Abstract
Objective
To explore the association between lymphocyte-high density lipoprotein ratio (LHR) and cognitive impairment in Chinese older adults.
Methods
This study included participants aged ≥65 years from the 2008 to 2014 waves of the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Cognitive function was assessed using the Mini-Mental State Examination, with a score of less than 24 points considered indicative of cognitive impairment. Multiple logistic regression analysis and restricted cubic spline were applied to investigate the association between LHR and cognitive impairment.
Results
Of 3556 participants, 1625 (45.7%) suffered from cognitive impairment. Multivariate logistic regression analysis indicated that low LHR was associated with cognitive impairment [odds ratio (OR) = 1.34; 95% confidence interval (CI) = 1.11-1.62, P = 0.002].
Conclusions
Lower LHR was associated with cognitive impairment in Chinese older people. This finding suggests LHR could serve as a novel and accessible biomarker for identifying high-risk aging populations.
Keywords
Introduction
Cognitive impairment remains a significant public health challenge globally, particularly in aging populations. 1 It is characterized by dysfunctions in memory, language, executive function, attention and other cognitive functions. Previous studies have shown that, the prevalence of cognitive impairment among older people in China ranges from 5-28%, in which 50% progressing to dementia within 5 years.2,3 Which imposes a heavy public health burden.4-6 Given the lack of effective treatment for cognitive impairment currently, it is crucial to identify potential risk factors associated with cognitive impairment, especially in fast-aging developing countries such as China. 7
Previous study has shown that advanced age and age-related hearing loss were associated with cognitive impairment. 8 In addition, a recent observational study showed that lifestyle-related (lower cognitive activities), psychosocial (higher loneliness and absence of meaning in life), as well as health-related (functional impairment) factors associated with cognitive impairment in community-dwelling and institutionalized older individuals from Germany. 9 However, there are still under-explored risk factors for cognitive impairment.
Research has demonstrated that systemic inflammation plays a pathogenic role in the development of cognitive impairment and Alzheimer’s disease.10,11 Lymphocytes, a crucial component of the immune system, have been reported to correlate with cognitive dysfunction in many clinical settings, including stoke, diabetes and Parkinson’s Disease.12-15 In addition, previous studies have found that neutrophil-lymphocyte ratio (NLR) was independently associated with cognitive impairment.16,17 Moreover, increasing evidence suggests serum high density lipoprotein (HDL) is a potentially negative predictor of cognitive impairment in older adults.18,19 However, the relationship between lymphocyte-high density lipoprotein ratio (LHR) and cognitive impairment has not been thoroughly investigated in Chinese older adults.
In the current study, we explored the association between LHR and cognitive impairment in older adults from Chinese Longitudinal Healthy Longevity Survey (CLHLS). Our study provided a novel avenue for early detection, risk stratification, and targeted interventions to mitigate cognitive decline and improve the quality of life for older adults.
Methods
Data Source and Participants
We extracted data of participants aged over 65 years from CLHLS. The CLHLS was established in 1998 and implemented recent follow-up surveys in 2018. 20 Totally, 22 provinces in China were randomly recruited in the CLHLS, which covering about 85% of total population in China. Biomarker-based studies were performed in 2008, 2012 and 2014. The CLHLS study was approved by the Biomedical Ethics Committee of Peking University (IRB00001052-13074) and all participants have signed informed consent.
To screen participants surveyed for this cross-sectional study, participants who met the criteria below were included: first survey from 2008 to 2014, age ≥65 years. Participants with missing data on lymphocyte or HDL were excluded. Multiple imputation was used to deal with variables of the missing data less than 10% except for lymphocyte count and high-density lipoprotein.
A total of 4166 participants were included in the survey from 2008, 2012, 2014 waves of the CLHLS. We further excluded 281 participants with age <65 years, 329 participants with missing lymphocyte or high-density lipoprotein. Finally, a total of 3556 participants were included in our analysis. A detailed description of the flowchart is shown in Figure 1. Flowchart of Study Population
Outcome Variables
The Chinese version of the Mini-Mental State Examination (CMMSE) was used to measure cognitive function, which evaluated 5 dimensions with 24 items: orientation, registration, attention and calculation, recall and language. 21 Previous study has validated the reliability of MMSE. 22 The total score of CMMSE ranges from 0 to 30 with higher scores indicating better cognitive function. Consistent with previous study, MMSE score of 24 was identified as the cut-off point to distinguish cognitive impairment (<24), including individuals with dementia or normal cognitive function (≥24) in our study. 23
Covariates
Based on existing literature and clinical practice, 2 we extracted the following variables from the CLHLS database in 2008, 2012, 2014. Demographic and comorbidities included: age, sex, BMI, central obesity, education, ethnic, residence of birth, hypertension, diabetes, heart disease and stroke or cerebrovascular disease. Lifestyle included: current smoking, current drinking, regular exercise, total sleep time and limited in at least one activity of daily living (ADL). Dietary habits included: fruits, vegetables, animal oil, meat, fish, eggs, food made from beans, salt-preserved vegetables, sugar, garlic, milk products, nut products, mushroom or algae, vitamins, and medicinal plants. We recorded the dietary habits as “eat” or “don’t eat” according to the previous study. 24 Laboratory results included: lymphocyte counts, high-density lipoprotein, creatinine, triglyceride, total cholesterol, hemoglobin, platelet. In addition, we extracted the household income, marriage status and medical service of the participants. LHR was calculated using lymphocyte count (10 9 /L) / high-density lipoprotein (mmol/L).
Statistical Analysis
All participants were divided into 2 groups based on cognitive status. Continuous variables with normally distributed data were described as mean ± SD and compared using Student’s t-test. Mann-Whitney U test was used to compare continuous variables with non-normal distribution data described as medians (IQR). Categorical variables were presented as frequency (%) and analyzed using Chi-square test.
Multiple logistic regression models were used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for investigating the association between LHR and cognitive impairment. We selected variables with P < 0.05 in univariate analysis for model adjustment. Model I adjusted for nothing; model II adjusted for age, sex, marriage status, ethnic, total sleep time, education, central obesity, stroke or cerebrovascular disease and limited in at least one ADL; model III adjusted for model II, current smoking, current drinking, regular exercise, fruits, vegetables, meat, fish, salt-preserved vegetables, sugar, garlic, milk products, nut products, mushroom or algae, and medicinal plants; In model IV, hemoglobin, creatinine, and triglyceride were further adjusted. In addition, we also performed receiver operating characteristic curves to compare the predictive power of LHR and lymphocyte for cognitive impairment. Meanwhile, we also performed the logistic regression analysis based on complete cases data as sensitive analysis to test the consistency of our results.
We used restricted cubic splines with four spline knots at 5%, 35%, 65% and 95% based on the Regression Modeling Strategies 25 and the sample in our study, to explore the potential nonlinear relationship between cognitive impairment and LHR. Stratified and interaction analyses were applied according to age (<80 or ≥80 years), sex (male or female), ethnic (Han or others), married (yes or no), limited in at least one ADL (yes or no) in the multiple logistic regression model adjusted for all variables with P < 0.05, excluding stratification factor itself.
R 4.2.2 software (https://www.Rproject.org; The R Foundation, Vienna, Austria) and Free Statistics software version 1.7.1 (Beijing Free Clinical Medical Technology Co, Ltd, Beijing, China) were used to conduct all statistical analyses. Statistical differences were considered significant at P < 0.05.
Results
Participants Characteristics
Characteristics of the Study Participants by Cognitive Status at 2008-2014 Waves of CLHLS
Data are presented as mean ± SD or median (IQR) and frequency (%). BMI, body mass index; ADL, activity of daily living; LHR, lymphocyte-high density lipoprotein ratio; NA, missing value.
Association Between LHR and Cognitive Impairment
The cut-off point of LHR was 1.29 calculated by the median. The linear correlation between LHR and cognitive impairment is shown in Figure 2. Multivariate Logistic regression analysis indicated that LHR was related to cognitive impairment regarding of continuous variable (OR = 0.79, 95% CI = 0.72∼0.86) or categorical variable (OR = 1.44, 95% CI = 1.26∼1.64) in the unadjusted model. Moreover, the relationship of LHR with cognitive impairment was not affected after adjusting for confounding factors. LHR as a continuous variable was negatively associated with cognitive impairment (OR = 0.86, 95% CI = 0.75∼0.98) in model IV. Meanwhile, as a categorical variable, low LHR was also independently related to cognitive impairment (OR = 1.34, 95% CI = 1.11∼1.62) in model IV (Table 2). Sensitive analysis after excluding participants with missing data also showed the similar results (Supplemental Table 1). In addition, we found that the area under the curve of LHR (0.714, 95% CI = 0.698∼0.731) was higher than lymphocyte (0.563, 95% CI = 0.544∼0.582) (Supplemental Figure 1). Curve Fitting of LHR and Cognitive Impairment in Chinese Older Adults. Data Were Fit by a Logistic Regression Model Based on Restricted Cubic Splines. LHR was Entered as Continuous Variable. Data Were Adjusted for the Factors (Age, Sex, Married, Ethnic, Total Sleep Time, Education, Central Obesity, Stroke or Cerebrovascular Disease, Limited in at Least One ADL, Current Smoking, Current Drinking, Regular Exercise, Fruits, Vegetables, Meat, Fish, Salt-Preserved Vegetables, Sugar, Garlic, Milk Products, Nut Products, Mushroom or Algae, and Medicinal Plants, Hemoglobin, Creatinine, and Triglyceride). The Curves Line and Shaded Areas Around Depict the Estimated Values and Their Corresponding 95% Confidence Intervals. Curves Below Depict the Distribution of the LHR and Only 99% of the Data is Displayed. LHR, Lymphocyte-High Density Lipoprotein Ratio; ADL, Activity of Daily Living Univariable and Multivariable Logistic Regression Analysis to Assess the Association Between LHR and Cognitive Impairment Model I, adjusted for nothing; model II, adjusted for age, sex, married status, ethnic, total sleep time, education, central obesity, stroke or cerebrovascular disease, limited in at least one ADL; model III, adjusted for model II, current smoking, current drinking, regular exercise, fruits, vegetables, meat, fish, salt-preserved vegetables, sugar, garlic, milk products, nut products, mushroom or algae, and medicinal plants; model IV, adjusted for model III, hemoglobin, creatinine, and triglyceride. LHR, lymphocyte-high density lipoprotein ratio; ADL, activity of daily living; OR, odds ratio; CI, confidence interval; Rf, reference.
Subgroup Analysis
Subgroup analysis revealed an interaction between LHR and limited in at least one ADL on cognitive impairment (P for interaction = 0.018). A forest plot of the results also indicated that low LHR was independently associated with cognitive impairment in participants aged ≥88 (OR = 1.42, 95% CI = 1.11∼1.81), those who were female (OR = 1.39, 95% CI = 1.10∼1.76), Han ethnic (OR = 1.30, 95% CI = 1.07∼1.59), unmarried (OR = 1.34, 95% CI = 1.08∼1.66) and limited in at least one ADL (OR = 1.42, 95% CI = 1.15∼1.75) (Figure 3). Association Between LHR and Cognitive Impairment in Sub-groups for Chinese Older Adults. High LHR was the Reference for Low Lymphocyte. Each Stratification Adjusted for the Factors (Age, Sex, Married, Ethnic, Total Sleep Time, Education, Central Obesity, Stroke or Cerebrovascular Disease, Limited in at Least One ADL, Current Smoking, Current Drinking, Regular Exercise, Fruits, Vegetables, Meat, Fish, Salt-Preserved Vegetables, Sugar, Garlic, Milk Products, Nut Products, Mushroom or Algae, and Medicinal Plants, Hemoglobin, Creatinine, and Triglyceride) in the Multivariable Logistic Regression, Except for the Stratification Factor Itself. LHR, Lymphocyte-High Density Lipoprotein Ratio; ADL, Activity of Daily Living; OR, Odds Ratio; CI, Confidence Interval
Discussion
The present study included 3556 Chinese older adults, and the prevalence of cognitive impairment was 45.7%. We found a linear relationship between LHR and cognitive impairment. Meanwhile, we revealed that lower LHR levels were associated with cognitive impairment in Chinese older adults. In addition, subgroup analysis showed that lower LHR levels were independently related to cognitive impairment in individuals with aged over 88 years old and those who were female, Han ethnic, unmarried and limited in at least one ADL. Furthermore, there was an interaction between LHR and limited in at least one ADL on cognitive impairment.
Previous studies have shown that systematic inflammation has emerged as a significant contributor to cognitive impairment.26,27 The animal study found that inflammation and oxidative stress in brain play a vital role in the pathophysiological mechanisms of age-related cognitive impairment. 28 Lymphocytes are components of the adaptive immune system and play a major role in the body’s immune inflammation response, including pathogen identification, immunologic surveillance, immune defenses and the regulation of inflammation. 29 In addition, decreased lymphocyte was associated with chronic inflammation in clinical settings,30,31 which was the mechanism of the cognitive impairment. Moreover, several studies have demonstrated that decreased levels of lymphocytes were associated with cognitive decline,32,33 which was consistent with our study.
HDL, as a component of lipid profile, not only has anti-thrombosis, anti-inflammation effects, but also has antioxidant properties.34,35 HDL also can exhibit immunomodulation by interacting with neutrophil, inhibiting inflammation-induced cell aggregation and infiltration. 36 Recent study reported that HDL is increasingly recognized for its neuroprotective benefits. 37 In addition, previous study has shown that low HDL was linked to cognitive impairment. 19 Our study found that there appeared to be an increasing trend in HDL level among older adults with cognitive impairment compared to cognitively normal patients, but further investigation is needed due to lack of statistical significance.
LHR was a composite indicator derived from lymphocyte and HDL. Therefore, low LHR may be associated with the chronic inflammation status in the older adults. Previous study has shown that LHR was associated with some mental disorders, including schizophrenia, bipolar disorder and depression. 38 In addition, recent study uncovered a significant association between LHR and depression using a representative sample of 4216 Americans from NHANES data. 39 Consistent with previous studies, we found that lower LHR levels were associated with cognitive impairment in Chinese older adults.
However, the definite causes and pathophysiological mechanisms underlying the relationship between LHR and cognitive impairment remain unclear. Based on these above data, it can be said that the LHR is a comprehensive body reserve involving inflammation and oxidative stress and may be more useful than one variable in assessing cognitive impairment. Moreover, LHR is simple and easy to calculate, and is convenient for clinical use, which is not affected by individual subjectivity.
This study offers several clinical implications and strengths. First, we performed the investigation of the association between the LHR and cognitive impairment for the first time, using a nationally representative sample among Chinese older adults. Additionally, the robustness of this study is bolstered by adjustment of multiple critical covariates and sensitive analysis, which enhances the reality of conclusions. Moreover, to verify the consistency of the association between LHR and cognitive impairment, we conducted the analyses in different subgroups.
However, there were several limitations in this study. First, the present study failed to elucidate causality due to the nature of the cross-sectional study. Therefore, additional longitudinal studies are necessary to clarify the association between dynamic changes in LHR and cognitive impairment in the future. Second, we failed to investigate the association between NLR and cognitive impairment due to the inability to obtain neutrophil count in the database. Third, cognitive function was only assessed by MMSE score, which can lead to bias in definition of cognitive impairment. Forth, our study focused on a Chinese population, which may limit the generalizability of our findings. Future research should validate this relationship in diverse populations due to the influence of ethnicity and culture on that. Lastly, our study design did not control for ApoE genotyping, which was associated with cognitive function in older adults. Future studies incorporating genetic data would be valuable to further explore these associations. Despite these limitations, it is the first study to investigate the link between LHR and cognitive impairment in Chinese older adults.
Conclusion
This nationally representative cross-sectional study indicated a significant correlation between low LHR levels and cognitive impairment in Chinese older adults, uncovering LHR’s potential as a novel biomarker for cognitive impairment. Further larger-scale prospective investigations are in need to establish a causal relationship between LHR and cognitive impairment in older adults.
Supplemental Material
Supplemental Material - Association Between Lymphocyte-High Density Lipoprotein Ratio and Cognitive Impairment in Chinese Older Adults: A Population-Based Cross-Section Study
Supplemental Material for Association Between Lymphocyte-High Density Lipoprotein Ratio and Cognitive Impairment in Chinese Older Adults: A Population-Based Cross-Section Study by Jinhui Yang, Wenbin Lu, Hao Wang, Xiaofei Li, Liangliang Lu, Jinjun Bian and Xiaoming Deng in American Journal of Alzheimer's Disease & Other Dementias.
Footnotes
Acknowledgments
We thank all investigators and participants who conducting and participating the Chinese Longitudinal Healthy Longevity Survey.
Ethical Consideration
The studies concerning human participants were reviewed and approved by the ethics committee of Peking University. The participants participated in the study by providing written informed consent.
Author Contributions
Xiaoming Deng and Jinjun Bian conceived and designed the study; Hao Wang and Xiaofei Li collected and processed the data; Liangliang Lu interpreted and analyzed the data; Wenbin Lu and Jinhui Yang drafted the manuscript; Xiaoming Deng and Jinjun Bian revised the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was funded by the National Natural Science Foundation of China (82272205).
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Data Availability Statement
The data supporting the findings of this study can be obtained from the corresponding author according to reasonable request, and the corresponding author/s can be directly contacted for further inquiry.
Supplemental Material
Supplemental material for this article is available online.
References
Supplementary Material
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