Association of Unhealthy Lifestyle and Genetic Risk Factors With Mild Cognitive Impairment in Chinese Older Adults.

Importance: Apolipoprotein E polymorphism ε4 (APOE ε4) and methylenetetrahydrofolate reductase (MTHFR) TT genotype are genetic risk factors of mild cognitive impairment (MCI), but whether this risk can be changed by modifiable lifestyle factors is unknown. Objective: To explore whether unhealthy lifestyle (unhealthy dietary intake, current smoking, nonlimited alcohol consumption, and irregular physical activities) is associated with a higher risk of age-related MCI considering genetic risk. Design, Setting, and Participants: This population-based cohort study used data from Tianjin Elderly Nutrition and Cognition (TENC) study participants, recruited from March 1, 2018, through June 30, 2021, and followed up until November 30, 2022. Participants were Chinese adults aged 60 years or older who completed the neuropsychological assessments, general physical examinations, and a personal interview. Exposures: Healthy lifestyle was defined according to the Chinese Dietary Guidelines 2022, including healthy diet, regular physical activity, limited alcohol consumption, and no current smoking, categorized into healthy and unhealthy lifestyles according to weighted standardized lifestyle score. Genetic risk was defined by MTHFR TT genotype and APOE ε4, categorized into low and high genetic risk according to weighted standardized genetic risk score. Main Outcomes and Measures: The main outcome was newly diagnosed MCI as identified using a modified version of Petersen criteria. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazard regression models. Results: A total of 4665 participants were included (mean [SD] age, 67.9 [4.9] years; 2546 female [54.6%] and 2119 male [45.4%]); 653 participants with new-onset MCI (mean [SD] age, 68.4 [5.4] years; 267 female [40.9%] and 386 male [59.1%]) were identified after a median follow-up of 3.11 years (range, 0.82-4.61 years). Individuals with a low genetic risk and an unhealthy lifestyle (HR, 3.01; 95% CI, 2.38-3.79), a high genetic risk and a healthy lifestyle (HR, 2.65; 95% CI, 2.03-3.44), and a high genetic risk and an unhealthy lifestyle (HR, 3.58; 95% CI, 2.73-4.69) had a higher risk of MCI compared with participants with a low genetic risk and a healthy lifestyle. There was a synergistic interaction between lifestyle categories and genetic risk (ß = 3.58; 95% CI, 2.73-4.69). Conclusions and Relevance: In this cohort study of TENC participants, the findings show that unhealthy lifestyle and high genetic risk were significantly associated with a higher risk of MCI among Chinese older adults. Unhealthy lifestyle factors were associated with a higher risk of MCI regardless of genetic risk, and lifestyle and genetic risk had synergistic interactions. These findings could contribute to the development of dietary guidelines and the prevention of early-stage dementia.

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.

Association of dietary inflammatory index and leukocyte telomere length with mild cognitive impairment in Chinese older adults.

BACKGROUND: There are minimal data on the relationship between DII and MCI in an elderly Chinese population and no research has assessed the potential effect of LTL. OBJECTIVE: We investigated the association between DII and MCI while taking into account the potential effect of LTL. METHODS: This cross-sectional study included 3,386 participants aged ≥ 60 years of age from the Tianjin Elderly Nutrition and Cognition Cohort study. DII score was constructed based on a validated self-administered food frequency questionnaire was calculated based on the method developed by Shivappa et al. LTL was measured by quantitative real-time polymerase chain reaction. Multivariable logistic regression analysis was used to analyze the association between DII, LTL and MCI. Moreover, mediation analysis was employed to test the mediation effect of LTL on the total effect of DII on MCI. RESULTS: Compared with the participants in the lowest tertiles of LTL and DII score, the odds ratios (ORs) of MCI in the highest tertiles were 0.386(95% CI: 0.281-0.529) and 1.650 (95% CI: 1.232-2.209), respectively. The significant association between DII score and MCI persisted after further adjusting for LTL (OR: 1.595; 95% CI: 1.189-2.140). The link between DII score and MCI was mediated partially by LTL (ßindirect effect= -0.008, P<0.05). CONCLUSION: High DII score was positively associated with MCI prevalence in an elderly Chinese population and the link between DII scores and MCI seemed to be mediated partially by LTL.

Triglyceride Level- and MTHFR- Specific Mediation Effect of Handgrip Strength on the Association of Dietary Protein Intake and Cognitive Function in the Chinese Elderly.

BACKGROUND: Recent findings suggest that both dietary protein intake and hand grip strength (HGS) were associated with cognitive function, however, few studies have been devoted specifically to the mediation effect of HGS on the association of dietary protein with cognitive function. OBJECTIVES: To confirm the hypothesis that HGS mediated the association of dietary protein intake with cognitive function in the elderly, which was modified by triglyceride level and methylenetetrahydrofolate reductase (MTHFR) gene status. METHODS: This cross-sectional study included 3,268 participants. Dietary protein intake, HGS, and cognitive function were collected by food frequency questionnaires (FFQ), grip measurements and mini mental state examination (MMSE), respectively. In this mediation analysis, dietary protein intake was entered as independent variable, HGS was entered as mediator, and cognitive function was entered as dependent variable. RESULTS: HGS significantly mediated the associations of dietary protein (ß = 0.0013, 95% CI: 0.0007, 0.0022), animal protein (ß = 0.0024, 95% CI: 0.0012, 0.0037), and plant protein intake (ß = 0.0011, 95% CI: 0.0001, 0.0023) with cognitive function in total participants, with the mediated proportion of 16.19%, 12.45% and 20.57%, respectively. Furthermore, significant mediation effects of HGS on the associations of dietary protein, animal protein, and plant protein intake with MMSE score were found in the elderly without hypertriglyceridemia or in MTHFR C677T CC/CT carriers. CONCLUSION: This study suggested that HGS mediated the association of dietary protein intake with cognitive function, and this mediation effect was modified by triglyceride level and MTHFR C677T gene status.

Circulating Amyloid-ß and Methionine-Related Metabolites to Predict the Risk of Mild Cognitive Impairment: A Nested Case-Control Study.

BACKGROUND: The high cost, limited availability, and perceived invasiveness of amyloid PET and cerebrospinal fluid biomarkers limit their use for the diagnosis of Alzheimer's disease. OBJECTIVE: The present study aimed to assess the associations of mild cognitive impairment (MCI) with circulating amyloid-ß (Aß), methionine circulating metabolites (MCMs), and their downstream products, and to develop a nomogram based on these easily accessible blood indexes for the individualized prediction of MCI risk in older adults. METHODS: In this nested case-control study, we recruited 74 MCI patients and, for each, 3 matched controls (n = 222) within the context of the Tianjin Elderly Nutrition and Cognition (TENC) cohort, a population-based prospective study in China. Concentrations of Aß, MCMs, and their circulating downstream factors (i.e., leukocyte telomere length and inflammatory cytokines) were evaluated in fasting blood sample using standard procedures. We constructed a nomogram for MCI harnessed multivariable logistic models incorporating variables selected in the Lasso regression. RESULTS: Among the many biomarkers examined, the final prediction nomogram retained only 3 factors: Aß42/Aß40 ratio, Hcy, and SAM/SAH ratio. The model achieved favorable discrimination, with a C-statistic of 0.75 (95% confidence interval 0.69-0.81) in internal validation after adjustment of optimism. The calibration accuracy was satisfactory; the Brier score of the model was 0.161 in internal validation after adjustment of optimism. CONCLUSION: his study presents an individualized prediction nomogram incorporating only three blood biomarkers (i.e., Aß42/Aß40 ratio, Hcy, and SAM/SAH ratio), which can be conveniently utilized to facilitate early identification and the development of high-risk prevention strategies for MCI in older adults.

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.

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.

Association of Dietary Habits with Mild Cognitive Impairment among Elderly in Rural Area of North China.

BACKGROUND: Recent findings suggest a possible role of diet, particularly nutrient intakes and dietary patterns, in the prevalence of mild cognitive impairment (MCI); few studies, however, have been explicitly devoted to the relationship between dietary habits and MCI. OBJECTIVES: We aimed to explore the association between dietary habits, including meal timing, and MCI among older Chinese adults. METHODS: This cross-sectional study involved data collected at the baseline of the Tianjin Elderly Nutrition and Cognition Cohort (TENCC) study, in which 3,111 community-dwelling older adults (326 MCI patients and 2,785 non-MCIs) from a rural area of Tianjin, China, were recruited. In March 2018 to June 2019, all participants underwent a detailed neuropsychological evaluation that allowed for psychometric MCI classification. Information on self-reported dietary behaviors was gathered via face-to-face interviews. Crude and multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression models. RESULTS: In the multivariable-adjusted models, eating breakfast 4 to 6 times per week (vs. ≤3 times per week, OR: 0.45; 95% CI: 0.26, 0.75), drinking water before breakfast (yes vs. no, OR: 0.64; 95% CI: 0.51, 0.82), consuming water ≥1.5L per day (vs. <1.5L per day, OR: 0.64; 95% CI: 0.51, 0.82), and having lunch after 12:00 (vs. before 12:00, OR: 0.59; 95% CI: 0.47, 0.75) were associated with decreased risk of MCI. Participants who consumed higher amounts of cooking oil were at a higher risk of MCI (moderate vs. low, OR: 1.42; 95% CI: 1.04, 1.92; high vs. low, OR: 1.40; 95% CI: 1.07-1.83). CONCLUSION: This study suggests that dietary habits, including breakfast frequency, daily water consumption, cooking oil consumption, and meal timing, may be associated with the risk of MCI. If replicated, these findings would open new possibilities of dietary interventions for MCI.

Early 1,25-Dihydroxyvitamin D3 Supplementation Effectively Lowers the Incidence of Type 2 Diabetes Mellitus via Ameliorating Inflammation In KK-Ay Mice.

Few studies have been performed to investigate the effect of vitamin D supplementation and T2DM in type 2 diabetic animal models. The present study aimed to explore the relationship between early 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and the incidence of T2DM and determine whether early 1,25(OH)2D3 supplementation was associated with inflammation in KK-Ay mice. The KK-Ay mice were divided into 4 vitamin D treatment groups, the low-dose vitamin D supplementation group (VDS-L, 1.5 µg/kg 1,25(OH)2D3), moderate-dose vitamin D supplementation group (VDS-M, 3.0 µg/kg 1,25(OH)2D3), high-dose vitamin D supplementation group (VDS-H, 6.0 µg/kg 1,25(OH)2D3) and the model control group (MC). C57BL/6J mice were used as the controls. The treatment period lasted for 9 wk. During this treatment period, fasting blood glucose (FBG) level of the mice was measured on a weekly basis. The levels of lipid profile, insulin and inflammation biomarkers were determined after 9 wk of 1,25(OH)2D3 intragastric gavage. After 9 wk of 1,25(OH)2D3 intragastric gavage, FBG level was significantly decreased in the vitamin D treatment groups compared with the MC group. The number of T2DM incidence in the VDS-L group (n=7), VDS-M group (n=5) and VDS-H group (n=3) was lower than those in the MC group (n=10) on week 9. Moreover, serum C-reactive protein (CRP) and interleukin-6 (IL-6) in the vitamin D treatment groups were significantly suppressed by 1,25(OH)2D3 administration compared with the MC group. Early 1,25(OH)2D3 supplementation could effectively lower the incidence of T2DM via ameliorating inflammation in KK-Ay mice.