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(Stroke. 1997;28:316-321.)
© 1997 American Heart Association, Inc.

Articles

Atrial Fibrillation and Dementia in a Population-Based Study

The Rotterdam Study

Alewijn Ott, MD; Monique M.B. Breteler, MD, PhD; Martine C. de Bruyne, MD; Frans van Harskamp, MD; Diederick E. Grobbee, MD, PhD Albert Hofman, MD, PhD

the Department of Epidemiology and Biostatistics (A.O., M.M.B.B., M.C.d.B., D.E.G., A.H.), Erasmus University Medical School, Rotterdam; Department of Medical Informatics (M.C.d.B.), Erasmus University Medical School, Rotterdam; and Department of Neurology (F.v.H.), Erasmus University Medical School, Rotterdam, The Netherlands.

Correspondence to A. Ott, MD, Department of Epidemiology and Biostatistics, Erasmus University Medical School, Dr Molewaterplein 50, PO Box 1738, 3000 DR Rotterdam, The Netherlands. E-mail ott@epib.fgg.eur.nl.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Atrial fibrillation is a frequent disorder in the elderly and a known risk factor for cerebrovascular stroke. We investigated the association of atrial fibrillation with dementia and cognitive impairment in a large cross-sectional, population-based study in the elderly.

Methods Of the 6584 participants in the Rotterdam Study aged 55 to 106 years, detailed information on dementia status and ECG abnormalities was available. Dementia was diagnosed in three phases. First, participants were screened. Screen-positive subjects were tested further. Those with possible dementia underwent an extensive diagnostic workup. Dementia and dementia subtypes were diagnosed according to prevailing criteria. Cognitive impairment was defined as a Mini-Mental State Examination test score of <26 points for a nondemented subject.

Results Atrial fibrillation was diagnosed in 195, dementia in 276, and cognitive impairment in 635 subjects. We found significant positive associations of atrial fibrillation with both dementia and impaired cognitive function (age- and sex-adjusted odds ratios, 2.3 [95% confidence interval, 1.4 to 3.7] and 1.7 [95% confidence interval, 1.2 to 2.5]), respectively). The strongest association was found not for vascular dementia but rather for Alzheimer's disease with cerebrovascular disease. The associations were stronger in women, and the relation with dementia was more pronounced in the relatively younger elderly. A history of stroke in subjects with atrial fibrillation could not account for these associations.

Conclusions Dementia and subtypes Alzheimer's disease and vascular dementia may be related to atrial fibrillation even if no clinical stokes have occurred.

Key Words: Alzheimer's disease • atrial fibrillation • cognition • dementia • epidemiology

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Atrial fibrillation is a common finding in the elderly.¹ Patients with atrial fibrillation frequently develop cerebral infarctions, which often remain clinically silent.^{2 3} The inefficient cardiac performance that accompanies atrial fibrillation may result in cerebral underperfusion, which compromises the aging brain.⁴ Although it was suggested in 1977 that cardiac dysrhythmias could aggravate or even precipitate senile dementia,⁵ studies on cognitive performance in patients with atrial fibrillation are rare. An association with vascular dementia has been suggested but not well quantified. We studied the association of atrial fibrillation with dementia, its subtypes, and cognitive function in a large community-based study.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The Rotterdam Study is a population-based prospective cohort study of the occurrence and progression of chronic diseases of the elderly.⁶ The study focuses on neurological, cardiovascular, locomotor, and ophthalmological diseases. All inhabitants of Ommoord, a suburb of Rotterdam, who were 55 years old, including those living in institutions, were invited to participate in the study. Of the 10 275 eligible subjects, 7983 (78%) participated in the study. Between 1990 and 1993, all participants were interviewed extensively in their homes and examined at a specially equipped research center to allow collection of baseline data and determination of health status. For 577 participants, no data on cognitive function were available, mostly because of refusal. An additional 822 subjects had no ECG performed, usually because of technical or logistic problems. In the present analysis, 6584 participants (82%) were included who had a completed ECG and dementia workup.

Examinations
Participants were interviewed in their homes regarding their medical history and subsequently examined at the research center. Examinations of institutionalized subjects were performed in the institution. All participants underwent a short neurological examination. Dementia was assessed with a three-phase approach.⁷ First, the population was screened for dementia with the use of a combined Mini-Mental State Examination⁸ and Geriatric Mental State Schedule (A, organic level)⁹ . Second, screen-positive subjects (combined Mini-Mental State Examination score of <26 and Geriatric Mental State Score of >0) were examined by a physician through the use of the Cambridge Examination for Mental Disorders of the Elderly diagnostic interview,¹⁰ which includes an informant interview. Third, all independently living and some institutionalized participants suspected of dementia were invited for examination by the study neurologist (F.v.H.). On his indication, participants were referred for a 2-hour neuropsychological testing and brain MRI, which was obtained in half of the independently living patients. For most institutionalized patients (who were on average older, had more physical constraints, and were more severely demented) and for other patients in whom the dementia workup was limited, additional information was obtained from the medical records. A panel consisting of the neurologist, neuropsychologist, and study physician reviewed all available data and made a diagnosis of dementia according to Diagnostic and Statistical Manual of Mental Disorders, 3rd ed revised,¹¹ criteria with a subdiagnosis of Alzheimer's disease based on National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association¹² criteria and of vascular dementia in accordance with National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN)¹³ criteria. Briefly, for the distinction between Alzheimer's disease and vascular dementia, review of the data focused on cerebrovascular disorders as determined through neurological examination or MRI, their relation with the onset of dementia, the acuteness of onset and pattern of progression, and the distribution of cognitive defects over the distinct domains of cognition. If a cerebrovascular event occurred within 3 months before the onset of dementia, this strongly favored a diagnosis of vascular dementia. The presence of cerebrovascular disorders did not prohibit a diagnosis of Alzheimer's disease. In accordance with above-mentioned NINDS-AIREN criteria, patients with Alzheimer's disease were subdivided into a group without and a group with cerebrovascular disease. This subdivision was based on evidence of strokes or transient ischemic attacks in the medical history or on cerebral MRI. In subjects with the clinical presentation of Alzheimer's disease, a history of stroke was considered not directly etiologically related to the dementia if the stroke had occurred definitely before or after the onset of dementia.

We defined cognitive impairment as a Mini-Mental State Examination score of <26 in subjects who were not demented.

The presence of atrial fibrillation was assessed with standard 12-lead ECGs, which were recorded at the research center with an ACTA Gnosis IV ECG recorder (Esaote/Biomedic) and digitally stored. The ECGs were analyzed with the Modular ECG Analysis System (MEANS) software.¹⁴ The program contains a module for rhythm classification of the ECG, contour analysis, and Minnesota coding. Its algorithm calculates ECG diagnoses, which have been shown to be highly reliable.¹⁵ For this study, the ECG diagnoses of atrial fibrillation and myocardial infarction with the software were used. Myocardial infarction was graded at four different levels of certainty and was assumed present if the diagnosis was probable or definite.

In addition to myocardial infarction, the following possible confounders were measured: systolic and diastolic blood pressure; presence of peripheral atherosclerosis or diabetes mellitus, patient's educational level; and antihypertensive, ß-blocker, digoxin, verapamil, anticoagulation, and thyroid drug treatment. Systolic and diastolic blood pressure were measured with a random zero sphygmomanometer. The ankle-to-brachial index (ratio of the systolic blood pressure measured at the ankle to that at the upper arm) was used as a measure of peripheral atherosclerosis: a ratio of 0.9 was considered evidence of atherosclerosis.¹⁶ Diabetes mellitus was defined as the use of antidiabetic medication or a random or postload serum glucose level of >11 mmol/L.¹⁷ The level of education was assessed during the initial home interview and graded in four levels, from primary school only to college and higher. Also, current drug use was assessed during the interview. Participants were asked to show all medications they were using. Of institutionalized subjects, medication was reported by the medical staff. We combined diuretics with the group of specific antihypertensive drugs.

Stroke was considered a possible intermediate in the relation between atrial fibrillation and cognitive deficits. We had information only on clinically overt strokes. This was determined by asking participants whether they ever had a stroke, which was diagnosed by a physician. In demented patients, this was asked in the informant interview. All histories of stroke were verified with medical records.

Statistical Analysis
In the analysis, subjects with dementia and those with impaired cognitive function without dementia were treated as separate groups. The characteristics of subjects with dementia or cognitive impairment were compared with those with normal cognition. Because the age distributions in demented and nondemented participants were very different, we calculated age- and sex-adjusted differences with multivariate regression analysis.

The association between atrial fibrillation and dementia or cognitive impairment was examined by calculating odds ratios with the use of multivariate logistic regression analysis with dementia or cognitive impairment as the dependent variable and atrial fibrillation, age, and sex as the independent variables in the model. In the analyses on dementia, subjects with cognitive impairment were excluded, and vice versa. We subsequently added myocardial infarction, systolic and diastolic blood pressure, peripheral atherosclerosis, diabetes mellitus, educational level, and antihypertensive, ß-blocker, digoxin, verapamil, anticoagulation, and thyroid drug treatment to the regression model to adjust for possible confounding. Missing values on the confounding variables were handled with the indicator method.¹⁸

We repeated the multiple regression analyses in subjects without a history of stroke to examine the association of atrial fibrillation with cognitive disorders in the absence of clinical strokes.

To assess whether women with atrial fibrillation had disproportionally more vascular comorbidity than men with atrial fibrillation, we performed logistic regression analyses with the various vascular determinants as the dependent variable and age, sex, atrial fibrillation, and the product term of sex and atrial fibrillation as the independent variables in the model.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Of the 6584 participants (age range, 55 to 106 years) in the study, 635 (9.6%) had cognitive impairment without dementia, whereas 276 (4.2%) were diagnosed with dementia (Table 1). In 206 subjects, the dementia was of the Alzheimer's disease type (75%); 41 subjects had vascular dementia (15%); and 29 had other dementias, including one undefined dementia (11%). Of the patients with Alzheimer's disease, 40 (19%) had cerebrovascular disease that was considered not directly related to the dementia. Both cognitive impairment and dementia prevalence increased strongly with age.⁷ Because the proportion of women was markedly higher in older age groups, there were relatively more women with cognitive disorders. Atrial fibrillation was found in 195 of the 6584 participants (3.0%) and was more frequent in men (3.3%) than in women (2.7%). The age-specific prevalence of atrial fibrillation in men increased from 0.9% at 55 years to 3.0% at 65 years, 7.6% at 75 years, and 13.2% at 85 years. In women, these prevalences were 0.3%, 1.8%, 5.2%, and 10.6%, respectively. Table 1 gives the age- and sex-adjusted characteristics of subjects with and without cognitive disorders.

View this table: [in this window] [in a new window]   Table 1. Characteristics of Study Population, Patients With Dementia, and Subjects With Mild Cognitive Impairment

Dementia was more than twice as common in subjects with atrial fibrillation than in those without (Table 2). We also found a significant positive association between cognitive impairment and atrial fibrillation, but this association was less strong. Stratification for sex showed that associations were restricted to women. Table 3 shows that the relation between dementia and atrial fibrillation was modified by age and that associations were stronger at <75 years of age in both men and women. No such age effect was found for cognitive impairment. Additional adjustments for myocardial infarction, blood pressure, peripheral atherosclerosis, diabetes mellitus, educational level, and various medication use only slightly changed the associations (Tables 2 and 3). Only in subjects <75 years old did the association between dementia and atrial fibrillation become smaller when subjects with a history of stroke were excluded.

View this table: [in this window] [in a new window]   Table 2. Association of Atrial Fibrillation to Cognitive Impairment and Dementia by Sex

View this table: [in this window] [in a new window]   Table 3. Association of Atrial Fibrillation With Dementia

Table 4 shows the relation between atrial fibrillation and subtypes of dementia. Positive associations were observed for both Alzheimer's disease and vascular dementia. In particular, Alzheimer's disease with cerebrovascular disease was strongly associated with atrial fibrillation. Additional adjustment for possible confounders resulted in reduced odds ratios but did not essentially change the relation.

View this table: [in this window] [in a new window]   Table 4. Association Between Atrial Fibrillation and Subtypes of Dementia

We further explored the sex differences in the association of atrial fibrillation with cognitive disorders. If men and women with atrial fibrillation are treated differently, this could result in variations in the occurrence of complications. Therefore, we compared treatment regimens between men and women. Similar proportions of men and women with atrial fibrillation were treated with digoxin glycosides (38% and 42%, respectively) and verapamil (13% and 16%). A larger proportion of men than women used antithrombotic drugs (34% versus 20%). In both men and women without atrial fibrillation, 4% used treatment for cardiac arrhythmia. Of these subjects, 28% of men and 36% of women used digoxin, 20% of both men and women used verapamil, and 23% of men and 4% of women used antithrombotic drugs. There was more vascular comorbidity in women than in men with atrial fibrillation, and this difference was significant for diabetes mellitus and antihypertensive drug use and borderline significant for ECG myocardial infarction.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In the present study, we found that atrial fibrillation is significantly associated with dementia. In particular, women and subjects <75 years old with atrial fibrillation have an increased prevalence of dementia. Atrial fibrillation appears to be associated with vascular dementia but also with Alzheimer's disease, particularly in patients with concomitant cerebrovascular disease.

This is a cross-sectional study, and there is some potential for bias. First, 18% of the Rotterdam Study participants had to be excluded from these analyses because of incomplete data. An ECG was more often missing in demented (especially severely demented) participants, and nonresponders were on average older than those who could be included in the present study. However, we consider it unlikely that the association between atrial fibrillation and dementia among nonresponders was opposite to what we found. Therefore, we do not think that nonresponse led to essential biases in our estimates. Second, because our analyses were cross-sectional, there is a potential for survival effects. If coexisting atrial fibrillation and dementia reduce survival, the combination would be seen less and the association would be underestimated. Most likely, this survival effect is stronger in more severe disease and could have attributed to a reduced association in men, in older subjects, and in those with vascular dementia. A third possible bias could result from misclassification. Because we used a very sensitive screening for dementia, it is unlikely that many cases were missed. Also, the thorough diagnostic workup ensured minimal false-positive diagnoses. However, misclassification may have occurred in dementia subtyping. Even though the criteria we used for the diagnosis of Alzheimer's disease have a high sensitivity and specificity for the autopsy-proven diagnosis,¹⁹ subtyping dementia remains uncertain without postmortem confirmation or additional brain imaging data. Also, there is increasing evidence that Alzheimer's disease and vascular dementia are not clear entities or can be distinguished as sharply as is suggested by the common use of these labels. Atrial fibrillation has undoubtedly been underdiagnosed. Because only one ECG was recorded, we did not detect all paroxysmal atrial fibrillation. In the Cardiovascular Heart Study, a population-based study in persons of 65 years, it was shown that a 10-second resting ECG (which we used) detected 74% of all subjects with atrial fibrillation on 24-hour ambulatory ECG.²⁰ Other cardiac arrhythmias were also not taken into account in the present analyses. Both undetected atrial fibrillation and other arrhythmias may have diluted the association and thus led to an underestimation of the true effect of atrial arrhythmias. Finally, in our definition of cognitive impairment, we did not account for additional causes of decreased Mini-Mental State Examination test scores, such as depressive symptoms, sensory impairments, and physical disabilities. We consider it, however, unlikely that this has confounded the association between cognitive impairment and atrial fibrillation.

With respect to the stronger association in women than in men, several hypotheses were considered. Antithrombotic drugs are more often prescribed for men, and it is possible that complications as a result of atrial fibrillation are more adequately prevented in men than in women. Women with atrial fibrillation had more coincident cardiovascular disorders than did men with atrial fibrillation. Two prospective studies on atrial fibrillation in the community showed similar sex differences; in both the Copenhagen City Heart Study and the Framingham Study, women with atrial fibrillation had higher relative risks of developing a stroke than did men.^{21 22} It is possible that the combination of atrial fibrillation and other cardiovascular disorders is more lethal in men than in women. A decreased survival reduces the probability to be detected as demented in a cross-sectional study and could explain the reduced association with dementia in the oldest group.

When studying atrial fibrillation as a correlate of cognition, it should be kept in mind that atrial fibrillation is often a consequence of underlying cardiac disease. The leading causes in the elderly are ischemic heart disease, hypertension, and, to a lesser extent, thyrotoxicosis.⁴ In <8% of the cases in a community-based study, no causes were found.¹ Therefore, the association with atrial fibrillation could be the result of the underlying disease. Our results show that adjustment for factors related to these diseases did not weaken the association and thus plead for an independent effect of atrial fibrillation on cognition. Atrial fibrillation results in hemodynamic disturbances that might be responsible for brain lesions; ineffective atrial clearance promotes the formation of thrombi. In 1978, the Framingham Heart Study reported a fivefold increased risk of stroke among patients with chronic nonrheumatic atrial fibrillation.²³ In our study, the age- and sex-adjusted association of stroke history to atrial fibrillation was lower (odds ratio, 1.9; 95% confidence interval, 1.1 to 3.1), although hypertension was often treated, and 26% of the patients with atrial fibrillation used antithrombotic medication. Two findings in our study indicate that clinical strokes were not a major cause of the positive relation of atrial fibrillation with cognitive disorders; exclusion of subjects with a history of stroke did not result in reduced associations, and vascular dementia was not particularly associated with atrial fibrillation. However, silent infarctions may underlie the relation between dementia and atrial fibrillation. In previous studies, silent infarctions were noticed in 15% to 26% of patients with atrial fibrillation.^{2 24} In a community-based autopsy series, silent infarctions (13%) were associated with higher age, blood pressure, and atrial fibrillation.²⁵ Silent infarctions tend to be small and located deep in the brain.^{24 25} Multiple silent infarctions could very well resemble Alzheimer's disease because the few neurological symptoms that may be found are nonspecific, especially in the very old, or they could accelerate the conversion of subclinical Alzheimer's disease to a conclusive dementia.

Atrial fibrillation results not only in thromboembolism but also in reduced cardiac output. This reduction is greater at fast ventricular rates and could lead to cerebral underperfusion.²⁶ This reduced capacity to maintain adequate brain perfusion could be a second mechanism of brain damage and cognitive decline.^{27 28} The association of white matter lesions to low blood pressure and atrial fibrillation²⁹ suggests a hemodynamic etiology. White matter lesions were found to be correlated with reduced cognition^{28 30} and are approximately threefold more prevalent in patients with Alzheimer's disease than in normal control subjects.^{31 32} Subnormal cardiac output could be one of the probably many cerebral affronts that finally result in the common picture of plaques and neurofibrillary tangles.⁵

Because the present study was cross-sectional, no conclusions can be drawn regarding causality. We believe that our results most likely indicate that patients with atrial fibrillation have an increased risk of cognitive decline and dementia. Atrial fibrillation has been suggested to be a risk factor for vascular dementia.^{33 34} Adequate treatment of atrial fibrillation may help prevent multi-infarct dementia^{33 35} but could also be beneficial for those predisposed to develop an Alzheimer's disease–type dementia.

	Acknowledgments

 
This study was supported by the NESTOR Stimulation Program for Geriatric Research in The Netherlands (Ministry of Health and Ministry of Education), The Netherlands Organization for Scientific Research (NWO), The Netherlands Prevention fund, and the municipality of Rotterdam. We are grateful for the assistance in data collection by the staff of the Rotterdam Study Center. We also acknowledge the collaboration with the general practitioners in Ommoord.

Received June 27, 1996; revision received October 18, 1996; accepted November 12, 1996.

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