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IOS Press
Lung Function Impairment and the Risk of Incident Dementia: The Rotterdam Study
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Tian Xiaoa,1, Sara R.A. Wijnanta,b,c,1, Silvan Lichera, Natalie Terzikhana, Lies Lahoussec, M. Kamran Ikrama,d, Guy G. Brussellea,b,e,∗and M. Arfan Ikrama,∗
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aDepartment of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
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bDepartment of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium
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cDepartment of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium
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dDepartment of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands
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eDepartment of Respiratory Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
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Accepted 26 April 2021
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Pre-press 28 May 2021
11
Abstract.
12
Background:The etiology of dementia may partly be underpinned by impaired lung function via systemic inflammation and hypoxia.
13 14
Objective:To prospectively examine the association between chronic obstructive pulmonary disease (COPD) and subclinical impairments in lung function and the risk of dementia.
15 16
Methods:In the Rotterdam Study, we assessed the risk of incident dementia in participants with Preserved Ratio Impaired Spirometry (PRISm; FEV1/FVC≥0.7, FEV1 < 80%) and in participants with COPD (FEV1/FVC < 0.7) compared to those with normal spirometry (controls; FEV1/FVC≥0.7, FEV1≥80%). Hazard ratios (HRs) with 95% confidence intervals (CI) for dementia were adjusted for age, sex, education attainment, smoking status, systolic blood pressure, body mass index, triglycerides, comorbidities and Apolipoprotein E (APOE)genotype.
17 18 19 20 21
Results: Of 4,765 participants, 110 (2.3%) developed dementia after 3.3 years. Compared to controls, participants with PRISm, but not COPD, had an increased risk for all-type dementia (adjusted HRPRISm 2.70; 95% CI, 1.53–4.75; adjusted HRCOPD1.03; 95% CI, 0.61–1.74). These findings were primarily driven by men and smokers. Similarly, participants with FVC% predicted values in the lowest quartile compared to those in the highest quartile were at increased risk of all-type dementia (adjusted HR 2.28; 95% CI, 1.31–3.98), as well as Alzheimer’s disease (AD; adjusted HR 2.13; 95% CI, 1.13–4.02).
22 23 24 25 26
Conclusion:Participants with PRISm or a low FVC% predicted lung function were at increased risk of dementia, compared to those with normal spirometry or a higher FVC% predicted, respectively. Further research is needed to elucidate whether this association is causal and how PRISm might contribute to dementia pathogenesis.
27 28 29
Keywords: Alzheimer’s disease, chronic obstructive pulmonary disease, dementia, forced vital capacity (FVC), preserved ratio impaired spirometry
30 31
1These authors contributed equally to this work.
∗Correspondence to: Guy G. Brusselle, PhD, Department of Respiratory Medicine, University Hospital Ghent, Corneel Hey- manslaan 10, 9000 Ghent, Belgium. E-mail: guy.brusselle@
ugent.be and M. Arfan Ikram, PhD, Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. E-mail:
m.a.ikram@erasmusmc.nl.
INTRODUCTION 32
Dementia is characterized by poor cognitive per- 33 formance interfering with activities of daily living 34 and impaired health-related quality of life at older 35 ages [1], with an increasing prevalence worldwide 36 [2]. In order to mitigate the burden of dementia 37 through postponement or prevention, and to respond 38 adequately on such a major health problem, the 39 ISSN 1387-2877 © 2021 – The authors. Published by IOS Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (CC BY-NC 4.0).
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identification of key modifiable risk factors is war-
40
ranted and include smoking, obesity, hypertension,
41
depression, sleep apnea, diabetes, and hyperlipidemia
42
[3]. Chronic obstructive pulmonary disease (COPD)
43
and decreased lung volume capacity have also been
44
associated with a greater risk of dementia and com-
45
promised cognitive ability [4]. Possible etiological
46
links with dementia comprise systemic inflammation
47
and hypoxia induced oxidative stress [4–6].
48
More recently, preserved ratio impaired spirome-
49
try (PRISm)—with a prevalence ranging from 3% to
50
20% in adults [7]—has emerged as a clinically rele-
51
vant entity related to premature mortality [7, 8], but
52
thus far has been largely understudied, because of a
53
hitherto stronger focus on COPD. The term PRISm
54
encompasses the findings of restrictive respiratory
55
pattern with impaired spirometry, i.e., decreased
56
forced expiratory volume in one second (FEV1) or
57
forced vital capacity (FVC) but preserved FEV1/FVC
58
ratio [7]. People with PRISm suffer from lung func-
59
tion restriction but due to normal range of FEV1/FVC
60
ratio would not be diagnosed as COPD according to
61
the GOLD guidelines in clinical practice [7, 9]. Pre-
62
vious studies have suggested PRISm is a fluctuating
63
state, serving as an intermediate phase between nor-
64
mal spirometry and COPD [8, 10]. However, very
65
little is known about the clinical sequelae of PRISm,
66
including risk of dementia.
67
Therefore, the aim of this study was to investi-
68
gate the association of both COPD and subclinical
69
reduced lung function, as evidenced by the pres-
70
ence of impaired lung volumes (PRISm), with the
71
risk of dementia at follow-up within a prospective
72
population-based cohort study.
73
METHODS
74
This study was conducted within the Rotterdam
75
Study, a prospective cohort study that started in 1990,
76
comprising almost 15,000 participants aged at least
77
45 years, with the aim of studying chronic diseases
78
in the general population [11]. Every four to five
79
years, participants underwent follow-up examina-
80
tions, consisting of a home interview and various
81
physical examinations at the research center. We used
82
data collected between 2009 and 2014 as baseline
83
for this study, when participants underwent spirom-
84
etry at the research center. A total of 4,765 persons
85
with interpretable spirometry and without asthma and
86
without prevalent dementia were retained for analy-
87
ses (Fig. 1).
Fig. 1. Flow chart for participants with interpretable spirometry at baseline, informed consent for follow-up and graph for definition of lung function categories.
Standard protocol approvals, registrations, and 88
patients consents 89
The study had been approved by the medical ethics 90 committee of the Erasmus Medical Centre (Rotter- 91 dam, the Netherlands), and the review board of the 92 Netherlands Ministry of Health, Welfare and Sports 93 (1068889-159521-PG). Informed consent was pro- 94
vided by all participants. 95
Spirometry test 96
Lung function was assessed via pre-bronchodilator 97 spirometry performed by trained paramedical person- 98 nel using a Master Screen PFT Pro (Care Fusion, 99 Netherlands) according to the American Thoracic 100 Society (ATS)/European Respiratory Society (ERS) 101 guidelines [12]. Predicted FVC and predicted FEV1 102
values were calculated using Global Lung Initiative 103 (GLI) reference equations taking age, sex, height, 104 and ethnicity into account [13]. Based on these val- 105 ues, the following subgroups were defined: COPD 106 (FEV1/FVC < 70%), PRISm (FEV1/FVC≥70% and 107 FEV1 < 80% predicted), and normal spirometry 108 (FEV1/FVC≥70% and an FEV1≥80% predicted) 109 were distinguished [7, 9]. Spirometry was conducted 110 in accordance with the ATS/ERS guidelines [12, 111
13], with specific preparatory instructions, e.g., with 112 respect to smoking or other factors. In order to guar- 113 antee the reliability and reproducibility, at least two 114 spirometry tests were implemented on each partici- 115 pant, and the best reading was obtained. No specific 116 preparatory instructions were given (e.g., related to 117 smoking or other factors). The quartile categories of 118
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lung function parameters were derived from values
119
in this study, which is similar to quintile subgroups
120
in a previous study [14]. For calculation of trend-
121
ing hazard ratio with 10% change in lung function,
122
lung function parameters were included in cox mod-
123
els after being divided by 10. Airflow limitation
124
was confirmed by the value of a post-bronchodilator
125
FEV1/FVC below 0.7 [9].
126
Dementia assessment
127
Dementia assessment was conducted for partici-
128
pants at baseline and subsequent center visits with
129
the Mini-Mental State Examination and the Geriatric
130
Mental Schedule [15]. Those with a Mini-Mental
131
State Examination score < 26 or Geriatric Mental
132
Schedule score > 0 underwent further investigation
133
along with an interview with a research physi-
134
cian, that contained the Cambridge Examination for
135
Mental Disorders of the Elderly. The whole popu-
136
lation also underwent routine cognitive assessment.
137
Moreover, the entire cohort was continuously under
138
surveillance for dementia through electronic link-
139
age of the study database with medical records from
140
general practitioners and the regional institute for
141
outpatient mental health care. If available clinical
142
neuroimaging was used for determining demen-
143
tia subtype [11]. An adjudication panel led by a
144
consultant neurologist established the final diag-
145
nosis according to standard criteria for dementia
146
(Diagnostic and Statistical Manual of Mental Dis-
147
order, Third Edition-Revised: DSM-III-R) and AD
148
(National Institute of Neurological and Communica-
149
tive Disorders and Stroke-Alzheimer’s Disease and
150
Related Disorders Association: NINCDS–ADRDA).
151
Follow-up until 14 December 2017 was virtually
152
complete (95.5% of potential person-years). Within
153
this period, participants were followed until the date
154
of dementia and AD diagnosis, death, loss to follow-
155
up or 14 December 2017, whichever came first.
156
Covariates
157
The following variables were considered as pos-
158
sible confounders, primarily based on previous
159
literature and their role as shared causes between lung
160
function and dementia. Demographic information
161
included age, sex, education level (primary educa-
162
tion, lower education, intermediate education, higher
163
education), smoking status (never, former, current),
164
systolic blood pressure (mmHg), body mass index
165
(BMI, kg/m2, calculated by weight [kg] divided by
166
height [m] squared), and chronic comorbid condi- 167 tions (diabetes and stroke) [11]. Blood samples were 168 extracted for determination of levels of triglycerides 169 and DNA at the research center. Apolipoprotein E 170 (APOE) genotype was determined using a PCR in 171 the original cohort (RS-I, starting between July 1989 172 and September 1993) and a bi-allelic TaqMan assay 173 (rs7412 and rs429358) on labeled DNA samples in 174 the two cohorts (RS-II-3, starting between Febru- 175 ary 2000 and December 2001; and RS-III-2, starting 176 between February 2006 and December 2008), respec- 177 tively. This study included these three sub-cohorts. 178 APOE4 represented carrier of one or two4 alle- 179 les. Participants were categorized into three groups: 180 high genetic risk (2/4,3/4, or4/4 genotypes), 181
intermediate risk (3/3), or low risk (2/2 or2/3) 182 [16]. As the strongest genetic risk factor for dementia, 183 APOEhas additionally potent cardiovascular effects, 184 including arteriosclerosis and cardiac function. In this 185 regard, APOE may also impact lung function. We 186 therefore includedAPOE in the models as possible 187 confounder [14, 17]. Missing values were handled by 188 five-times imputation using chained equation [18]. 189
Statistical analysis 190
Baseline characteristics are described among sub- 191 groups of lung function. Data are expressed as 192 mean±standard deviation (SD) for normally dis- 193 tributed variables or as median (interquartile range 194
[IQR]) for non-normally distributed variables. 195 For analyses of the association between lung func- 196 tion at baseline and risk of incident dementia, we 197 used Cox proportional-hazards regression analyses. 198 Lung function was categorized as normal spirom- 199 etry, PRISm, and COPD. In addition, lung volume 200 capacity comprised subgroups of quartiles of FEV1% 201 predicted, FVC% predicted and ratio of FEV1/FVC. 202 Follow-up time started on the date of spirometry 203 test at baseline and ended until diagnosis of demen- 204 tia, death, lost to follow-up, or December 14, 2017. 205 The proportional hazards assumption was checked 206 using Schoenfeld residuals. Model 1 was adjusted 207 for APOE category, age, sex, and education level. 208 Model 2 was additionally adjusted for smoking sta- 209
tus, BMI, systolic blood pressure, triglyceride, and 210 comorbidity (history of stroke and diabetes mellitus). 211 Covariates above were selected based on previous 212 literature knowledge, clinical relevance and availabil- 213 ity of the data. Given the relatively small number 214 of incident cases of dementia, we also constructed 215 a third model in which the covariates were accounted 216
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Table 1
Baseline characteristics of participants, stratified by lung function category
Normal PRISm COPD p
n(%) 3683 (77.3) 319 (6.7) 763 (16.0) -
Age, y 67.8 (12.5) 68.6 (14.4) 70.6 (13.4) < 0.001
Female, (%) 2120 (57.6) 171 (53.6) 324 (42.5) < 0.001
Education level
Primary education 246 (6.8) 31 (9.9) 81 (10.7) < 0.001
lower education 1445 (39.7) 117 (37.1) 279 (36.9)
Intermediate education 1089 (29.8) 93 (29.5) 249 (32.9)
Higher education 864 (23.7) 74 (23.5) 148 (19.6)
Smoking status, (%)
Never 1383 (37.6) 97 (30.4) 135 (17.7) < 0.001
Former 1960 (53.2) 177 (55.5) 415 (54.4)
Current 340 (9.2) 45 (14.1) 213 (27.9)
Systolic pressure 141 (29) 142 (29) 142 (26) 0.369
Body mass index, kg/m2 27.0 (5.0) 28.4 (5.9) 26.1 (5.0) < 0.001
Triglycerides, mg/dl 1.3 (0.7) 1.4 (0.9) 1.2 (0.7) < 0.001
History of stroke 34 (0.9) 7 (2.2) 12 (1.6) 0.040∗
History of diabetes mellitus 292 (8.0) 31 (10.0) 73 (9.7) 0.200
Apolipoprotein E genotype, (%)
4-allele positive 937 (27.3) 66 (22.8) 196 (27.8) 0.142
4-allele negative 2496 (72.7) 224 (77.2) 509 (72.2)
FEV1/FVC 78.7 (6.4) 76.1 (7.1) 65.6 (7.6) < 0.001
FEV1% predicted 103.2 (18.7) 73.8 (10.6) 79.1 (24.7) < 0.001
FVC% predicted 101.2 (17.9) 72.2 (11.7) 94.0 (24.9) < 0.001
COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; PRISm, preserved ratio impaired spirometry. Data represent original data without imputed values.
Missing values were present for education attainment (1.0%), systolic blood pressure (2.8%), triglyceride (1.7%), and history of diabetes (7.1%).∗Fisher’s exact test.
for using propensity scores. Propensity scores were
217
employed to reduce the number of covariates through
218
summarizing information of variables into a single
219
score, thus avoiding any problem of overfitting the
220
models [19, 20]. In this study, propensity scores are
221
the predicted probabilities of PRISm and COPD and
222
derived by fitting logistic regression models adjusting
223
for age, sex, education level, smoking status, systolic
224
blood pressure, BMI, triglycerides, chronic comorbid
225
conditions (diabetes and stroke), and APOEpheno-
226
types.
227
We also studied how PRISm and COPD related
228
to the risk of mortality to gauge the possible effect
229
of competing risk in our associations. The compet-
230
ing risk, such as death before occurrence of incident
231
dementia, are considered as independent event but is
232
neglected in conventional methods for survival anal-
233
yses, thus the true observation of the event of interest
234
could be hindered in the presence of competing risk
235
and then distort the association we explored [21].
236
For unadjusted survival analyses intended to por-
237
tray absolute risks, we used sub-distribution hazard
238
models to account for competing risks to estimate
239
cumulative incidence of dementia and all-cause death
240
[22].
In addition, we conducted stratified analyses in 241
women, men, non-smoking participants, smokers and 242 participants withoutAPOE4 allele and history of 243 stroke and diabetes. These were selected as possi- 244 ble effect modifiers based on previous literature and 245 biological plausibility [3, 23–27]. 246
RESULTS 247
Clinical and lung functional characteristics of 248
participants 249
Among 4,765 participants (mean age 68.2±12.9 250 years, 54.9% women), 16.0% (n= 763) had COPD, 251 6.7% (n= 319) had PRISm, and 77.3% (n= 3683) 252 had normal spirometry. More than twenty percent 253 (23.0%) of the participants received higher edu- 254 cation, and two thirds (66.1%) were current or 255
former smokers. The participants had a median 256 BMI of 27.0±5.1 Kg/m2, systolic blood pres- 257 sure of 141±29.0 mmHg, and triglyceride level of 258 1.3±0.8 mg/dl. While 8.4% (n= 396) had a history 259 of diabetes mellitus, 1.1% of them experienced stroke 260 before (n= 53). 1,199 (27.1%) participants carried 261 APOE4 allele (Table 1).
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Table 2
Lung function category and risk of dementia All-type dementia
cases/death/N FU, years HR1 (95% CI) HR2 (95% CI) HR3 (95% CI)
Normal 75/179/3683 3.3 (1.6) 1.0 1.0 1.0
PRISm 15/25/319 3.4 (1.6) 2.42 (1.38;4.24) 2.70 (1.53;4.75) 2.47 (1.40;4.35) COPD 20/88/763 3.4 (1.6) 1.06 (0.63;1.77) 1.03 (0.61;1.74) 1.08 (0.63;1.83)
AD
cases/death/N FU, years HR1 (95% CI) HR2 (95% CI) HR3 (95% CI)
Normal 65/179/3673 3.3 (1.6) 1.0 1.0 1.0
PRISm 9/25/313 3.4 (1.6) 1.70 (0.84;3.43) 1.87 (0.92;3.81) 1.74 (0.86;3.54) COPD 15/88/758 3.4 (1.6) 0.89 (0.49;1.60) 0.87 (0.48;1.59) 0.89 (0.49;1.63) AD, Alzheimer’s disease; COPD, chronic obstructive pulmonary disease; CI, confidence interval; FU, follow- up; HR, hazard ratio; PRISm, preserved ratio impaired spirometry; Model 1, Cox regression adjusted forAPOE genotype, age, sex, and education level; Model 2, Model 1 plus adjustment smoking status, BMI, systolic blood pressure, triglycerides, and history of comorbidities (stroke and diabetes mellitus); Model 3, Cox regression adjusted for propensity scores∗, age, and sex.∗Propensity scores was calculated with age, sex, education level, smoking status, BMI, systolic blood pressure, triglyceride, history of comorbidities (stroke and diabetes mellitus) andAPOE genotype; follow-up time started after spirometry at baseline.
Lung function and risk of incident
262
dementia and AD
263
During a median of 3.3 years of follow-up, 110
264
participants (2.3%) developed incident dementia, of
265
whom 89 (1.9%) developed AD. Moreover, among
266
all participants, 292 (6.1%) died due to non-dementia
267
related causes within the follow-up period (Table 2).
268
First, we evaluated the association between lung
269
function impairment at baseline and risk of incident
270
dementia. As shown in Table 2, higher proportion of
271
participants with PRISm developed dementia com-
272
pared to participants with normal spirometry, while
273
COPD patients did not. Compared with participants
274
with normal spirometry, participants with PRISm
275
exhibited a higher risk of all-type dementia (Model
276
2 hazard ratio [HR], 2.70; 95% confidence interval
277
[CI], 1.53–4.75), while subjects with COPD did not
278
(HR2, 1.03; 95% CI, 0.61–1.74), after accounting for
279
all covariates. After being adjusted for propensity
280
score, age and sex, results of model 3 were similar
281
to model 2 (Table 2). Hazard ratios of association of
282
PRISm and COPD with all-type dementia were 2.47
283
(95% CI, 1.40–4.35) and 1.08 (95% CI, 0.63–1.83),
284
respectively.
285
Concurrently, participants with PRISm were also
286
at increased risk of AD, albeit this did not reach sta-
287
tistical significance (HR2, 1.87; 95% CI, 0.92–3.81).
288
COPD was not significantly associated with AD
289
(HR2, 0.87; 95% CI, 0.48–1.59) (Table 2).
290
We also investigated the risk of developing demen-
291
tia associated with lower lung function by using
292
continuous parameters (FEV1%, FVC%, FEV1/
293
FVC%) and their categorized quartiles (Fig. 2). A 294 lower value in FEV1% predicted was associated with 295
an elevated risk of all-type dementia (HR2, 1.12; 95% 296
CI, 1.02–1.23). Relative to participants with the high- 297 est FVC% predicted values (Quartile 4), those with 298 the lowest FVC% predicted values (Quartile 1) were 299 at increased risk of both all-type dementia (Model 300 2 hazard ratio [HR2], 2.28; 95% confidence inter- 301 val [CI], 1.31–3.98) and AD (HR2, 2.13; 95% CI, 302 1.13–4.02), after accounting for demographics and 303 APOEgenotypes. A lower value in FVC% predicted 304 was significantly associated with an increased risk 305 of both all-type dementia and AD in all models. 306 FEV1/FVC was not associated with dementia risk in 307
any model (Fig. 2). 308
Moreover, a competing risk model was used to 309 measure the competing risk of mortality during the 310
follow-up period on the observation of dementia 311 events. Although participants with PRISm suffered 312 from higher cumulative incidence of all-cause mor- 313 tality than participants with normal spirometry, 314 participants with PRISm still exhibited significantly 315 higher cumulative incidence of all-type dementia 316 (p= 0.018), but not of AD (p> 0.05) (Supplementary 317
Figure 1). 318
Stratified analysis 319
Methods and figures on the stratified analyses are 320 presented in the Supplementary Material. Regarding 321 the association between COPD or PRISm and the 322 risk of incident dementia, stratified analyses were 323 performed in women, men, smokers, non-smoking 324
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Fig. 2. Respiratory indexes (FEV1% predicted, FVC % predicted and FEV1/FVC ratio) and risk of dementia (A) and Alzheimer’s disease (B).
AD, Alzheimer’s disease; A, All-type dementia; B, Alzheimer’s disease; CI, confidence interval; HR, hazard ratio; FEV1, Forced Expiratory volume in one second; FVC, forced vital capacity; HR1, HR from Cox Proportional-Hazard regression analysis adjusted forAPOEgenotype, age, sex, and education level; HR2, HR1 with additional adjustment for current or ever smoking, BMI, systolic blood pressure, triglyceride, and history of comorbidities (stroke and diabetes mellitus). Participants in the highest percentile (Quartile 4) of spirometry indexes were regarded as reference group (hidden).∗follow-up time start after spirometry at baseline.
participants, participants without history of stroke
325
and diabetes, andAPOE4 non-carriers. Significant
326
associations were found between PRISm and all-
327
type dementia in men (adjusted HR = 5.29, 95% CI,
328
2.40–11.65), but not in women (adjusted HR = 1.65,
329
95% CI, 0.71–3.87); current or former smokers
330
(adjusted HR = 3.36, 95% CI, 1.71–6.60), but not
331
in never-smoking participants (adjusted HR = 1.95,
332
95% CI, 0.68–5.57); participants without a history of
333
stroke (adjusted HR = 2.58, 95% CI, 1.45–4.59) and 334 diabetes (adjusted HR = 2.56, 95% CI, 1.38-4.78); 335 and participants withoutAPOE4 allele (HR = 1.56, 336 95% CI, 0.71–3.45). Significant association between 337 PRISm and AD risk were only observed among men 338
(Supplementary Figure 2). 339
We have tested the effect of interaction of lung 340 function and sex, and interaction of lung function and 341 smoking status in cox models, respectively, which 342
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tests for multiplicative interaction. These tests of
343
interaction did not reach statistical significance (data
344
not shown).
345
In addition, Supplementary Figure 3 shows the
346
association between continuous spirometry param-
347
eters with the risk of newly diagnosed dementia
348
(Supplementary Figure 3A) or newly diagnosed
349
AD (Supplementary Figure 3B), stratified by sex,
350
smoking status and absence of stroke, diabetes,
351
and APOE 4 non-carriers. A lower FEV1% pre-
352
dicted was associated with a greater risk of all-type
353
dementia only among women, never-smoking partic-
354
ipants, and those without prior stroke, but not among
355
men, current or former smoking participants, and
356
participants without prior diabetes andAPOE4 non-
357
carriers. A lower FVC% predicted was associated
358
with an increased risk of all-type dementia among
359
all subgroups except APOE4 non-carriers. Statis-
360
tical significance was not found between decreased
361
FEV1/FVC and risk of all-type dementia. Regarding
362
elevated risk of AD, reduced FVC% predicted and
363
FEV1/FVC elevated were associated with AD among
364
women, nonsmokers and those without prior stroke,
365
while FEV1% predicted did not show an increased
366
risk of AD among those without prior stroke.
367
DISCUSSION
368
In this population-based cohort study, individu-
369
als with PRISm were at increased risk of all-type
370
dementia, while those with COPD were not. Espe-
371
cially, predicted FVC% was strongly associated with
372
a higher risk of dementia among the whole study
373
population.
374
The main finding of this study is that PRISm
375
was associated with an increased risk of dementia.
376
Comorbidities, such as diabetes and stroke, are more
377
common among participants of this restrictive lung-
378
function pattern [28], and may confound the link with
379
impaired cognition and the increased risk for demen-
380
tia. However, while we found a higher prevalence of
381
prior stroke in participants with PRISm, the associ-
382
ation between PRISm and dementia persisted after
383
adjusting for these comorbidities. There are several
384
possible mechanisms linking PRISm with dementia.
385
Firstly, ambient pollution and inhalational exposures
386
are associated with higher risk of PRISm [29], which
387
could also contribute to the development of dementia
388
[30, 31]. For example, fine particulate matter in air
389
could not only lead to impaired lung function through
390
disturbing alveolarization process and altering lung
391
elastance at an earlier life stage [32], but also be linked 392 to higher dementia risk via accumulation of A42and 393 alteration on neuroinflammation and brain immune 394 response, as exposure to certain level of air pollu- 395 tion could upregulate expression of mRNA COX2 396 and IL-1in olfactory bulb, disrupt tight junctions in 397 frontal blood-brain barrier and activate nuclear NFκB 398 in brain endothelial cells [31, 33]. 399 Secondly, some studies reported that FVC decline 400 in subjects with PRISm was accompanied with sys- 401 temic inflammation [34–36]. Systemic inflammation 402 in turn may be linked with cognitive impairment and/ 403 or occurrence of dementia [37]. Serum inflammatory 404 cytokines, like (IL)-18, IL-1 receptor antagonist and 405 IL-6, have been linked with AD [38], and high lev- 406
els of serum IL-6 were associated with a greater risk 407 of non-AD dementia as well [39]. Unfortunately, we 408 did not have inflammatory markers available in this 409 population to test this hypothesis. 410 Thirdly, reduced lung function could limit peak 411 oxygen uptake and oxygen saturation, resulting in 412 potential hypoxia [6, 40, 41]. In turn, hypoxia has 413 been reported to induce cognitive deficiency and 414 dementia in both human and animal studies [42, 415 43]. Mice with hypoxia exhibited tau hyperphos- 416 phorylation, A upregulation, and dysfunction of 417
neurotransmitter system [43]. 418
In stratified analyses, we found that the association 419 between PRISm and dementia was present in men, 420 current and past smokers, and participants without 421
history of stroke and diabetes. 422
Though speculative, sex differences can poten- 423 tially be explained by unmeasured confounding by 424 sex hormones [44, 45]. Indeed, estrogen has protec- 425 tive effects on systemic and cerebrovascular athero- 426 sclerosis, which in turn impact both lung function 427 and dementia risk [24, 44]. In this population-based 428 study, we could not corroborate this speculation and 429 future research is therefore needed to explore these 430
hypotheses further. 431
The effect modification by smoking status indi- 432 cates that the effect of poor lung function on risk of 433 dementia is further aggravated in presence of smok- 434 ing. This may be related to direct toxic effects of 435 smoking in the brain, for instance increased levels of 436
oxidants and free radical species, which promotes for- 437 mation of senile plaque and neurofibrillary tangles. In 438 turn, these pathological processes may interact with 439 cerebral hypoxia and hypoperfusion due to poor lung 440
function [46, 47]. 441
With respect to stroke,APOE4 carriership and 442 diabetes, we only had sufficient power to show the 443
Uncorrected Author Proof
largest stratum and found that associations among
444
persons without stroke,APOE4 non-carriers, and
445
non-diabetics remained largely similar to the overall
446
population.
447
Among continuous lung function parameters,
448
FVC% predicted, but not FEV1/FVC ratio or FEV1%
449
predicted, was significantly associated with both all-
450
type dementia and AD risk. Previous studies have
451
varyingly reported on FEV1, FEV1/FVR ratio, or
452
FVC% predicted to be associated with dementia.
453
Heterogeneity across study population, including
454
differences in age-range, sampling strategy and co-
455
morbid conditions may explain differences in the
456
strength of associations of the various parameters
457
with dementia.
458
We did not demonstrate an association between
459
COPD and the risk of dementia, in contrast to the prior
460
study [14]. Previously, we found participants with
461
PRISm and COPD to suffer from increased all-cause
462
and cardiovascular mortality [7], and similarly the
463
present competing risk model suggested the highest
464
figure of all-cause mortality in COPD group. There-
465
fore, mortality may hinder the occurrence of incident
466
dementia during the follow-up period.
467
Strengths and limitations
468
An important strength of this study is the rela-
469
tively large number of elderly participants included
470
for assessment of the lung function through standard-
471
ized protocols and dementia data based on continuous
472
follow-up. Competing risks is a limitation when
473
using traditional cox proportion-hazard regression
474
analyses. However, we used competing risk model
475
to calculate cumulative risk of dementia to correct
476
effect of variable of interest. The small number of
477
incident dementia cases limited our study power,
478
but we applied propensity scores to avoid poten-
479
tial overfitting problem with adjustment for extensive
480
covariates.
481
CONCLUSIONS
482
As a conclusion, among this community-dwelling
483
population, participants with PRISm or participants
484
with a low FVC% predicted lung function were at
485
increased risk of dementia, compared to those with
486
normal spirometry or a higher FVC% predicted,
487
respectively. Further research is needed to elucidate
488
whether this association is causal and how PRISm
489
might contribute to dementia pathogenesis. There-
490
fore, it is necessary to recognize PRISm and evaluate
491
status of FVC% predicted when conducting spirom- 492
etry tests in clinical settings. 493
ACKNOWLEDGMENTS 494
The authors thank the study participants, the staff 495 from the Rotterdam Study and the participating gen- 496 eral practitioners. This research was funded by the 497
‘Funds for Scientific Research Flanders (Fonds voor 498 Wetenschappelijk Onderzoek Vlaanderen)’, grant 499 number 3G037618. The Rotterdam Study is sup- 500 ported by the Erasmus MC and Erasmus University 501 Rotterdam; the Netherlands Organisation for Scien- 502
tific Research (NWO); the Netherlands Organisation 503 for Health Research and Development (ZonMW); 504 the Research Institute for Diseases in the Elderly 505 (RIDE); the Netherlands Genomics Initiative; the 506 Ministry of Education, Culture and Science; the Min- 507 istry of Health, Welfare and Sports; the European 508 Commission (DG XII); and the Municipality of Rot- 509 terdam. Further funding for this study was obtained 510 through ZonMW grant number 733051107 as part 511 of the “From air pollution to brain pollution – novel 512 biomarkers to unravel the link of air pollution and 513 Alzheimer’s disease” (ADAIR) consortium under the 514 umbrella of the Joint Programme - Neurodegenera- 515 tive Diseases Research (JPND). The funding sources 516 had no involvement in the collection, analysis, writ- 517
ing, interpretation, or in the decision to submit the 518
paper for publication. 519
Authors’ disclosures available online (https:// 520 www.j-alz.com/manuscript-disclosures/21-0162r1). 521 SUPPLEMENTARY MATERIAL 522
The supplementary material is available in the 523 electronic version of this article: https://dx.doi.org/ 524
10.3233/JAD-210162. 525
DATA AVAILABILITY 526
Data may be shared on request through contacting 527
with Dr. Arfan. 528
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