleep disturbances, lower CSF PGRN was found in males who woke up during sleep (ß = - 0.0121, p = 0.0062) and in females who had breathing difficulties (ß = - 0.0258, p = 0.0271). Meanwhile, sleep efficiency was associated with CSF PGRN (ß = - 0.0512, p = 0.0497). No significant interaction effects between sleep characteristics and APOE4 status were found. Meanwhile, we did not find a nonlinear relationship between nocturnal sleep duration and CSF PGRN. Sleep problems may influence the metabolism of PGRN, thus attenuating the protective effects of PGRN on neurodegeneration diseases.

Serum Uric Acid May Aggravate Alzheimer's Disease Risk by Affecting Amyloidosis in Cognitively Intact Older Adults: The CABLE Study.

BACKGROUND: Serum uric acid (SUA) affects the reaction of oxidative stress and free radicals in the neurodegenerative processes. However, whether SUA impacts Alzheimer's disease (AD) pathology remains unclear. OBJECTIVE: We aimed to explore whether high SUA levels can aggravate the neurobiological changes of AD in preclinical AD. METHODS: We analyzed cognitively intact participants (n = 839, age 62.16 years) who received SUA and cerebrospinal fluid (CSF) biomarkers (amyloid-ß [Aß], total tau [t-Tau], and phosphorylated tau [p-Tau]) measurements from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database using multivariable-adjusted linear models. RESULTS: Levels of SUA in the preclinical AD elevated compared with the healthy controls (p = 0.007) and subjects with amyloid pathology had higher concentration of SUA than controls (p = 0.017). Roughly, equivalent levels of SUA displayed among cognitively intact individuals with or without tau pathology and neurodegeneration. CSF Aß1 - 42 (p = 0.019) and Aß1 - 42/Aß1 - 40 (p = 0.027) were decreased and CSF p-Tau/Aß1 - 42 (p = 0.009) and t-Tau/Aß1 - 42 (p = 0.043) were increased with the highest (> 75th percentile) SUA when compared to lowest SUA, implying a high burden of cerebral amyloidosis in individuals with high SUA. Sensitivity analyses using the usual threshold to define hyperuricemia and precluding drug effects yielded robust associations. Nevertheless, the quadratic model did not show any U-shaped relationships between them. CONCLUSION: SUA may aggravate brain amyloid deposition in preclinical AD, which corroborated the detrimental role of SUA.

Left Ventricular Ejection Fraction and Cerebrospinal Fluid Biomarkers of Alzheimer's Disease Pathology in Cognitively Normal Older Adults: The CABLE Study.

BACKGROUND: Heart failure has been considered as a potential modifiable risk factor for cognitive impairment and dementia. Left ventricular ejection fraction (LVEF), an indicator of cardiac dysfunction, has also been associated with cognitive aging. However, the effect of LVEF on Alzheimer's disease (AD) pathology is still less known. OBJECTIVE: We aimed to investigate the associations of LVEF with cerebrospinal fluid (CSF) biomarkers for AD in cognitively normal elders. METHODS: A total of 423 cognitively normal individuals without heart failure were included from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study. Participants were divided into low LVEF group (50%≤LVEF < 60%) and high LVEF group (LVEF≥60%). The associations of LVEF with CSF AD biomarkers including CSF amyloid-ß 42 (Aß42), total-tau (t-tau), and phosphorylated tau (p-tau) were analyzed using multivariate linear regression models. RESULTS: Participants with low LVEF had higher levels of CSF t-tau (ß= -0.009, p = 0.006) and t-tau/Aß42 ratios (ß= -0.108, p = 0.026). Subgroup analyses showed that the associations only existed in female and middle-aged groups (< 65 years old). Besides, participants with low LVEF had higher levels of CSF p-tau (ß= -0.002, p = 0.043) in middle-aged group. CONCLUSION: In conclusion, our findings revealed the associations between LVEF and AD pathology, which may provide new insights into AD prevention through maintaining cardiac function.