To the Editor:
Emerging evidence from cross-sectional studies has suggested that lung function might be a risk factor of dementia (1–4), although the longitudinal associations of lung function with subsequent cognitive decline remain inconsistent (2, 5–8). The ELSA (English Longitudinal Study of Ageing), with its lung-function measurements at baseline (forced expiratory volume in 1 second [FEV1] and forced vital capacity [FVC]) and biennial cognitive assessments over 12 years based on a large, nationally representative cohort, provides us with the opportunity to explore the longitudinal association of lung function with the temporal pattern of subsequent cognitive decline.
Methods
The ELSA is an ongoing and longitudinal cohort study conducted in a representative sample of the English population aged 50 and over living in England (9, 10). The ELSA cohort was established in 2002/2003 (wave 1) and has been followed up every 2 years until 2016/2017 (wave 8). Lung function was first measured at wave 2 (2004/2005), which was therefore regarded as the baseline of the present study, and follow-up of cognitive function was conducted from waves 3–8 (2006/2007–2016/2017). A flowchart of the study population is presented in Figure 1. Finally, 6,107 individuals were included in this study. The London Multicentre Research Ethics Committee approved the ELSA (MREC/01/2/91), and all participants provided informed consent at each wave.
Figure 1.
Flowchart of participant selection for the present study population.
Cognitive assessment was conducted in all waves and included three aspects: memory, executive function and orientation (11, 12). The z-score for global cognitive function was calculated by averaging the z-scores of three tests and restandardizing to baseline according to the mean and standard deviation (SD) of the baseline global cognitive z-scores (13, 14). Prebronchodilation measures of FEV1 and FVC were conducted by trained nurses using a spirometer (Escort; Vitalograph) in each participant’s house at wave 2. The percentage of the FEV1 predicted and the percentage of the FVC predicted were calculated on the basis of published equations for white individuals (15).
Covariates at baseline that might be related to both lung function and cognitive decline were selected a priori for this analysis. Linear mixed models were used to evaluate the longitudinal associations between baseline lung function and cognitive decline over time. All analyses in this study were divided by sex, as both lung function and cognitive function are significantly different between sexes (16).
Results
The mean ± SD of age at baseline (2004/2005) for men and women was 65.5 ± 9.1 and 65.8 ± 9.4 years, respectively. The median follow-up period was 12 years (interquartile range, 8–12 yr). The scores for memory, executive function, and orientation increased linearly with increasing quartiles of FEV1 in both men and women.
In women, for each of the lung-function indicators, a lower baseline level was significantly associated with a faster decline of global cognitive z-scores after multivariable adjustment (Table 1). However, in men, only FEV1 and FVC were significantly associated with global cognitive decline (Table 1). In both men and women, we observed that FEV1 and FVC were significantly associated with a faster decline of memory, executive function, and orientation z-scores.
Table 1.
Longitudinal associations between baseline indicators of lung function and the rate of change in global cognitive z-scores (SD/yr) using linear mixed models
| Indicators of Lung Function | Women (n = 3,343) |
Men (n = 2,764) |
||
|---|---|---|---|---|
| β (95% CI)* for the Interaction | P Value* | β (95% CI)* for the Interaction | P Value* | |
| FEV1 (per 100-ml decrease) | −0.004 (−0.005 to −0.003) | <0.001 | −0.002 (−0.003 to −0.001) | <0.001 |
| FEV1% pred (per 20% decrease)† | −0.006 (−0.010 to −0.002) | 0.005 | −0.001 (−0.006 to 0.003) | 0.527 |
| FVC (per 100-ml decrease) | −0.003 (−0.004 to −0.002) | <0.001 | −0.002 (−0.002 to −0.001) | <0.001 |
| FVC% pred (per 20% decrease)† | −0.004 (−0.009 to −0.000) | 0.032 | −0.004 (−0.009 to 0.001) | 0.120 |
| FEV1/FVC ratio (per 0.20 decrease) | −0.009 (−0.016 to −0.002) | 0.008 | −0.003 (−0.009 to 0.004) | 0.461 |
Definition of abbreviations: CI = confidence interval; FEV1 = forced expiratory volume in 1 second; FEV1% pred = percentage of the FEV1 predicted; FVC = forced vital capacity; FVC% pred = percentage of the FVC predicted; SD = standard deviation.
Models included each indicator, time, the indicator × time interaction, age, ethnicity, education, height, body mass index, current smoking, cigarettes per day, alcohol consumption, chronic lung disease, asthma, stroke, and cancer.
Age, ethnicity, and height were not included in these models, as these covariates had been already adjusted for when generating a percentage of the value predicted: a 20% decrease of the absolute percentage of the values predicted.
Cognitive z-scores declined faster with decreasing quartiles of FEV1 at baseline, with the trend being statistically significant (Table 2). Compared with the highest quartile of FEV1, the rate of decline of global z-scores associated with the lowest quartile was faster by −0.069 SD/yr (95% confidence interval [95% CI], −0.082 to −0.056 SD) and −0.049 SD/yr (95% CI, −0.063 to −0.034 SD) in women and men, respectively.
Table 2.
Longitudinal associations between baseline quartiles of FEV1 and the rate of change in cognitive z-scores (SD/yr) using linear mixed models
| Mean Difference in the Rate of Change in Cognitive z-Scores (95% CI)* across Sex-Specific Quartiles of FEV1 |
P for Trend* | ||||
|---|---|---|---|---|---|
| Quartile 1 (<2.27 L) | Quartile 2 (2.27 to 2.84 L) | Quartile 3 (2.85 to 3.37 L) | Quartile 4 (≥3.37 L) | ||
| Women, N = 3,343 | |||||
| Global cognitive z-score | −0.069 (−0.082 to −0.056) | −0.052 (−0.065 to −0.039) | −0.023 (−0.036 to −0.009) | Reference | <0.001 |
| Memory z-score | −0.046 (−0.056 to −0.037) | −0.026 (−0.035 to −0.016) | −0.010 (−0.020 to −0.001) | Reference | <0.001 |
| Executive function z-score | −0.038 (−0.048 to −0.028) | −0.030 (−0.040 to −0.020) | −0.011 (−0.021 to −0.001) | Reference | <0.001 |
| Orientation z-score | −0.054 (−0.070 to −0.038) | −0.045 (−0.061 to −0.029) | −0.022 (−0.038 to −0.006) | Reference | <0.001 |
| Men, N = 2,764 | |||||
| Global cognitive z-score | −0.049 (−0.063 to −0.034) | −0.033 (−0.047 to −0.018) | −0.013 (−0.028 to 0.002) | Reference | <0.001 |
| Memory z-score | −0.031 (−0.041 to −0.021) | −0.019 (−0.029 to −0.009) | −0.001 (−0.011 to 0.010) | Reference | <0.001 |
| Executive function z-score | −0.032 (−0.043 to −0.021) | −0.025 (−0.037 to −0.014) | −0.012 (−0.024 to 0.001) | Reference | <0.001 |
| Orientation z-score | −0.039 (−0.056 to −0.022) | −0.026 (−0.043 to −0.008) | −0.012 (−0.030 to 0.006) | Reference | <0.001 |
Definition of abbreviations: CI = confidence interval; FEV1 = forced expiratory volume in 1 second; SD = standard deviation.
Models included quartile, time, the quartile × time interaction, age, ethnicity, education, height, body mass index, current smoking, cigarettes per day, alcohol consumption, chronic lung disease, asthma, stroke, and cancer.
Discussion
As far as we know, this is one of the largest cohort studies that simultaneously employed multiple pulmonary measurements to explore the association of lung function and cognitive decline. Previous studies focusing on this association only used one or two pulmonary measurements and therefore yielded conflicting results. Few cohort studies have investigated the relationship between baseline lung function and consequent decline of cognitive function in general populations (17). Recently, the ARIC (Atherosclerosis Risk in Communities) study reported that baseline lung function was associated with incident dementia and mild cognitive impairment (18). In this study, we found that global z-scores in the lowest quartile of FEV1 declined faster by −0.069 SD/yr and −0.049 SD/yr compared with that in the highest quartile in women and men, respectively. Previous studies have defined that a change of 0.5 SDs in a health-related indicator is a clinically significant change (19, 20). According to this definition, accelerated cognitive decline in participants within the lowest quartile would achieve a clinically significant change in approximately 7–10 years; therefore, our results support the findings from the ARIC study.
Interestingly, significant longitudinal associations were only detected between the FEV1 and FVC and global cognitive performance and were not detected between the calculated indicators (percentage of the FEV1 predicted, percentage of the FVC predicted, and FEV1/FVC ratio) and global cognitive performance. We consider that the results are reasonable because both the numerator and the denominator of a calculated indicator of lung function were significantly associated with cognitive function, which would dilute the relationship of the calculated indicator with cognitive function.
Our study has several strengths, including its large sample size; nationally representative longitudinal design; long-term follow-up; and inclusion of seven repeated measurements of cofunction, multiple indicators of lung function, three measurements of lung function, and multiple domains of cognitive function. However, several potential limitations should be considered before performing causal inference. First, its observational design had inherent limitations in terms of determining the causal relationship. Second, 746 participants with complete baseline data were excluded from our analyses on the basis of being lost to follow-up, which might have led to selection bias. Third, the present study had adjusted for a number of covariates; however, unmeasured covariates, like APOE status, might still cause confounding bias. Last, the present study focused on English adults aged over 50, and 98% of them were white; thus, the findings might not be completely generalizable to young people or other populations.
In conclusion, this prospective cohort study demonstrated that baseline FEV1 and FVC were significantly associated with cognitive decline over 12 years. Our results suggest that physicians should carefully and prospectively monitor cognitive function of older adult patients with reduced lung function in clinical practice.
Supplementary Material
Acknowledgments
Acknowledgment
The authors thank the original data creators, depositors, and copyright holders; funders of data collection; and the UK Data Archive for the use of data from ELSA: waves 0–8, 1998–2017. The original data creators, depositors, or copyright holders bear no responsibility for the current analysis or interpretation.
Footnotes
Supported by the National Natural Science Foundation of China (project no. 81974490), the Beijing Natural Science Foundation (project no. 7182108), the Newton International Fellowship from the Academy of Medical Sciences (project no. NIF001-1005-P56804), and the 2019 Irma and Paul Milstein Program for Senior Health Research Project Award.
Author Contributions: Conceived and designed the study: W.X. and L.X. Statistical analysis: W.X. and F.Z. Wrote the manuscript: W.X. and F.Z. Discussed the results and implications and commented on the manuscript at all stages: all co-authors.
Author disclosures are available with the text of this letter at www.atsjournals.org.
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