Associations of Lung Function Decline with Risks of Cognitive Impairment and Dementia: A Meta-Analysis and Systematic Review

Abstract

Background:

There are controversies surrounding the effects of lung function decline on cognitive impairment and dementia.

Objective:

We conducted a meta-analysis and systematic review to explore the associations of lung function decline with the risks of cognitive impairment and dementia.

Methods:

The PubMed, EMBASE, and the Cochrane Library were searched to identify prospective studies published from database inception through January 10, 2023. We pooled relative risk (RR) and 95% confidence intervals (CI) using random-effects models. The Egger test, funnel plots, meta-regression, sensitivity, and subgroup analyses were conducted to detect publication bias and investigate the source of heterogeneity.

Results:

Thirty-three articles with a total of 8,816,992 participants were subjected to meta-analysis. Poorer pulmonary function was associated with an increased risk of dementia (FEV: RR = 1.25 [95% CI, 1.17–1.33]; FVC: RR = 1.40 [95% CI, 1.16–1.69]; PEF: RR = 1.84 [95% CI, 1.37–2.46]). The results of the subgroup analyses were similar to the primary results. Individuals with lung diseases had a higher combined risk of dementia and cognitive impairment (RR = 1.39 [95% CI, 1.20–1.61]). Lung disease conferred an elevated risk of cognitive impairment (RR = 1.37 [95% CI, 1.14–1.65]). The relationship between lung disease and an increased risk of dementia was only shown in total study participants (RR = 1.32 [95% CI, 1.11–1.57]), but not in the participants with Alzheimer’s disease (RR = 1.39 [95% CI, 1.00–1.93]) or vascular dementia (RR = 2.11 [95% CI, 0.57–7.83]).

Conclusion:

Lung function decline was significantly associated with higher risks of cognitive impairment and dementia. These findings might provide implications for the prevention of cognitive disorders and the promotion of brain health.

Keywords

Cognitive impairment dementia lung function lung disease meta-analysis

INTRODUCTION

Pulmonary function exhibits a gradual decreasing trend during the normal aging process [1]. There are some aging-related physiological alterations in respiratory function, such as reduced chest wall compliance, reduced static elastic contraction of the lungs and increased gas retention, resulting from calcification of costal cartilage and rib-vertebral articulations, narrowing of the intervertebral disk spaces, an increase in the anteroposterior thoracic diameter, collapse of the small airways in the lungs, and an increase in alveolar enlargement [2]. However, the lung function decline includes not only physiological decline but also pathological decline caused by lung diseases, especially chronic obstructive pulmonary disease (COPD) and asthma [3 –6]. The potential mechanism might be that lung diseases promotes the occurrence of chronic inflammation, which leads to lung tissue damage and impaired lung tissue repair [7, 8]. In cases of persistent decline in lung function conditions, the body tends to be subjected to hypoxic conditions. Hypoxia has been associated with central nervous system pathology in a number of diseases including stroke, head trauma, neoplasia, and neurodegenerative disease [9]. Neurons are extremely susceptible to impairments in oxygen homeostasis due to their oxygen-dependence [10, 11]. In the neocortex, hippocampus, and basal ganglia, neural changes from hypoxia contributed to the onset and progression of cognitive impairment and dementia [11 –14]. Additionally, systemic inflammation and immune alterations resulted from some lung diseases may contribute to neuroinflammation in the brain, and then proinflammatory cytokines penetrated the blood-brain barrier to exacerbate inflammation [15]. And immune mediators may activate brain microglia and impair the clearance function of microglia for amyloid-β (Aβ), ultimately leading to Aβ accumulation [16]. Neuroinflammation and deposition of Aβ are the critical component of Alzheimer’s disease (AD) pathologies [17].

Dementia is an acquired loss of cognition in multiple cognitive domains severe enough to interfere with activities of daily life, imposing huge economic, care, and psychological burden on patients, their families and the society [18]. The most common forms of dementia are AD and vascular dementia (VaD). There has been an increasing prevalence of dementia worldwide, and the number of demented people is expected to rise to 131 million by 2050 [18, 19]. Currently, there are no specific pharmacological therapies which could modify the progression of dementia [20]. Patients often present with cognitive decline or mild cognitive impairment in the early stages of dementia. The primary prevention of dementia and the management of cognitive decline and cognitive impairment are equally important in dementia prevention [21]. If we identify the relationships between lung function decline and the cognitive outcomes, the results might inform future dementia prevention trials which focus on the prevention and management of lung function decline. To date, there are conflicting reports on the associations of lung function decline with the risk of cognitive impairment or dementia. Some studies showed lung function decline might result in decreases in the oxygen and blood supply to the brain, thus affecting cognitive function and increasing the risk of cognitive impairment or dementia [22 –27]. However, Sibbett argued that increased FEV1 was not associated with a reduced risk of dementia [28]. Besides, Xiao et al. and Cherbuin et al. suggested that there was no association between COPD and the risk of incident dementia [8, 29]. This inconsistency might be partially due to the differences in study characteristics, sample size, population source and disease background.

For the studies on the associations of lung function decline with risks of cognitive impairment and dementia, we conducted an updated meta-analysis of these studies, considering the increasing study number and the great heterogeneity in study characteristics across them. Besides, subsequent necessary sensitivity analyses and subgroup analyses were also performed to evaluate the stability of the results and identify potential impact factors, such as population characteristics, degree of factor-adjustment, and characteristics of lung disease.

MATERIALS AND METHODS

Search strategy

This systematic review and meta-analysis about the association of lung function decline with the risk of cognitive impairment and dementia was conducted according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) and the PRISMA 2009 guidelines [30, 31]. The protocol was registered with PROSPERO (registration number CRD42021291062). We searched PubMed, EMBASE, and the Cochrane Library to identify prospective studies published from database inception through January 10, 2023. The search terms were as follows: (pulmonary OR lung OR respiratory OR obstructive OR COPD OR emphysema OR bronchiectasis OR tuberculosis OR dyspnea OR asthma OR pneumonia OR bronchopneumonia OR interstitial OR expiratory OR inspiratory OR FEV OR FVC OR PEF OR “peak flow” OR “diffusing capacity” OR “total capacity” OR TLC OR “vital capacity” OR “maximal pressures” OR “volume measurements” OR “tidal volume” OR spirometry OR “maximal voluntary ventilation” OR “diffusing capacity for carbon monoxide” OR MIP OR MEP) AND (cognition OR dementia OR Alzheimer OR VD OR ACD OR MCI OR frontotemporal OR “Lewy body” OR VAD OR FTLD OR FTD OR DLB OR LBD) AND (longitudinal OR prospective OR cohort OR “follow-up”). There was no language restriction in the search process. In addition, we also hand-searched the reference lists of relevant articles to contain as many available studies as possible.

Selection criteria

Studies were considered eligible if the following criteria were simultaneously met: 1) the study used a longitudinal cohort study design; 2) the study investigated the association between lung function decline and the risk of dementia or cognitive impairment; 3) the study gave outcomes measured by standard criteria, such as international classification of disease (ICD), diagnostic and statistical manual of mental disorders (DSM), or a Mini-Mental State Examination (MMSE) score of less than 24; 4) the study had a follow-up period of at least 1 year; 5) the study reported hazard ratio (HR), relative risk (RR), odds ratio (OR), and corresponding 95% confidence intervals (CIs), or the raw data that can be used to calculate RR/HR. And studies were excluded if they met any of the following exclusion criteria: 1) they were reviews, commentaries, letters, conference abstracts, or editorials; 2) they had a sample size less than 100; 3) they were animal studies; 4) they were mechanistic studies; 5) they included patients of dementia or cognitive impairment at baseline; 6) the full texts of them were not accessible. Of the included articles, the diagnosis of cognitive impairment was based on standard criteria or cognitive score change (Supplementary Table 1), and dementia was diagnosed according to ICD, DSM, or other methods (e.g., self-report, structured interview, death certificates, electronic hospital records, or the national standardized evaluation system’s data). When multiple articles were based on the same cohort in our analyses, we selected the suitable study according to cohort size, follow-up years, primary exposures, and outcomes. These criteria were reviewed by two independent investigators and any disagreement was resolved by discussion with a third author until a consensus was achieved.

Data extraction

For each article, the following data were extracted: study characteristics (author, year of publication, cohort name, sample size, follow-up duration), baseline demographics of participants (region, source, age, gender proportion, baseline cognitive status), description of the exposure (various indices of lung function, types of lung disease), outcome (dementia or cognitive impairment), diagnosis criteria, and result assessments (adjusted factors, risk estimates). Remarkably, we mainly extracted the following indicators of lung function: forced expiratory volume (FEV), forced vital capacity (FVC), FEV1/FVC ratio, and peak expiratory flow (PEF). The maximally adjusted estimate was applied when multiple adjusted models were reported in a study. The particular formula was used to convert OR to RR. Ultimately, we use RR uniformly for aggregate analysis in the meta-analysis [32]. In addition, in the lung function indicator analysis, the highest range was used as the reference group and the RR value of per standard deviation (SD) increase was transformed into the RR value of per SD decrease [33]. We contacted the corresponding author for uncertain details. Nevertheless, no responses were received.

Evaluation of study quality

The Newcastle-Ottawa Quality Assessment Scale (https://www.ohri.ca/programs/clinical_epidemiology/nosgen.pdf) guidelines were used to evaluate the article quality. The scale was composed of three domains: selection (four stars), comparability (two stars), and outcome (three stars). And the maximum score is nine, representing the highest quality. The studies with less than 5 scores were defined as low-quality articles and then excluded.

Statistical analysis

The baseline characteristics of all 33 articles included in the study was presented in Table 1. Several statistical analyses were performed to explore the associations of lung function and lung disease with the risk dementia or cognitive impairment. Firstly, the pooled RR and 95% CI were calculated using a random-effects meta-analysis. Heterogeneities across studies were quantified using the I² statistic. Heterogeneities were classified as low (I² < 25%), moderate (I²: 25–50%), or high (I² > 50%) [34, 35]. Secondly, the publication bias was evaluated using the visual examination of the funnel plot and Egger’s test. If the statistical difference was significant, the trim and fill method was used to adjust for bias. Thirdly, sensitivity analyses were further conducted to explore the potential sources of heterogeneity and to investigate whether the pooled result was stable. Next, the univariable regression analyses were carried out to explore whether the individual confounders could be the source of heterogeneity (if n≥10), and then we performed the subgroup analyses to further confirm the results. We conducted six subgroup analyses stratified by the analytical methods for lung function indicators (High versus Low/per SD decrease), type of dementia (AD/VaD), type of pulmonary disease (chronic obstructive pulmonary disease, COPD/Asthma/Pneumonia), region (Asia/North America/Europe), sample size of the study (<5,000/≥5,000), follow-up year (<20 y/≥20 y), source (population/community/clinical), diagnostic criteria (DSM-III/DSM-IV/ICD-9/ICD-10/Other methods), and exposure assessment (self-report/standard measured). The interaction between subgroup relative risks was tested by dividing the difference in log relative risk by its standard error [36]. Comparisons were 2-trailed using a threshold of p < 0.05 for significance for all analyses. Statistical analyses were conducted using R version 4.0.5 and Stata version 16.0.

Table 1
Characteristics of studies included in the meta-analysis for lung function and lung disease

Author; y; cohort name; region; source Age (mean [SD] or median, y) [Range]; female (%) Baseline cognitive status Lung function Lung disease Follow-up years Sample size Outcome (n) Diagnosis criteria Adjusted factors

Simons et al.; 2006; The Dubbo Study; Australia; community [37] 60; 56.04 NC PEF NA 16 y 2,805 Dementia (285) ICD-9; ICD-10 Age, sex

Guo et al.; 2007; the Prospective Population Study of Women in Gothenburg; Sweden; population [22] 52 (6)/58 (6); 100 Without dementia PEF; FVC; FEV NA 29,739 person-years 1,291/1,168 Dementia (147/134) DSM-III-R/ NINCDS-ADRDA Age, height, BMI, education, physical activity, smoking, asthma, chronic bronchitis, myocardial infarction, angina pectoris, and hypertension at baseline.

Alonso et al.; 2009; the Seven Countries Study; Mixed; population [24] 49.2 (5.6) [40 –59]; 0 Without dementia FVC NA 40 y 10,211 Dementia (160) ICD-8 Age, study, cohort, occupation, height, smoking status, BMI, serum cholesterol, hypertension, and previous history of cardiovascular disease.

Giltay et al.; 2009; SCS; European; population [23] ɛ4–50.9 (4.4), ɛ4+ 51.4 (4.6) [45 –64]; 0 Without dementia FEV; FVC NA 25 y 646 Dementia ɛ4–(142); ɛ4+(41) CDR Age, country, chronic disease including COPD at baseline, socioeconomic status, job-related physical activity, marital status, smoking status, BMI, height, systolic blood pressure, and prevalent chronic disease

Pathan et al.; 2011; ARIC; America; community [38] [47 –70]; 56.85 NC FEV1; FVC NA 14.1 y (median) 9,837 Dementia (205) ICD-9 Age, gender, race, cigarette smoking, pack-years of smoking, systolic blood pressure, body mass index, total cholesterol, HDL cholesterol, APOE genotype, use of hypertension medications, diabetes, use of lipid lowering medications, education, occupation, income, and sports-related physical activity.

Vidal et al.; 2013; AGES-RS; Iceland; population [25] 52.3 [5.3]; 67 NC FEV1/height ² NA 23 y 3,665 Dementia (288); MCI (128) DSM-IV Age, sex, higher education, occupation class, midlife BMI and physical activity, depressive symptoms, COPD, CHD, hypertension, diabetes mellitus, and smoking habits.

Russ et al.; 2015; four Health Surveys for England, two Scottish Health Surveys; UK; community [39] 46.8 (17.6) [16–100]; 53.50 Without dementia FEV1; FVC; PEF NA 11.7±3.7 y 48,025 Dementia (393) ICD-9 Age, sex, height, ethnicity, socioeconomic status (occupational social class and educational attainment), health behaviors (smoking, alcohol consumption, and BMI), and illness (self-rated general health and self-reported longstanding illness).

Gilsanz et al.; 2018; KPNC; Mixed; clinical [40] 41.8 (4.2) [35 –50]; 54.1 Without dementia FEV1; FEV2; VC NA >23 y 27,387 Dementia (7,519) ICD-9 Age, race/ethnicity, education, height, hypertension, body mass index, smoking status, stroke, diabetes, heart failure

Sibbett et al.; 2018; LBC1921; Scotland; population [28] 79.04 (0.55); 57.35 NC FEV1 NA 16 y 484 Dementia (106) Death certificates, electronic hospital records, and clinical reviews Age, sex, history of hypertension, smoking status, age 11 IQ, grip strength, 6-m walk time, APOE ɛ4 carrier status, height, history of cardiovascular or cerebrovascular disease, history of diabetes

Donahue et al.; 2022; NHATS; US; population [42] [> = 65y]; 55.4 without dementia PEF NA 3 y 5,935 Dementia (536) 1. self-report; 2. AD8 Dementia Screening Interview; 3. cognitive tests Sex, age, race/ethnicity, education, body mass index, history of smoking, lung disease, history of heart attack, heart disease, high blood pressure, stroke, and diabetes

Wang et al.; 2022(a); MAP; US; community [43] 78.35 (7.60); 78.07 without dementia PF NA 21 y 985 MCI (486) NINCDS/ ADRDA Age, sex, education, income, smoking, alcohol consumption, physical activity, body mass index, heart disease, hypertension, diabetes, stroke, depression, and APOE ɛ4

Zhou et al.; 2022; UKB; UK; population [44] 56.3 (8.0); 52.60 without dementia FEV1; FVC NA 12.6 y 308,534 Dementia (3,607); AD (1525); VaD (743) ICD-10 Age, sex, education, Townsend deprivation index, smoking status, waist-to-hip ratio, systolic blood pressure, physical activity, APOE risk, cholesterol-lowering medications, antihypertensive medications, diabetes, coronary heart disease, heart failure and stroke, pre-existing lung diseases, recent medications on lung diseases, baseline cognitive performance

Minami et al.; 1995; the Sendai Longitudinal Study of Aging.; Japan; population [45] 72.71; 58.4 Without dementia NA Respiratory disease 3 y 2,461 Dementia (105) DSM-III-R Age, sex

Eriksson et al.; 2008; Eriksson’s; Sweden; population [46] 52.9 [37 –71]; 55.54 Without dementia NA Asthma 22.6±7.7 y 22,188 twins Dementia (1,332 twins) CDR Age, sex, history of smoking, level of education, and myocardial infarction

Thakur et al.; 2010; FLOW; America; clinical [47] 58.26 (6.20); 58.24 NC NA COPD 5 y 1,504 Cognitive impairment (73) MMSE Age, sex, race, smoking history, and educational attainment

Shah et al.; 2013; CHS; America; population [48] 72.8 (5.6); 57.6 Without dementia NA Pneumonia 10 y 5,888 Dementia (707) 3MS Demographics, health behaviors, other chronic health conditions, and for trajectories of physical and cognitive decline before pneumonia hospitalization, atrial fibrillation, blocks walked, and income

Chen et al.; 2014; NHIRD; China; population [49] 60.88 (10.39); 58.3 Without dementia NA Asthma 8.0±3.04 y 55,150 Dementia (1,681) ICD-9-CM Age, sex, demographic data, health system utilization, medical comorbidities, use of inhaled steroid

Singh et al.; 2014; MCSA; America; population [50] 79.29 [70,89, 70,89]; 49.82 NC NA COPD 5.1 y 1,425 Cognitive impairment (370) Neuropsychological battery Age, education, sex, Beck Depression Inventory II depression score, history of stroke, APOE ɛ4 genotype, smoking, diabetes mellitus, hypertension, coronary artery disease, baseline global z Scores, and body mass index

Liao et al.; 2015(a); NHI; China; clinical [51] 68.76 (10.74); 37.96 Without dementia NA COPD 10 y 25,920 Dementia (1,228) ICD-9-CM Age, gender, urbanization, coronary artery disease, stroke, hyperlipidemia, hypertension, diabetes, and head injury

Liao et al.; 2015(b); NHIRD; China; population [52] 67.4 (12.5); 28.66 Without dementia NA COPD 6.50 (3.48) y 61,257 Dementia (4,250) ICD-9-CM Age, sex, urbanization, and comorbidities

Peng et al.; 2015; LHID; China; population [53] 53.72 (17.38); 54.23 Without dementia NA Asthma 11 y 63,855 Dementia (2,337) ICD-9-CM Age, sex, comorbidities, annual OPD visits and oral corticosteroids used

Yeh et al.; 2018; (LHID2000); China; population [54] 65.53 (11.87); 43 Without dementia NA ACOS 10 y 30,773 Dementia (1,920) ICD-9-CM Age, sex, comorbidity, inhaled corticosteroids, and oral steroids

Cherbuin et al.; 2019; Cherbuin’s; Mixed; population [8] 74; 62 Without dementia NA COPD 3 y 15,394 Dementia (1,065) DSM-IV Age, sex, education, smoking status, physical, hypertension, depression and hazardous alcohol consumption.

Xie et al.; 2019; CLHLS; China; community [55] 82.9 (9.74); 54.11 NC NA COPD 3 y 4,735 Dementia (83); Cognitive impairment (712) MMSE score Age, gender, marital status, education level, alcohol drinking, current exercise, baseline BMI, smoking status, baseline hypertension, diabetes, and stroke

Siraj et al.; 2020; THIN; England; population [56] 65.85 (10.98); 47.44 NC NA COPD 4.4 y 292,224 Cognitive impairment or dementia (25,999) Read code Age, sex, GP, BMI, smoking status, modified CCI, CV disease, corticosteroid use, socioeconomic class

Tao et al.; 2020; NHIRD; China; population [57] 74.88 (6.72); 38.50 without AD NA COPD 7 y 26,876 AD (6,988) ICD-9-CM Sex, age, insurance status, and payroll bracket

Chu et al.; 2022; NHIRD; China; clinical [58] 68.01 (11.65) [> = 45y]; 40.7 without dementia NA Bacterial pneumonia 17 y 128,832 Dementia (,1817); AD (175); VaD (307) ICD-9-CM Demographic data, comorbidities, CCI score, and all-cause clinical visits

Hendel et al.; 2022; SNAC-K; Sweden; population [59] 81.50 (8.95) [> = 60y]; 63.76 without dementia NA Pneumonia 15 y 712 Dementia (86) DSM-IV Age, sex, education, and number of hospitalizations unrelated to pneumonia

Joh et al.; 2022; The Korean National Health Insurance; Korea; population [15] 54.4 (10.5) [> = 40y]; 49.9 without dementia NA Asthma 8.1 y 6,785,948 Dementia (260,705); AD (195,739); VaD (32,789) ICD-10 Age, sex, body mass index, smoking status, alcohol use, regular physical activity, income, area of residence, history of hypertension, dyslipidemia, diabetes, stroke, and myocardial infarction, systolic blood pressure, glucose, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and estimated glomerular filtration rate

Khairan et al.; 2022; JAGES; Japan; population [60] 73.14 (6.01) [> = 65y]; 52.96 without dementia NA Pneumonia 6 y 9,952 Dementia (939) the national standardized LTCI evaluation system’s data Age, sex, BMI, history of hypertension, history of diabetes, the length of education, marital status, employment status, frequency of meeting friends, low-intensity of physical activity, moderate-intensity of physical activity, tooth loss, the status of pneumonia vaccination, smoking status, alcohol drinking, history of hearing disease, and frailty

Wang et al.; 2022(b); NA; US; clinical [61] 73.70 (7.75) [> = 65y]; 53.6 without AD NA COVID-19 1.5 y 820,956 AD (4,626) ICD-10 Demographics, adverse socioeconomical determinants of health including problems with education, occupational exposure, physical, social and psychosocial environment, and known risk factors for Alzheimer’s disease

Lutsey et al.; 2019; ARIC; America; community [41] 54.2(5.8), [45 –64]; 55.3 Without dementia FEV1; FVC FEV1/FVC COPD 23.0 y (median) 14,184 Dementia (1,407) ICD-9 Age, sex, study center, education level, and race-center, cigarette smoking and pack-years smoking, physical activity, BMI, systolic blood pressure, blood pressure medication use, diabetes, HDL cholesterol, LDL cholesterol, lipid-lowering medications, prevalent CHD, heart failure, stroke, APOE genotype, and fibrinogen.

Xiao et al.; 2021; Rotterdam Study; Netherlands; population [29] 68.3 (12.82); 54.88 Without dementia FVC COPD >3 y 4,765 Dementia (110) DSM-III-R; NINCDS–ADRDA Age, sex, education level, smoking status, BMI, systolic blood pressure, triglycerides, and history of comorbidities (stroke and diabetes mellitus)

Author; y; cohort name; region; source	Age (mean [SD] or median, y) [Range]; female (%)	Baseline cognitive status	Lung function	Lung disease	Follow-up years	Sample size	Outcome (n)	Diagnosis criteria	Adjusted factors
Simons et al.; 2006; The Dubbo Study; Australia; community [37]	60; 56.04	NC	PEF	NA	16 y	2,805	Dementia (285)	ICD-9; ICD-10	Age, sex
Guo et al.; 2007; the Prospective Population Study of Women in Gothenburg; Sweden; population [22]	52 (6)/58 (6); 100	Without dementia	PEF; FVC; FEV	NA	29,739 person-years	1,291/1,168	Dementia (147/134)	DSM-III-R/ NINCDS-ADRDA	Age, height, BMI, education, physical activity, smoking, asthma, chronic bronchitis, myocardial infarction, angina pectoris, and hypertension at baseline.
Alonso et al.; 2009; the Seven Countries Study; Mixed; population [24]	49.2 (5.6) [40 –59]; 0	Without dementia	FVC	NA	40 y	10,211	Dementia (160)	ICD-8	Age, study, cohort, occupation, height, smoking status, BMI, serum cholesterol, hypertension, and previous history of cardiovascular disease.
Giltay et al.; 2009; SCS; European; population [23]	ɛ4–50.9 (4.4), ɛ4+ 51.4 (4.6) [45 –64]; 0	Without dementia	FEV; FVC	NA	25 y	646	Dementia ɛ4–(142); ɛ4+(41)	CDR	Age, country, chronic disease including COPD at baseline, socioeconomic status, job-related physical activity, marital status, smoking status, BMI, height, systolic blood pressure, and prevalent chronic disease
Pathan et al.; 2011; ARIC; America; community [38]	[47 –70]; 56.85	NC	FEV1; FVC	NA	14.1 y (median)	9,837	Dementia (205)	ICD-9	Age, gender, race, cigarette smoking, pack-years of smoking, systolic blood pressure, body mass index, total cholesterol, HDL cholesterol, APOE genotype, use of hypertension medications, diabetes, use of lipid lowering medications, education, occupation, income, and sports-related physical activity.
Vidal et al.; 2013; AGES-RS; Iceland; population [25]	52.3 [5.3]; 67	NC	FEV1/height ²	NA	23 y	3,665	Dementia (288); MCI (128)	DSM-IV	Age, sex, higher education, occupation class, midlife BMI and physical activity, depressive symptoms, COPD, CHD, hypertension, diabetes mellitus, and smoking habits.
Russ et al.; 2015; four Health Surveys for England, two Scottish Health Surveys; UK; community [39]	46.8 (17.6) [16–100]; 53.50	Without dementia	FEV1; FVC; PEF	NA	11.7±3.7 y	48,025	Dementia (393)	ICD-9	Age, sex, height, ethnicity, socioeconomic status (occupational social class and educational attainment), health behaviors (smoking, alcohol consumption, and BMI), and illness (self-rated general health and self-reported longstanding illness).
Gilsanz et al.; 2018; KPNC; Mixed; clinical [40]	41.8 (4.2) [35 –50]; 54.1	Without dementia	FEV1; FEV2; VC	NA	>23 y	27,387	Dementia (7,519)	ICD-9	Age, race/ethnicity, education, height, hypertension, body mass index, smoking status, stroke, diabetes, heart failure
Sibbett et al.; 2018; LBC1921; Scotland; population [28]	79.04 (0.55); 57.35	NC	FEV1	NA	16 y	484	Dementia (106)	Death certificates, electronic hospital records, and clinical reviews	Age, sex, history of hypertension, smoking status, age 11 IQ, grip strength, 6-m walk time, APOE ɛ4 carrier status, height, history of cardiovascular or cerebrovascular disease, history of diabetes
Donahue et al.; 2022; NHATS; US; population [42]	[> = 65y]; 55.4	without dementia	PEF	NA	3 y	5,935	Dementia (536)	1. self-report; 2. AD8 Dementia Screening Interview; 3. cognitive tests	Sex, age, race/ethnicity, education, body mass index, history of smoking, lung disease, history of heart attack, heart disease, high blood pressure, stroke, and diabetes
Wang et al.; 2022(a); MAP; US; community [43]	78.35 (7.60); 78.07	without dementia	PF	NA	21 y	985	MCI (486)	NINCDS/ ADRDA	Age, sex, education, income, smoking, alcohol consumption, physical activity, body mass index, heart disease, hypertension, diabetes, stroke, depression, and APOE ɛ4
Zhou et al.; 2022; UKB; UK; population [44]	56.3 (8.0); 52.60	without dementia	FEV1; FVC	NA	12.6 y	308,534	Dementia (3,607); AD (1525); VaD (743)	ICD-10	Age, sex, education, Townsend deprivation index, smoking status, waist-to-hip ratio, systolic blood pressure, physical activity, APOE risk, cholesterol-lowering medications, antihypertensive medications, diabetes, coronary heart disease, heart failure and stroke, pre-existing lung diseases, recent medications on lung diseases, baseline cognitive performance
Minami et al.; 1995; the Sendai Longitudinal Study of Aging.; Japan; population [45]	72.71; 58.4	Without dementia	NA	Respiratory disease	3 y	2,461	Dementia (105)	DSM-III-R	Age, sex
Eriksson et al.; 2008; Eriksson’s; Sweden; population [46]	52.9 [37 –71]; 55.54	Without dementia	NA	Asthma	22.6±7.7 y	22,188 twins	Dementia (1,332 twins)	CDR	Age, sex, history of smoking, level of education, and myocardial infarction
Thakur et al.; 2010; FLOW; America; clinical [47]	58.26 (6.20); 58.24	NC	NA	COPD	5 y	1,504	Cognitive impairment (73)	MMSE	Age, sex, race, smoking history, and educational attainment
Shah et al.; 2013; CHS; America; population [48]	72.8 (5.6); 57.6	Without dementia	NA	Pneumonia	10 y	5,888	Dementia (707)	3MS	Demographics, health behaviors, other chronic health conditions, and for trajectories of physical and cognitive decline before pneumonia hospitalization, atrial fibrillation, blocks walked, and income
Chen et al.; 2014; NHIRD; China; population [49]	60.88 (10.39); 58.3	Without dementia	NA	Asthma	8.0±3.04 y	55,150	Dementia (1,681)	ICD-9-CM	Age, sex, demographic data, health system utilization, medical comorbidities, use of inhaled steroid
Singh et al.; 2014; MCSA; America; population [50]	79.29 [70,89, 70,89]; 49.82	NC	NA	COPD	5.1 y	1,425	Cognitive impairment (370)	Neuropsychological battery	Age, education, sex, Beck Depression Inventory II depression score, history of stroke, APOE ɛ4 genotype, smoking, diabetes mellitus, hypertension, coronary artery disease, baseline global z Scores, and body mass index
Liao et al.; 2015(a); NHI; China; clinical [51]	68.76 (10.74); 37.96	Without dementia	NA	COPD	10 y	25,920	Dementia (1,228)	ICD-9-CM	Age, gender, urbanization, coronary artery disease, stroke, hyperlipidemia, hypertension, diabetes, and head injury
Liao et al.; 2015(b); NHIRD; China; population [52]	67.4 (12.5); 28.66	Without dementia	NA	COPD	6.50 (3.48) y	61,257	Dementia (4,250)	ICD-9-CM	Age, sex, urbanization, and comorbidities
Peng et al.; 2015; LHID; China; population [53]	53.72 (17.38); 54.23	Without dementia	NA	Asthma	11 y	63,855	Dementia (2,337)	ICD-9-CM	Age, sex, comorbidities, annual OPD visits and oral corticosteroids used
Yeh et al.; 2018; (LHID2000); China; population [54]	65.53 (11.87); 43	Without dementia	NA	ACOS	10 y	30,773	Dementia (1,920)	ICD-9-CM	Age, sex, comorbidity, inhaled corticosteroids, and oral steroids
Cherbuin et al.; 2019; Cherbuin’s; Mixed; population [8]	74; 62	Without dementia	NA	COPD	3 y	15,394	Dementia (1,065)	DSM-IV	Age, sex, education, smoking status, physical, hypertension, depression and hazardous alcohol consumption.
Xie et al.; 2019; CLHLS; China; community [55]	82.9 (9.74); 54.11	NC	NA	COPD	3 y	4,735	Dementia (83); Cognitive impairment (712)	MMSE score	Age, gender, marital status, education level, alcohol drinking, current exercise, baseline BMI, smoking status, baseline hypertension, diabetes, and stroke
Siraj et al.; 2020; THIN; England; population [56]	65.85 (10.98); 47.44	NC	NA	COPD	4.4 y	292,224	Cognitive impairment or dementia (25,999)	Read code	Age, sex, GP, BMI, smoking status, modified CCI, CV disease, corticosteroid use, socioeconomic class
Tao et al.; 2020; NHIRD; China; population [57]	74.88 (6.72); 38.50	without AD	NA	COPD	7 y	26,876	AD (6,988)	ICD-9-CM	Sex, age, insurance status, and payroll bracket
Chu et al.; 2022; NHIRD; China; clinical [58]	68.01 (11.65) [> = 45y]; 40.7	without dementia	NA	Bacterial pneumonia	17 y	128,832	Dementia (,1817); AD (175); VaD (307)	ICD-9-CM	Demographic data, comorbidities, CCI score, and all-cause clinical visits
Hendel et al.; 2022; SNAC-K; Sweden; population [59]	81.50 (8.95) [> = 60y]; 63.76	without dementia	NA	Pneumonia	15 y	712	Dementia (86)	DSM-IV	Age, sex, education, and number of hospitalizations unrelated to pneumonia
Joh et al.; 2022; The Korean National Health Insurance; Korea; population [15]	54.4 (10.5) [> = 40y]; 49.9	without dementia	NA	Asthma	8.1 y	6,785,948	Dementia (260,705); AD (195,739); VaD (32,789)	ICD-10	Age, sex, body mass index, smoking status, alcohol use, regular physical activity, income, area of residence, history of hypertension, dyslipidemia, diabetes, stroke, and myocardial infarction, systolic blood pressure, glucose, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and estimated glomerular filtration rate
Khairan et al.; 2022; JAGES; Japan; population [60]	73.14 (6.01) [> = 65y]; 52.96	without dementia	NA	Pneumonia	6 y	9,952	Dementia (939)	the national standardized LTCI evaluation system’s data	Age, sex, BMI, history of hypertension, history of diabetes, the length of education, marital status, employment status, frequency of meeting friends, low-intensity of physical activity, moderate-intensity of physical activity, tooth loss, the status of pneumonia vaccination, smoking status, alcohol drinking, history of hearing disease, and frailty
Wang et al.; 2022(b); NA; US; clinical [61]	73.70 (7.75) [> = 65y]; 53.6	without AD	NA	COVID-19	1.5 y	820,956	AD (4,626)	ICD-10	Demographics, adverse socioeconomical determinants of health including problems with education, occupational exposure, physical, social and psychosocial environment, and known risk factors for Alzheimer’s disease
Lutsey et al.; 2019; ARIC; America; community [41]	54.2(5.8), [45 –64]; 55.3	Without dementia	FEV1; FVC FEV1/FVC	COPD	23.0 y (median)	14,184	Dementia (1,407)	ICD-9	Age, sex, study center, education level, and race-center, cigarette smoking and pack-years smoking, physical activity, BMI, systolic blood pressure, blood pressure medication use, diabetes, HDL cholesterol, LDL cholesterol, lipid-lowering medications, prevalent CHD, heart failure, stroke, APOE genotype, and fibrinogen.
Xiao et al.; 2021; Rotterdam Study; Netherlands; population [29]	68.3 (12.82); 54.88	Without dementia	FVC	COPD	>3 y	4,765	Dementia (110)	DSM-III-R; NINCDS–ADRDA	Age, sex, education level, smoking status, BMI, systolic blood pressure, triglycerides, and history of comorbidities (stroke and diabetes mellitus)

NC, normal cognition; PEF, peak expiratory flow; ICD, International Classification of Diseases; FVC, forced vital capacity; FEV, forced expiratory volume; DSM-III-R, Diagnostic and Statistical Manual of Mental Disorders (third edition, revised) criteria; NINCDS-ADRDA, National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association; BMI, body mass index; SCS, Seven Countries Study; CDR, Cause of Death Register; COPD, chronic obstructive pulmonary disease; ARIC, Atherosclerosis Risk in Communities study; HDL, high density lipoprotein; APOE, apolipoprotein E; AGES-RS, Age, Gene/Environment Susceptibility—Reykjavik Study; MCI, mild cognitive impairment; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders; CHD, coronary heart disease; UK, United Kingdom; KPNC, Kaiser Permanente Northern California; LBC1921, Lothian Birth Cohort 1921; NHATS, The National Health and Aging Trends Study; US, United States; MAP, Rush Memory and Aging Project; PF, pulmonary function; UKB, UK Biobank; AD, Alzheimer’s disease; SNAC-K, Swedish National Study on Aging and Care in Kungsholmen; JAGES, the Japan Gerontological Evaluation Study; LTCI, long-term care insurance; MMSE, Mini-Mental State Examination; FLOW, the Function, Living, Outcomes and Work cohort study; CHS, Cardiovascular Health Study cohort; 3MS, Teng Modified Mini-Mental State examination; NHIRD, The Taiwan National Health Insurance Research Database; MCSA, Mayo Clinic Study on Aging; LHID, Longitudinal Health Insurance Database; ACOS, Association Of Asthma–Chronic Obstructive Pulmonary Disease Syndrome; CLHLS, Chinese Longitudinal Health Longevity Survey; THIN, The Health Improvement Network; CCI, Charlson Comorbidity Index; CV, cardiovascular.

RESULTS

Literature search

The systematic search of papers published before January 10, 2023 identified 60,207 articles after removing the duplicated items. After title and abstract screening, 627 articles were considered potentially eligible. Thirty-three articles were eligible after reviewing the full text of these articles and additional hand-searched articles. Fourteen articles explored the association between lung function and the risk of cognitive impairment or dementia [22–25 , 37–44]. Twenty-one articles investigated the association between lung disease and the risk of cognitive impairment or dementia [8 , 45–61]. Two articles studied both associations [29, 41]. The details of the article selection process were showed in Fig. 1.

Fig. 1

Flowchart of the literature search and study selection process.

3.2 Study characteristics

Thirty-three articles were included (total n = 8,816,992; median sample size n = 10,211; minimum n = 484; maximum n = 6,785,948). The mean age of participants in all articles ranged from 41.8–82.9 years. The female proportion of all the subjects was 50.17%. The follow-up duration ranged from 1.5 to 40 years. A total of 8,816,992 individuals had no history of cognitive impairment or dementia at baseline. During the follow-up period, 1,399 participants were diagnosed with cognitive impairment (4 articles; 10,889 individuals) and 332,516 participants developed dementia (31 articles; 8,814,503 individuals).

There were eight articles for FEV [22 , 38–41], eight for FVC [22–24 , 38–41], two for FEV/FVC [38, 41], four for PEF [22 , 42], and two for aggregated indicator of pulmonary function according to different methods [43, 44]. Among the 14 articles for lung function, 12 were independent cohorts, and two were a duplicate cohort [38, 41]. For lung disease, there were a total of 21 articles [8 , 45–61], of which seven were duplicate cohorts [49 , 58]. To prevent double-counting, the duplicate cohorts were used only in specific subgroup analyses. Moreover, the mean score of all included articles was 7.97 based on the NOS. The quality assessment of the contained cohort studies is presented in Supplementary Table 2.

Lung function and the risk of cognitive impairment or dementia

The meta-analyses showed that relatively poor lung function could increase the risk of dementia (FEV: RR = 1.25 [95% CI, 1.17–1.33], I² = 30%, seven studies, 95,559 individuals; FVC: RR = 1.40 [95% CI, 1.16–1.69], I² = 55%, seven studies, 106,386 individuals; PEF: RR = 1.84 [95% CI, 1.37–2.46], I² = 80%, four studies, 58,056 individuals. Fig. 2), and may also be associated with the increased risk of AD (FVC: RR = 1.57 [95% CI, 1.10–2.23], I² = 26%, two studies, 5,933 individuals (Fig. 2). Two articles on FEV1/FVC were based on the same cohort, and thus the meta-analysis for FEV1/FVC could not be performed. Also, there were no sufficient articles for us to carry out a meta-analysis of the association between lung function and the risk cognitive impairment. The results of the sensitivity analysis for FEV, FVC and PEF were stable (Supplementary Figures 1–3). The publication biases and meta-regression analyses for FEV, FVC, and PEF were not examined due to the limited numbers of included studies.

Fig. 2

Meta analyses and subgroup analyses of associations between lung function and the risk of dementia. Poorer pulmonary function was associated with the increased risk of dementia. The ratio of RRs between FEV and dementia did not differ significantly by analytical methods, sample size, follow-up year, diagnostic criteria, or data source. Subgroup-analyses about FVC and dementia revealed a significant difference between follow-up year subgroup. The subgroup about analytical methods for PEF revealed a significant difference. RR, relative risk; CI, confidence interval; L versus H, low versus high; DSM, Diagnostic and Statistical Manual of Mental Disorders; ICD, the International Classification of Diseases; AD, Alzheimer’s disease.

The detailed results of subgroup analyses were presented in Fig. 2. In the subgroup analysis stratified by follow-up duration for studies on FEV, the heterogeneity was reduced, but no significant interactions were found between subgroups. It was worth noting that in the studies with a follow-up of more than 20 years, the association between lower FVC and the risk of dementia was attenuated but still significant (RR = 1.27 [95% CI, 1.18–1.36]; five studies; 53,596 individuals) compared to studies with a follow-up of less than 20 years (RR = 2.33 [95% CI, 1.68–3.23]; three studies; 62,627 individuals; p value for interaction <0.01). In addition, for every standard deviation decrease in PEF, the risk of dementia increased by 39% (RR = 1.39 [95% CI, 1.25–1.56]; two studies; 49,316 individuals), and low versus high PEF was associated with an increased risk of dementia (Low versus High, RR = 2.12 [95% CI, 1.74–2.58]; three studies; 56,765 individuals). The latter method had a significantly greater effect than the former (p value for interaction <0.01). The forest plots of the above results were presented in Supplementary Figures 4–18.

Lung disease and the risk of cognitive impairment or dementia

In the primary analysis, lung disease was found to increase the combined risk of cognitive impairment and dementia (RR = 1.39 [95% CI, 1.20–1.61]; I² = 96%; 19 studies; 8,315,161 individuals; Fig. 3). There was no evidence of the publication bias for the primary result (Egger test, p = 0.116; Supplementary Figure 19). In the sensitivity analysis, none of the studies affected the result (Supplementary Figure 20). A subgroup analysis by cognitive outcomes showed that lung disease had significant association with the risks of cognitive impairment (RR = 1.37 [95% CI, 1.14–1.66]; I² = 56%; four studies; 299,888 individuals) and dementia (RR = 1.32 [95% CI, 1.11–1.57]; I² = 95%; 16 studies; 7,506,869 individuals (Fig. 3). However, lung disease was not associated with the risks of AD (RR = 1.39 [95% CI, 1.00–1.93]; I² = 98%; seven studies; 7,866,903 individuals) and VaD (RR = 2.11 [95% CI, 0.57–7.83]; I² = 99%; two studies; 6,914,780 individuals (Fig. 3). Four studies included in the meta-analysis for the risk of cognitive impairment investigated the same lung disease, COPD.

Fig. 3

Meta-analysis of associations between lung disease and cognitive outcomes. Lung disease was associated with an increased combined risk of cognitive impairment and dementia. Consistent association was shown with risks of cognitive impairment and dementia. No identifiable association was found between lung disease and the risks of AD and VaD. I² values indicated evident heterogeneity for all above analyses. RR, relative risk; CI, confidence interval; VaD, vascular dementia.

Given the considerable heterogeneity across the studies with the outcome of dementia, further analyses were conducted on the relationship between lung disease and dementia risk (Fig. 4). Sensitivity analysis showed that this result was robust, and no evidence of publication bias was detected (Egger test, p = 0.314; Supplementary Figures 21 and 22). The source of heterogeneity was not found in the meta-regression analyses (Supplementary Table 3). In the subgroup analysis by region, follow-up years, and source, the relationship between lung disease and dementia risk showed a significant difference between the subgroups (p value for interaction <0.05). Lung disease was positively related to the risk of dementia in the Asian cohorts (RR = 1.56 [95% CI, 1.26–1.92]; nine studies; 7,113,733 individuals) and North American cohorts (RR = 1.46 [95% CI, 1.05–2.03]; three studies; 841,028 individuals), but no association was found in the European cohorts (RR = 0.93 [95% CI, 0.85–1.01]; four studies; 357,670 individuals). In studies with a follow-up of shorter than 20 years (RR = 1.40 [95% CI, 1.18–1.67]; 15 studies; 8,269,265 individuals), lung disease was correlated with the risk of dementia, whereas we did not observe this relationship in studies with longer follow-up (RR = 1.03 [95% CI, 0.87–1.23]; two studies; 58,560 individuals). Studies that used population-based (RR = 1.18 [95% CI, 1.05–1.34]; 12 studies; 7,333,198 individuals) or clinic-based (RR = 2.02 [95% CI, 1.46–2.80]; three studies; 975,708 individuals) data also showed increases in the risk of dementia compared with studies that used community-based (RR = 1.34 [95% CI, 0.78–2.29]; two studies; 18,919 individuals) data. The ratio of RRs did not differ significantly by categories of illness, sample size, diagnostic criteria of outcome, or exposure assessment. The forest plots of the above results were presented in Supplementary Figures 23–32. The meta-analysis on the association between lung disease and the risk of cognitive impairment showed decreased heterogeneity, and the sensitivity analysis showed the result was robust (Supplementary Figures 33 and 34).

Fig. 4

Subgroup analyses of associations between lung disease and the risk of dementia. The differences in region, follow-up year, and population type of studies might be the potential source of heterogeneity. The ratio of RRs between lung disease and dementia did not differ significantly by categories of illness, sample size, diagnostic criteria or exposure assessment. RR, relative risk; CI, confidence interval; DSM, Diagnostic and Statistical Manual of Mental Disorders; ICD, the International Classification of Diseases.

DISCUSSION

This meta-analysis with 8,816,992 participants found that lung function decline was related to the risks of cognitive impairment and dementia. Poor lung function tested by single indicators (FEV, FVC, and PEF) was significantly associated with an increased risk of dementia. Results in subgroup analyses remained significant. Individuals with lung disease had significantly higher risks of cognitive impairment and dementia, but not for AD and VaD. The differences in region, follow-up year, and data source of studies might be the potential source of heterogeneity. Both effect values did not differ significantly after taking age, sex, sample size, diagnostic criteria, quality score, or APOE4 into consideration.

As for the association between lung function decline and dementia risk, our result was consistent with previous studies. A meta-analysis of 10 studies relating pulmonary function to later dementia risk reported a similar increased risk of dementia [62]. Moreover, a recent published article using an aggregated indicator of pulmonary function also revealed similar results [43]. A meta-analysis by Russ et al. of 11 relevant studies reported a significant association of lung disease with an increased risk of dementia [62]. However, our result differed from the previous meta-analyses about the relationship between COPD and the risk of dementia. In published meta-analyses, we found the increased risk of dementia in patients with COPD [63, 64]. This inconsistency might be explained by different inclusion criteria and analytical approaches. Additionally, our study focused on not only the risk of dementia but also the risk of cognitive impairment. Of note, a significant association was found between COPD and the risk of cognitive impairment, which was in line with the results of some previous meta-analyses [65, 66].

The mechanisms relating lung function decline to cognitive impairment or dementia are not exactly clear. It is now widely accepted that reduced lung function leads to cognitive decline via hypoxia and inflammation pathways, and the two pathways are closely interrelated with each other. When the organism is subjected to hypoxia, it firstly undergoes some adaptive changes. For example, hypoxia-inducible factors usually become more stable and bind to hypoxia response elements upon entering the nucleus to initiate the expression of many genes, such as cyclooxygenase4-2 subunit and erythropoietin, which could increase dendritic spine formation to improve cognitive performance [67]. However, if hypoxia persists and worsens, excess reactive oxygen species will be generated to amplify oxidative stress, which will lead to mitochondrial dysfunction, eventually resulting in neuronal degeneration/loss, disruption of neurotransmitter metabolism, and synaptic dysfunction [68, 69]. These findings imply that the severity of hypoxia influences the risk of cognitive dysfunction, which was also reflected in the results of our subgroup analysis for the association between PEF and the risk of dementia. And glial cells are also particularly vulnerable to hypoxia. Loss of hypoxia-inducible factors-2α, a major regulator of cyclooxygenase4-2 subunit and erythropoietin in astrocytes, leads to inhibition of local synaptic protein synthesis, eventually causing cognitive decline in the patients [67]. In addition, hypoxia can affect the degradation of Aβ by altering the expression of amyloid-β protein precursor and secretases, leading to extracellular deposition of Aβ. And Aβ deposition may induce and accelerate the onset of AD through the following mechanisms: 1) degeneration and loss of neurons, impaired synaptic activity, and loss of synapses, 2) promotion of tau pathology by facilitating tau phosphorylation, 3) triggering neuronal cell death using NADPH oxidase in microglia, and 4) impaired cerebral capillary blood flow [14, 70]. In addition, hypoxia plays a key role in triggering, regulating, and enhancing neuroinflammation [67]. During aging, inflammatory genetic programs might be driven by complementary and interdependent TF signaling pathways, possibly contributing cumulatively to inflammatory signaling and nerve cell degeneration [11]. Compared with physiological lung aging, lung diseases, especially COPD, could accelerate the decline in lung function. Hypoxia resulting from poor lung function could directly facilitate microglia activation, resulting in neuroinflammation and thereafter neurological damage [71]. These mechanisms may be relevant for understanding of our results. Participants with lower FVC showed higher risk of AD.

Besides hypoxia and inflammation, several studies suggested that induction of a procoagulant state is also an explanation. Lung function impairment could induce a procoagulant state, subsequently increase the risk of cerebrovascular injury and stroke, and thus eventually reduce oxygen supply to neurons [72, 73]. Moreover, epidemiologic studies have shown that the risk of cognitive impairment or dementia could also be influenced by other factors, such as genetic factors, environmental factors, lifestyle habits, disease conditions [74 –80]. As the development of dementia is a long process, the premature mortality which might be confounded by the above factors will have an impact on the incidence of dementia, as some participants will die before their diagnoses of dementia [81, 82]. This provides theoretical support for the finding in the FVC subgroup analyses that the difference was significant in the association of low FVC and dementia risk between the cohorts with shorter and longer follow-up duration. Although we only adopted the model with maximum adjustment for influencing factors within each study, the effects of confounding factors should be considered as thoroughly as possible in future studies to obtain reliable results due to the heterogeneity of studies.

As for the association between lung disease and the risk of dementia, the differences between our results and the previous studies could be explained as follows. Firstly, our meta-analysis adopted tighter inclusion and exclusion criteria. Secondly, we selected the multivariable-adjusted relative risk estimates in the process of data extraction, and converted OR into RR for aggregate meta-analysis. Thirdly, only the most representative studies among the duplicate cohort studies were selected for the pooled data analysis to avoid double-counting. And the duplicate cohorts were used only in specific subgroup analyses. Fourthly, our meta-analysis conducted subgroup-analyses and found that the difference in the association between lung disease and the risk of dementia was significant between different regions, follow-up years, and data sources. Lung disease was shown to be a risk factor for dementia in the Asian and North American cohorts, but not in the European cohorts. And this result only was shown in population-based or clinic-based studies, but not in community-based studies. There are some potential confounding factors which biased this result, such as the different prevention strategies for lung disease in different regions, various life expectancies across regions, insufficient number of articles conducted in North America and Europe [83 –87]. Thus, further collaboration globally is necessary to investigate the relationship between lung disease and cognitive outcomes.

We analyzed the relationships of lung disease types and cognitive outcomes, even if much heterogeneity remained in these subgroups. We found that COPD had a significant association with the risk of cognitive impairment rather than dementia, which was not consistent with a previous meta-analysis [62]. This inconsistency might be explained by the severity and treatment of COPD [88]. Moreover, there is a concomitant increase in other synergistic risk factors during the course of COPD, so timely treatment of obstructive airway disease plays an important role in reducing the risk of dementia [63 , 89]. Asthma is a common chronic inflammatory airways disease. Chronic systemic inflammation may influence the dementia pathogenesis, such as neuroinflammation [15]. And individuals with asthma also exhibit increased morbidity of depression, which could increase the risk of dementia [53]. In the present study, pneumonia could also increase likelihood of dementia. Currently, the COVID-19 pandemic has had various effects on global health [90]. The COVID-19 infection could affect multiple organ systems causing breathlessness, fatigue, difficulty concentrating, inflammatory neuropathy, cognitive dysfunction, and a variety of other symptoms [91]. While there were numerous studies on COVID-19–related sequelae, very few studies addressed dementia. This study included in our meta-analysis showed that COVID-19 was associated with the risk of AD [61]. Due to dementia was seen as the long-term processes, short-term outcomes may be more susceptible to reverse causation. Future studies are need with longer follow-up to examine this result and to explore the underlying mechanisms.

This study has several strengths. Firstly, we included the largest number of longitudinal studies to date with stricter inclusion criteria. Secondly, comprehensive meta-regression and subgroup analyses were used to minimize the confounding and other forms of bias, and the p values for interaction in the subgroups were noticed. These methods contributed to a more accurate analysis, either the relationship between lung function decline with cognitive outcomes or the sources of heterogeneity. Our results could provide suggestions for future studies to understand the contributions of these influential factors. There were also several limitations in our analysis. Firstly, statistical heterogeneity was high in the meta-analysis, which remained high in meta-regression and subgroup analyses, and some of planned subgroup analyses were not performed because of insufficient raw data. Secondly, we did not collect information on different levels of lung function decline and different severity of lung diseases to analyze their impact on cognitive outcomes. Thirdly, one of our greatest challenges is that the incidence of dementia might be biased by reverse causality, which means putative risk factors were influenced by the course of cognitive impairment.

In conclusion, this meta-analysis and systematic review comprehensively summarized the latest evidence concerning the associations between lung function decline with the risks of cognitive impairment and dementia. Individuals with lung function decline showed the increased risks of cognitive impairment and dementia. These findings suggested lung function decline as a novel target for the prevention of cognitive disorders. However, future studies on the association of pulmonary function decline with the risks of cognitive impairment and dementia in the global population are warranted, and some other types of lung diseases and disease severity should also be taken into consideration.

Footnotes

ACKNOWLEDGMENTS

This study was supported by grants from the National Natural Science Foundation of China (82071201, 81971032), Research Start-up Fund of Huashan Hospital (2022QD002), Excellence 2025 Talent Cultivation Program at Fudan University (3030277001).

FUNDING

CONFLICT OF INTEREST

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

DATA AVAILABILITY

The data supporting the findings of this study are available on request from the corresponding author.

The supplementary material is available in the electronic version of this article: .

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