Behaviorally meaningful functional networks mediate the effect of Alzheimer's pathology on cognition.

Tau pathology is associated with cognitive impairment in both aging and Alzheimer's disease, but the functional and structural bases of this relationship remain unclear. We hypothesized that the integrity of behaviorally meaningful functional networks would help explain the relationship between tau and cognitive performance. Using resting state fMRI, we identified unique networks related to episodic memory and executive function cognitive domains. The episodic memory network was particularly related to tau pathology measured with positron emission tomography in the entorhinal and temporal cortices. Further, episodic memory network strength mediated the relationship between tau pathology and cognitive performance above and beyond neurodegeneration. We replicated the association between these networks and tau pathology in a separate cohort of older adults, including both cognitively unimpaired and mildly impaired individuals. Together, these results suggest that behaviorally meaningful functional brain networks represent a functional mechanism linking tau pathology and cognition.

CTRP6 alleviates endometrial fibrosis by regulating Smad3 pathway in intrauterine adhesion†.

Intrauterine adhesion (IUA) is manifestations of endometrial fibrosis and excessive extracellular matrix deposition. C1q/tumor necrosis factor-related protein-6 (CTRP6) is a newly identified adiponectin paralog which has been reported to modulate the fibrosis process of several diseases; however, the endometrial fibrosis function of CTRP6 remains unknown. Our study aimed to assess the role of CTRP6 in endometrial fibrosis and further explore the underlying mechanism. Here, we found that the expression of CTRP6 was downregulated in the endometrial tissues of IUA. In vitro experiments demonstrated the reduced level of CTRP6 in facilitated transforming growth factor-ß1 (TGF-ß1)-induced human endometrial stromal cells (HESCs). In addition, CTRP6 inhibited the expression of α-smooth muscle actin (α-SMA) and collagen I in TGF-ß1-treated HESCs. Mechanistically, CTRP6 activated the AMP-activated protein kinase (AMPK) and protein kinase B (AKT) pathway in HESCs, and AMPK inhibitor (AraA) or PI3K inhibitor (LY294002) pretreatment abolished the protective effect of CTRP6 on TGF-ß1-induced fibrosis. CTRP6 markedly decreased TGF-ß1-induced Smad3 phosphorylation and nuclear translocation, and AMPK or AKT inhibition reversed these effects. Notably, CTRP6-overexpressing treatment alleviated the fibrosis of endometrium in vivo. Therefore, CTRP6 ameliorates endometrial fibrosis, among which AMPK and AKT are essential for the anti-fibrotic effect of CTRP6 via the Smad3 pathway. Taken together, CTRP6 may be a potential therapeutic target for the treatment of intrauterine adhesion.

Folic acid alleviated oxidative stress-induced telomere attrition and inhibited apoptosis of neurocytes in old rats.

PURPOSE: Oxidative stress has been reported to cause telomere attrition, which triggers cell apoptosis. Apoptosis of neurocytes may play an essential role in the pathogenesis of neurodegenerative diseases. This study hypothesized that folic acid (FA) supplementation decreased neurocyte apoptosis by alleviating oxidative stress-induced telomere attrition in 25-month-old Sprague Dawley (SD) rats. METHODS: Three-month-old male SD rats were randomly divided into four diet groups by different concentrations of folic acid in equal numbers, with intervention for 22 months. Folate, homocysteine (Hcy), reactive oxygen species (ROS) levels, antioxidant activities, and telomere length in the brain tissues were tested at 11, 18, and 22 months of intervention, and 8-hydroxy-deoxyguanosine (8-OHdG) levels, neurocyte apoptosis and telomere length in the cerebral cortex and hippocampal regions were tested during the 22-month intervention. An automated chemiluminescence system, auto-chemistry analyzer, Q-FISH, qPCR, and TUNEL assay were used in this study. RESULTS: The rats had lower folate concentrations and higher Hcy, ROS, and 8-OHdG concentrations in brain tissue with aging. However, FA supplementation increased folate concentrations and antioxidant activities while decreasing Hcy, ROS, and 8-OHdG levels in rat brain tissue after 11, 18, and 22 months of intervention. Furthermore, FA supplementation alleviated telomere length shortening and inhibited neurocyte apoptosis during the 22-month intervention. CONCLUSION: FA supplementation alleviated oxidative stress-induced telomere attrition and inhibited apoptosis of neurocytes in 25-month-old rats.

Afterpulse effects in quantum key distribution without monitoring signal disturbance.

The round-robin differential phase shift (RRDPS) quantum key distribution (QKD) protocol is the only one that does not require monitoring of signal disturbance. Moreover, it has been proven that RRDPS has excellent performance of resistance to finite-key effects and high error rate tolerance. However, the existing theories and experiments do not take the afterpulse effects into account, which cannot be neglected in high-speed QKD systems. Here, we propose a tight finite-key analysis with afterpulse effects. The results show that the non-Markovian afterpulse RRDPS model optimizes the system performance considering afterpulse effects. The advantage of RRDPS over decoy-state BB84 under short-time communication still holds at typical values of afterpulse.

Experimental Demonstration of Fully Passive Quantum Key Distribution.

The passive approach to quantum key distribution (QKD) consists of removing all active modulation from the users' devices, a highly desirable countermeasure to get rid of modulator side channels. Nevertheless, active modulation has not been completely removed in QKD systems so far, due to both theoretical and practical limitations. In this Letter, we present a fully passive time-bin encoding QKD system and report on the successful implementation of a modulator-free QKD link. According to the latest theoretical analysis, our prototype is capable of delivering competitive secret key rates in the finite key regime.

Accumulation, migration and health risk of trace metals in a soil-strawberry-human system of the Yangtze River Delta region, China.

Growing concern has been paid to metals in soil-strawberry system. In contrast, few attempts have been made to investigate bioaccessible metals in strawberries and further assess health risk based on bioaccessible metals. Moreover, the connections between soil parameters (e.g. soil pH, organic matter (OM), total and bioavailable metals) and metal transfer in soil-strawberry-human system still need to be systematically investigated as well. Considering that strawberries are extensively grown under plastic-shed conditions in China, a total of 18 paired plastic-shed soil (PSS) and strawberry samples were taken from the strawberry bases located in the Yangtze River Delta of China as a case study to assess accumulation status, migration and health risk of Cd, Cr, Cu, Ni, Pb, and Zn in the PSS-strawberry-human system. Overall, heavy application of organic fertilizers induced accumulation and contamination of Cd and Zn in PSS. In particular, 55.6% and 44.4% of PSS samples had considerable and moderate ecological risk caused by Cd, respectively. Despite no metal pollution in strawberry, PSS acidification mainly caused by high nitrogen input promoted Cd and Zn uptake by strawberry and enhanced bioaccessible concentrations of Cd, Cu, and Ni. In contrast, the increased soil OM caused by organic fertilizer application decreased Zn migration in PSS-strawberry-human system. Additionally, bioaccessible metals in strawberries induced limited non-cancer and cancer risk. To mitigate accumulation of Cd and Zn in PSS and metal transfer in the food chain, feasible fertilization strategies should be developed and carried out.

Nanocomposites based on nanoceria regulate the immune microenvironment for the treatment of polycystic ovary syndrome.

The immune system is closely associated with the pathogenesis of polycystic ovary syndrome (PCOS). Macrophages are one of the important immune cell types in the ovarian proinflammatory microenvironment, and ameliorate the inflammatory status mainly through M2 phenotype polarization during PCOS. Current therapeutic approaches lack efficacy and immunomodulatory capacity, and a new therapeutic method is needed to prevent inflammation and alleviate PCOS. Here, octahedral nanoceria nanoparticles with powerful antioxidative ability were bonded to the anti-inflammatory drug resveratrol (CeO2@RSV), which demonstrates a crucial strategy that involves anti-inflammatory and antioxidative efficacy, thereby facilitating the proliferation of granulosa cells during PCOS. Notably, our nanoparticles were demonstrated to possess potent therapeutic efficacy via anti-inflammatory activities and effectively alleviated endocrine dysfunction, inflammation and ovarian injury in a dehydroepiandrosterone (DHEA)-induced PCOS mouse model. Collectively, this study revealed the tremendous potential of the newly developed nanoparticles in ameliorating the proinflammatory microenvironment and promoting the function of granulosa cells, representing the first attempt to treat PCOS by using CeO2@RSV nanoparticles and providing new insights in combating clinical PCOS.

Telomere and mitochondria mediated the association between dietary inflammatory index and mild cognitive impairment: A prospective cohort study.

BACKGROUND: Diet and chronic inflammation might play a major role in the pathogenesis of mild cognitive impairment (MCI). In addition, peripheral blood leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn) might mediate the relationship between inflammation and MCI risk. The purpose of the present study is to evaluate whether inflammatory potential of diet assessed by dietary inflammatory index (DII), chronic inflammation, peripheral blood LTL, and mtDNAcn were associated with the risk of MCI. RESULTS: A population-based cohort study was conducted with a total of 2944 participants. During a median follow-up of 2 years, 438 (14.90%) individuals were new-onset MCI. After adjustment, a higher score of DII (hazard ratio [HR]: 1.056, 95% CI: 1.005, 1.109), a higher log systemic immune inflammation index (SII) (HR: 1.333, 95% CI: 1.089, 1.633) and log system inflammation response index (SIRI) (HR: 1.487, 95% CI: 1.024, 2.161) predicted elevated risk of MCI. An increased mtDNAcn (HR: 0.843, 95% CI: 0.712, 0.997), but not LTL, predicted a decreased risk of MCI. Negative associations of log SII with LTL (ß:-0.359, 95% CI: -0.445, -0.273) and mtDNAcn (ß:-0.048, 95% CI: -0.090, -0.006) were found. Additionally, negative associations of log SIRI with LTL (ß: -0.035, 95% CI: -0.052, -0.017) and mtDNAcn (ß:-0.136, 95% CI: -0.216, -0.056) were also found. Path analysis suggested that SIRI, LTL, and mtDNAcn, in series, have mediation roles in the association between DII score and MCI risk. CONCLUSIONS: Higher DII, SII, and SIRI might predict a greater risk of MCI, while a longer LTL and an increased mtDNAcn were linked to a reduced risk of MCI among the older population. LTL and mtDNAcn could play mediation roles in the association between DII and MCI risk.

Effect of obstructive sleep apnea on semen quality.

BACKGROUND: Obstructive sleep apnea (OSA) has several notable complications such as hypertension and diabetes. Studies have also shown that OSA is associated with erectile dysfunction and reduced androgen levels. However, the effect of OSA on semen quality remains poorly studied. METHODS: Men attending a tertiary reproductive center for semen analysis were tested with a portable sleep breathing monitor. Patients were divided into four groups based on their apnea hypopnea index: none, mild, moderate, and severe obstructive sleep apnea. Differences between groups were assessed using χ2, and associations were tested with multiple regression analysis. RESULTS: We included a total of 175 male subjects with a mean age of 32.2 ± 3.6 years. There were significant differences between groups in progressive sperm motility (%) (43 ± 16, 42 ± 17, 36 ± 18, 29 ± 18, respectively; p = 0.002), total motility (%) (59 ± 19, 59 ± 20, 49 ± 21, 42 ± 20, respectively; p = 0.010), and vitality (%) (80 ± 10, 81 ± 11, 79 ± 8, 72 ± 19, respectively; p = 0.039). Asthenospermia (progressive motility < 35%) was significantly more common in subjects with OSA (χ2 = 5.195, p = 0.023). In multiple regression models, after adjusting for age and body mass index, apnea hypopnea index remained negatively and significantly associated with progressive motility, total motility, and vitality. CONCLUSIONS: OSA is an independent risk factor for sperm motility and vitality, and further investigation is now needed to determine if continuous positive pressure ventilation or other therapies can improve semen quality in these patients.

Immune Regulation of Seminal Plasma on the Endometrial Microenvironment: Physiological and Pathological Conditions.

Seminal plasma (SP) accounts for more than 90% of semen volume. It induces inflammation, regulates immune tolerance, and facilitates embryonic development and implantation in the female reproductive tract. In the physiological state, SP promotes endometrial decidualization and causes changes in immune cells such as macrophages, natural killer cells, regulatory T cells, and dendritic cells. This leads to the secretion of cytokines and chemokines and also results in the alteration of miRNA profiles and the expression of genes related to endometrial tolerance and angiogenesis. Together, these changes modulate the endometrial immune microenvironment and contribute to implantation and pregnancy. However, in pathological situations, abnormal alterations in SP due to advanced age or poor diet in men can interfere with a woman's immune adaptation to pregnancy, negatively affecting embryo implantation and even the health of the offspring. Uterine pathologies such as endometriosis and endometritis can cause the endometrium to respond negatively to SP, which can further contribute to pathological progress and interfere with conception. The research on the mechanism of SP in the endometrium is conducive to the development of new targets for intervention to improve reproductive outcomes and may also provide new ideas for semen-assisted treatment of clinical infertility.

The circROBO1/KLF5/FUS feedback loop regulates the liver metastasis of breast cancer by inhibiting the selective autophagy of afadin.

BACKGROUND: Metastasis causes the majority of cancer-related deaths worldwide. Increasing studies have revealed that circRNAs are associated with the carcinogenesis and metastasis of many cancers. Nevertheless, the biological mechanisms of circRNAs in breast cancer (BC) liver metastasis remain extremely ambiguous. METHODS: In this study, we identified circROBO1 from three pairs of primary BC and metastatic liver sites by RNA sequencing. FISH assays and RT-qPCR were conducted to validate the existence and expression of circROBO1. The oncogenic role of circROBO1 was demonstrated both in vitro and in vivo. Western blot, ChIP, RIP, RNA pull-down, and dual-luciferase reporter assays were used to confirm the interaction of the feedback loop among circROBO1, miR-217-5p, KLF5, and FUS. Meanwhile, the regulation of selective autophagy was investigated by immunofluorescence, CoIP, and western blot. RESULTS: In this study, upregulated expression of circROBO1 was found in BC-derived liver metastases and was correlated with poor prognosis. Knockdown of circROBO1 strikingly inhibited the proliferation, migration, and invasion of BC cells, whereas overexpression of circROBO1 showed the opposite effects. Moreover, overexpression of circROBO1 promoted tumor growth and liver metastasis in vivo. Further research revealed that circROBO1 could upregulate KLF5 by sponging miR-217-5p, allowing KLF5 to activate the transcription of FUS, which would promote the back splicing of circROBO1. Therefore, a positive feedback loop comprising circROBO1/KLF5/FUS was formed. More importantly, we found that circROBO1 inhibited selective autophagy of afadin by upregulating KLF5. CONCLUSIONS: Our results demonstrated that circROBO1 facilitates the carcinogenesis and liver metastasis of BC through the circROBO1/KLF5/FUS feedback loop, which inhibits the selective autophagy of afadin by suppressing the transcription of BECN1. Therefore, circROBO1 could be used not only as a potential prognostic marker but also as a therapeutic target in BC.

The FUS/circEZH2/KLF5/ feedback loop contributes to CXCR4-induced liver metastasis of breast cancer by enhancing epithelial-mesenchymal transition.

BACKGROUND: Metastasis of breast cancer have caused the majority of cancer-related death worldwide. The circRNAs are associated with tumorigenesis and metastasis in breast cancer according to recent research. However, the biological mechanism of circRNAs in liver metastatic breast cancer remains ambiguous yet. METHODS: Microarray analysis of three pairs of primary BC tissues and matched hepatic metastatic specimens identified circEZH2. We used RT-qPCR and FISH assays to confirm circEZH2 existence, characteristics, and expression. Both in vivo and in vitro, circEZH2 played an oncogenic role which promoted metastasis as well. A range of bioinformatic analysis, Western blot, RNA pull-down, RIP, ChIP, and animal experiments were used to define the feedback loop involving FUS, circEZH2, miR-217-5p, KLF5, FUS, CXCR4 as well as epithelial and mesenchymal transition. RESULTS: In our research, circEZH2 was proved to be upregulated in liver metastases in BC and predicted the worse prognosis in breast cancer patients. Overexpression of circEZH2 notably accentuated the vitality and invasion of BC cells, whereas knockdown of circEZH2 elicited the literally opposite effects. Besides, overexpressed circEZH2 promoted tumorigenesis and liver metastasis in vivo. Moreover, circEZH2 could adsorb miR-217-5p to upregulate KLF5 thus leading to activate FUS transcription which would facilitate the back-splicing program of circEZH2. Meanwhile, KLF5 could upregulated CXCR4 transcriptionally to accelerate epithelial and mesenchymal transition of breast cancer. CONCLUSIONS: Consequently, a novel feedback loop FUS/circEZH2/KLF5/CXCR4 was established while circEZH2 could be novel biomarker and potential target for BC patients' therapy.

Integrated multi-omic data and analyses reveal the pathways underlying key ornamental traits in carnation flowers.

Carnation (Dianthus caryophyllus) is one of the most popular ornamental flowers in the world. Although numerous studies on carnations exist, the underlying mechanisms of flower color, fragrance, and the formation of double flowers remain unknown. Here, we employed an integrated multi-omics approach to elucidate the genetic and biochemical pathways underlying the most important ornamental features of carnation flowers. First, we assembled a high-quality chromosome-scale genome (636 Mb with contig N50 as 14.67 Mb) of D. caryophyllus, the 'Scarlet Queen'. Next, a series of metabolomic datasets was generated with a variety of instrumentation types from different parts of the flower at multiple stages of development to assess spatial and temporal differences in the accumulation of pigment and volatile compounds. Finally, transcriptomic data were generated to link genomic, biochemical, and morphological patterns to propose a set of pathways by which ornamental traits such as petal coloration, double flowers, and fragrance production are formed. Among them, the transcription factors bHLHs, MYBs, and a WRKY44 homolog are proposed to be important in controlling petal color patterning and genes such as coniferyl alcohol acetyltransferase and eugenol synthase are involved in the synthesis of eugenol. The integrated dataset of genomics, transcriptomics, and metabolomics presented herein provides an important foundation for understanding the underlying pathways of flower development and coloration, which in turn can be used for selective breeding and gene editing for the development of novel carnation cultivars.

Transmittance-invariant phase modulator for chip-based quantum key distribution.

In chip-based quantum key distribution (QKD) systems, the non-ideal quantum state preparation due to the imperfect electro-optic phase modulators (EOPM) decreases the secret key rate and introduces potential vulnerabilities. We propose and implement an on-chip transmittance-invariant phase modulator (TIPM) to solve this problem. Simulated and experimental results show that TIPM can eliminate the correlation between phase, intensity, and polarization of quantum states caused by phase-dependent loss. The design can tolerate a significant fabrication mismatch and is universal to multi-material platforms. Furthermore, TIPM increases the modulation depth achievable by EOPMs in standard process design kit (PDK). The proposal of TIPM can improve the practical security and performance of the chip-based QKD systems.

Afterpulse effect in measurement-device-independent quantum key distribution.

There is no doubt that measurement-device-independent quantum key distribution (MDI-QKD) is a crucial protocol that is immune to all possible detector side channel attacks. In the preparation phase, a simulation model is usually employed to get a set of optimized parameters, which is utilized for getting a higher secure key rate in reality. With the implementation of high-speed QKD, the afterpulse effect which is an intrinsic characteristic of the single-photon avalanche photodiode is no longer ignorable, this will lead to a great deviation compared with the existing analytical model. Here we develop an afterpulse-compatible MDI-QKD model to get the optimized parameters. Our results indicate that by using our afterpulse-compatible model, we can get a much higher key rate than the prior afterpulse-omitted model. It is significant to take the afterpulse effect into consideration because of the improvement of the system working frequency.

Charge state depletion nanoscopy with a nitrogen-vacancy center in nanodiamonds.

The development of super-resolution imaging has driven research into biological labeling, new materials' characterization, and nanoscale sensing. Here, we studied the photoinduced charge state conversion of nitrogen-vacancy (NV) centers in nanodiamonds (NDs), which show the potential for multifunction sensing and labeling at the nanoscale. Charge state depletion (CSD) nanoscopy is subsequently demonstrated for the diffraction-unlimited imaging of NDs in biological cells. A resolution of 77 nm is obtained with 50 nm NDs. The depletion laser power of CSD nanoscopy is approximately 1/16 of stimulated emission depletion (STED) microscopy with the same resolution. The results can be used to improve the spatial resolution of biological labeling and sensing with NDs and other nanoparticles.

Limits on Axions and Axionlike Particles within the Axion Window Using a Spin-Based Amplifier.

Searches for the axion and axionlike particles may hold the key to unlocking some of the deepest puzzles about our Universe, such as dark matter and dark energy. Here, we use the recently demonstrated spin-based amplifier to constrain such hypothetical particles within the well-motivated "axion window" (10 µeV-1 meV) through searching for an exotic dipole-dipole interaction between polarized electron and neutron spins. The key ingredient is the use of hyperpolarized long-lived ^{129}Xe nuclear spins as an amplifier for the pseudomagnetic field generated by the exotic interaction. Using such a spin sensor, we obtain a direct upper bound on the product of coupling constants g_{p}^{e}g_{p}^{n}. The spin-based amplifier technique can be extended to searches for a wide variety of hypothetical particles beyond the standard model.

Salidroside alleviates oxidative stress and apoptosis via AMPK/Nrf2 pathway in DHT-induced human granulosa cell line KGN.

In the past few years, emerging evidence established persistent oxidative stress to be a key player in the pathogenesis of polycystic ovary syndrome (PCOS). Particularly, it damages the function of granulosa cells, and thus hinders the development of follicles. The present study aimed to explore and establish the protective effects of salidroside on dihydrotestosterone (DHT)-induced Granulosa-like tumor cell line (KGN), mediated via antioxidant mechanisms. The study assessed the positive effects of salidroside on DHT-induced apoptosis, reactive oxygen species (ROS) accumulation, damage of antioxidant capacity, and mitochondrial membrane potential depolarization. Interestingly, salidroside partly reversed DHT mediated effects, via stimulation of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway and the downstream antioxidant proteins heme oxygenase-1(HO-1) and quinine oxidoreductase 1(NQO1). Additionally, the knockdown of Nrf2 partly moderated the antioxidant and anti-apoptosis effects of salidroside in DHT-treated KGN cells. Mechanistically, AMP-activated protein kinase (AMPK) was identified to be the upstream signaling involved in salidroside-induced Nrf2 activation, as silencing of AMPK partly prevented the upregulation of Nrf2 and the downstream proteins HO-1 and NQO1. Altogether, the present study is the first to effectively demonstrate the inhibitory effect of salidroside on DHT-stimulated oxidative stress and apoptosis in KGN cells, which was dependent on Nrf2 activation that involved AMPK.

Apolipoprotein E polymorphism ε4-stratified longitudinal association between daytime naps, sleep apnea and mild cognitive impairment: A prospective cohort study.

BACKGROUND AND PURPOSE: Sleep characteristics, including taking a nap and sleep apnea, have been proven to have effects on cognitive function, and apolipoprotein E polymorphism ε4 (APOEε4) has been confirmed to be a risk factor for mild cognitive impairment (MCI), but epidemiological studies linking sleep characteristics and APOEε4 are scarce. We aimed to explore the longitudinal association between sleep characteristics and MCI in an overall cohort, in APOEε4 carriers and in APOEε4 non-carriers. METHODS: We included 3053 older adults from the Tianjin Elderly Nutrition and Cognition Cohort (TENCC) study, recruited from March 2018 to June 2019, and followed up from March 2021 to June 2021. All participants underwent detailed neuropsychological evaluation that allowed psychometric MCI classification. Information on self-reported sleep characteristics was gathered via face-to-face interviews. Crude and multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard regression models. RESULTS: In the multivariable-adjusted models, taking a nap at noon was associated with decreased risk of MCI in all participants (yes vs. no: HR 0.723, 95% CI 0.592, 0.883) and in APOEε4 non-carriers (yes vs. no: HR 0.719, 95% CI 0.576, 0.897). Sleep apnea was associated with increased risk of MCI in all participants (vs. good: HR 2.213, 95% CI 1.171, 4.180) and in APOEε4 non-carriers (vs. good: HR 2.217, 95% CI 1.085, 4.529). CONCLUSIONS: This study suggests that taking a nap at noon might be a potential protective factor against development of MCI in APOEε4 non-carriers, and sleep apnea might be associated with increased incidence of MCI in APOEε4 non-carriers.

Circulating folate concentrations and the risk of mild cognitive impairment: A prospective study on the older Chinese population without folic acid fortification.

BACKGROUND: The longitudinal association between serum folate concentrations and the risk of cognitive impairment remains unclear in populations with low folate levels. We examined the association between serum folate concentrations and mild cognitive impairment (MCI) in older adults in China, where mandatory fortification of foods with folic acid has not been implemented. We further explored if homocysteine (Hcy) and leukocyte telomere length (LTL) mediate the association between serum folate and MCI. METHODS: We performed a longitudinal analysis of 3974 participants aged ≥60 years from the Tianjin Elderly Nutrition and Cognition (TENC) cohort study. The associations between serum folate level and the risk of cognitive impairment overall and stratified by apolipoprotein E (APOE) ε4 genotypes were evaluated using multivariable Cox proportional hazards models. The mediating effects of Hcy and LTL on the folate-MCI association were explored via a path analysis approach. RESULTS: Within a 3-year follow-up, we documented 560 incident MCI cases. After multivariable adjustment, higher serum folate concentrations were associated with lower incidence of MCI, with hazard ratios (95% confidence interval) across quartiles of folate (from lowest to highest concentrations) of 1.00 (reference), 0.66 (0.52, 0.83), 0.57 (0.45, 0.73), 0.66 (0.52, 0.84), respectively (p for trend <0.001). In mediation analyses, the status of serum folate deficiency and MCI were correlated via two intermediary pathways, Hcy and Hcy-telomere (p < 0.05). CONCLUSIONS: Lower folate concentrations, independently of APOE genotype, were associated with increased risk of MCI among elderly Chinese people, a population with relatively low folate intake. Our data were compatible with the mediation hypothesis that the association between folate status and MCI was mediated by Hcy and LTL.