Skip to main content
PMC home page
Europace logoLink to Europace
. 2022 Jan 21;24(8):1229–1239. doi: 10.1093/europace/euac003

Predictive role of atrial fibrillation in cognitive decline: a systematic review and meta-analysis of 2.8 million individuals 

Yu Han Koh 1,#, Leslie Z W Lew 2,#, Kyle B Franke 3, Adrian D Elliott 4, Dennis H Lau 5,6, Anand Thiyagarajah 7, Dominik Linz 8, Margaret Arstall 9,10, Phillip J Tully 11, Bernhard T Baune 12,13,14, Dian A Munawar 15,16,17, Rajiv Mahajan 18,19,✉
PMCID: PMC9435641  PMID: 35061884

Abstract

Aims

To systematic review and meta-analyse the association and mechanistic links between atrial fibrillation (AF) and cognitive impairment.

Methods and results

PubMed, EMBASE, and Cochrane Library were searched up to 27 March 2021 and yielded 4534 citations. After exclusions, 61 were analysed; 15 and 6 studies reported on the association of AF and cognitive impairment in the general population and post-stroke cohorts, respectively. Thirty-six studies reported on the neuro-pathological changes in patients with AF; of those, 13 reported on silent cerebral infarction (SCI) and 11 reported on cerebral microbleeds (CMB). Atrial fibrillation was associated with 39% increased risk of cognitive impairment in the general population [n = 15: 2 822 974 patients; hazard ratio = 1.39; 95% confidence interval (CI) 1.25–1.53, I2 = 90.3%; follow-up 3.8–25 years]. In the post-stroke cohort, AF was associated with a 2.70-fold increased risk of cognitive impairment [adjusted odds ratio (OR) 2.70; 95% CI 1.66–3.74, I2 = 0.0%; follow-up 0.25–3.78 years]. Atrial fibrillation was associated with cerebral small vessel disease, such as white matter hyperintensities and CMB (n = 8: 3698 patients; OR = 1.38; 95% CI 1.11–1.73, I2 = 0.0%), SCI (n = 13: 6188 patients; OR = 2.11; 95% CI 1.58–2.64, I2 = 0%), and decreased cerebral perfusion and cerebral volume even in the absence of clinical stroke.

Conclusion

Atrial fibrillation is associated with increased risk of cognitive impairment. The association with cerebral small vessel disease and cerebral atrophy secondary to cardioembolism and cerebral hypoperfusion may suggest a plausible link in the absence of clinical stroke. PROSPERO CRD42018109185.

Keywords: Atrial fibrillation, Cognitive impairment, Dementia, Meta-analysis, Silent brain infarction, Stroke, Cerebral small vessel disease

Graphical Abstract

What’s new?

  • Atrial fibrillation (AF) is associated with a 39% increased risk of cognitive impairment.

  • The cognitive impairment was early and more frequent after clinical stroke in presence of AF.

  • Cerebral small vessel disease, such as white matter hyperintensities, microbleeds, silent cortical and subcortical infarction, and decrease in cerebral volume, represents the plausible link between AF and cognitive impairment.

Introduction

Atrial fibrillation (AF) and cognitive impairment are important public health problems and represent significant burden on health resources.1,2 Population studies have suggested an association between AF and cognitive impairment. Atrial fibrillation and cognitive impairment share similar risk factors, such as age, diabetes, hypertension, and heart failure, which could confound the association.3–5 In addition, stroke, a serious complication of AF, is a well-described risk factor for cognitive impairment.6 Silent cerebral emboli and chronic hypoperfusion during AF may also represent a plausible pathophysiological link between AF and cognitive impairment, though evidence is unclear.

Cognitive impairment is defined as a decline from a previous level of performance in one or more cognitive domains (complex attention, executive function, learning and memory, language, perceptual motor, or social cognition). It is designated ‘mild’ when it does not interfere with the capacity for independence. On the other hand, severe cognitive impairment (dementia) is a more severe form that interferes with daily function, usually defined either by the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria or International Classification of Diseases (ICD) codes.

In this study, we undertook a meta-analysis and systematic review of (i) studies evaluating the association between AF and cognitive impairment, and (ii) neuropathological lesions in AF patients to better characterize the mechanistic link between AF patients and cognitive impairment.

Methods

This systematic review complies with the consensus statement outlined by the Meta-analysis of Observational Studies in the Epidemiology group and Preferred Reporting Items for Systematic Review and Meta-Analysis statements.7 The meta-analysis was registered with the PROSPERO International prospective register of systematic reviews (CRD42018109185).

Search strategy

The English scientific literature was searched using PubMed, EMBASE, and Cochrane Library from their inception to 27 March 2021 with the assistance of an experienced librarian. The following keywords: atrial fibrillation, cognitive impairment, major neurocognitive disorder, microbleeds, silent cerebral infarcts, and dementia were used (Supplementary material online, Methods S1).

Inclusion and exclusion criteria

Only prospective studies were included for the meta-analysis evaluating the relationship between AF and cognitive impairment. Furthermore, studies reporting neuropathological lesions in the AF population were included and reported in a systematic manner. The exclusion criteria were (i) reviews, editorials, letters, case series, case reports, and conference proceedings; (ii) sample size <50; (iii) studies lacking a control group; (iv) studies in which the control group was selected from patients with other types of arrhythmias; (v) studies where the measure of association was not reported; and (vi) studies that provided unadjusted analyses. Where multiple studies described the same population (sub- and follow-up studies), the study with the most comprehensive data was included.

Study selection and data extraction

The study selection and data extraction were performed using the predefined inclusion and exclusion criteria. Although review articles were excluded, their reference lists were examined for potentially relevant publications. During data extraction, information was collected on the study design, length of follow-up, outcome measures, method of assessing outcomes, inclusion/exclusion criteria, and results. The maximally adjusted risk ratios were extracted and pooled across studies. The data were reviewed by two authors independently (Y.H.K. and L.L.) and disagreements were resolved by consensus with the help of a third investigator (R.M.). The methodological qualities of the included studies were assessed using the modified Newcastle-Ottawa Scale. The outcomes of the meta-analysis were defined as (i) association of AF and cognitive impairment and (ii) impact of AF on progression of cognitive impairment. The outcome of the systematic review was to systematically define the neuro-pathological changes in AF.

Statistical analysis

Continuous variables are presented as the mean or median and categorical variables as n (%). Meta-analysis was performed using STATA (StataCorp, TX, Version 15). Hazard ratios (HRs) and risk ratios (RRs) were calculated using the metan function. A P-value <0.05 was considered significant. The heterogeneity was assessed using an I2 value to measure variability in observed effect estimates between the studies and heterogeneity was explored with meta-regression in comprehensive meta-analysis software.8 Utilizing the unrestricted maximum likelihood assumption, the univariate meta-regression shows the unit change in effect size (i.e. the HR for MCI) standardized to a 10 unit change in predictor variable (e.g. per 10-year increase in age), with associated 95% confidence interval (CI) and P value. Separate meta-analyses were performed for (i) cognitive impairment in all AF patients with (ii) a subgroup analysis of those without previous stroke, and (iii) post-stroke cohort; (iv) progression of cognitive impairment; (v) silent cerebral infarction (SCI); and (vi) microbleeds in AF patients. Incidence rate ratios were calculated using follow-up and event data; using the restricted maximum-likelihood estimator random effects model, Poisson-Normal model with log incidence rate as the outcome measure was fitted. Pooled incidence rate was calculated by performing back-transformation of log incidence rates. Where data could not be presented as a meta-analysis, it were reported in a systematic fashion.

Results

Search and synthesis of the literature

The online search of PubMed, EMBASE, and Cochrane Library from their inception to 27 March 2021 yielded 4534 citations. Manual searching of references for reviews did not yield additional citations. Subsequently, duplicate citations (656) and citations not conforming to inclusion and exclusion criteria (3627) were excluded from primary review. Two hundred and fifty-one citations were identified for secondary review. After removal of studies with sample size less than previously defined (n = 5), the lack of a control group (n = 12), cross-sectional studies (n = 7), inadequate data for stipulated research questions (n = 160), and redundant studies (n = 6), 61 studies were included in the final analysis. Of these, 15 studies reported on the association of AF and cognitive impairment in the general population, 6 reported on cognitive impairment in post-stroke population, and 4 on association of AF with progression of cognitive impairment. Using the same pool of retrieved articles, 36 studies reported the neuropathological lesions in the AF population. Of these, 13 reported on the association of AF and SCI, and 11 on cerebral microbleeds (CMB) in AF patients. Figure 1 provides the consort diagram for the data search.

Figure 1.

Figure 1

Open in a new tab

Search strategy.

Atrial fibrillation and cognitive impairment

General population studies

Fifteen prospective population studies,9–23 consisting of 2 822 974 patients were analysed. The baseline characteristics of these studies were listed in Supplementary material online, Table S1. Thirteen studies9,10,12,13,15–23 used severe cognitive impairment as their endpoint and two further studies11,14 used a combination of mild and severe cognitive impairment as their endpoint. The definition of mild and severe cognitive impairment was based on clinical diagnosis in most studies. International Classification of Diseases codes utilized in some studies (Supplementary material online, Table S1). The incidence of cognitive impairment amongst participants with and without AF was 17.5% (95% CI 10.9–24.2) and 9.7% (95% CI: 5.1–14.3) events per 1000 person-years of follow-up over a follow-up period of 3.8–25 years, respectively. In the combined analysis (Figure 2A), AF was associated with 39% increased risk of cognitive impairment (HR = 1.39, 95% CI 1.25–1.53, I2 = 90.3%, P < 0.001). All studies adjusted for cardiovascular risk factors.

Figure 2.

Figure 2

Open in a new tab

AF and cognitive impairment in (A) general population longitudinal studies; and (B) general population studies excluding previous history of stroke. AF, atrial fibrillation.

In a pre-specified analysis of studies excluding patients with previous stroke9–11,13,14,16–18,20 (n = 8, Figure 2B), AF was associated with 45% increased risk of cognitive impairment (HR = 1.45, 95% CI 1.24–1.66, I2 = 55.0%, P < 0.001).

Only use of anti-coagulants was identified as a source of heterogeneity between effect sizes (coefficient = −0.06, 95% CI −0.11 to 0.02, P = 0.005). Other covariate predictors were not identified as a source of heterogeneity; age (coefficient = −0.12, 95% CI −0.26 to 0.01, P = 0.08), heart failure (coefficient = −0.01, 95% CI −0.10 to 0.08, P = 0.76), hypertension (coefficient = −0.02, 95% CI −0.07 to 0.03, P = 0.41), diabetes (coefficient = −0.06, 95% CI −0.22 to 0.09, P = 0.43), coronary artery disease (coefficient = −0.07, 95% CI −0.16 to 0.03, P = 0.15), previous stroke (coefficient = 0.01, 95% CI −0.10 to 0.11, P = 0.99), and length of follow-up (coefficient = 0.05, 95% CI −0.16 to 0.25, P = 0.64).

Acute stroke cohort

Six prospective studies24–29 consisting of 2009 patients were analysed to evaluate the impact of AF on the risk of cognitive function after acute stroke. The proportion of post-stroke patients with and without AF, developing cognitive impairment was 55% (95% CI: 0.39–0.70) and 21% (95% CI 0.12–0.30), respectively. Overall, AF was associated with a 2.70-fold increased risk of cognitive impairment [adjusted odds ratio (aOR) = 2.70, 95% CI 1.66–3.74, I2 = 0.0%, P < 0.001] (Figure 3) over a follow-up period of 0.25–3.78 years.

Figure 3.

Figure 3

Open in a new tab

Impact of AF on risk of cognitive impairment after acute stroke. AF, atrial fibrillation.

Progression of cognitive impairment

Four studies consisting of 3186 patients23,30–32 were analysed to assess the impact of AF on the progression from mild to severe cognitive impairment. Overall, there was no significant increase in the risk of progression from mild to severe cognitive impairment [relative risk (RR) = 2.75, 95% CI 0.46–5.04, I2 = 45.6%) in patients with AF as compared to the control population (Figure 4) over 2.8–10 years.

Figure 4.

Figure 4

Open in a new tab

AF and progression of cognitive impairment. AF, atrial fibrillation.

Atrial fibrillation and neuropathological lesions

Thirty-six studies reported the neuropathological lesions in the AF population. Of these, 32 described findings from brain imaging,33–64 while the remaining 4 studies described post-mortem results.65–68 The neuropathological changes of the imaging and autopsy studies are listed in Table 1. Autopsy studies reported gross and subcortical infarcts in patients with AF.65–68 Neuritic plaques66 and neurofibrillary tangles,68 usually seen with Alzheimer’s disease, were noted to be absent. Imaging studies demonstrated association of decrease in cerebral perfusion,53,54 and total cerebral volume with AF, after adjusting for infarction,35,49,50 and ApoEε4.35,49 There was greater decrease in total cerebral volume in permanent as compared to paroxysmal AF.50 In addition, decreased frontal lobe and hippocampal volume were associated with AF.49 Atrial fibrillation was not associated with Alzheimer’s pattern of 18F-FDG PET hypometabolism or PiB uptake (β-amyloid accumulation).35

Table 1.

Neuropathological abnormalities in patients with AF

Infarction

  • Autopsy

    • Gross cortical and subcortical infarcts64–67

    • Absence of neuritic plaques65 and neurofibrillary tangles67

  • Brain imaging (CT/ MRI)

    • Silent cortical infarction32–44,50

      • More in persistent AF as compared to paroxysmal AF35

    • Subcortical infarction32–34,45,46

    • Severe periventricular white matter lesions/ hyperintensities45–47

    • Cerebral microbleeds54–63Decreased brain volume

  • Decrease in total cerebral volume

    • Greater decrease in permanent as compared to paroxysmal AF49

    • Decrease frontal lobe volume,48 adjusted for ApoEε4

    • Decrease hippocampal volume

  • Decreased cerebral perfusion52,53FDG hypometabolism

  • Absence of Alzheimer’s disease pattern34
Open in a new tab

AF, atrial fibrillation; CT, computed tomography; FDG, 18F-Deoxyglucose; MRI, magnetic resonance imaging.

Silent cerebral infarction in patients with atrial fibrillation

Thirteen studies, consisting of 6188 patients [9 magnetic resonance imaging (MRI) studies33,35,36,39,40,42–44,69 and 4 computed tomography (CT) studies37,38,41,45] were analysed to assess the association of SCI with AF. Supplementary material online, Table S2 provides the study characteristics and baseline parameters of subjects in the studies. Silent cerebral infarction was defined as hypodense foci on CT studies. The MRI studies used definitions mostly consistent with STRIVE criteria.70 Lacunar infarct was defined as focal lesions ≥3 and ≤15 mm and hyperintense on T2-weighted and iso/hypointense on T1-weighted images. Most studies excluded SCI <3 mm due to difficulty in differentiation them from perivascular spaces under 3 mm.37 The studies reporting cortical infarct defined them as ≥10 mm in cortical regions. Silent cerebral infarction were noted to be lacunar,33,42,44,45 cortical,35,37,38 or both.36,40,43 One study defined cerebral micro-infarcts as <5 mm.39 Ten of 13 included studies excluded patients with previous stroke. In the remaining studies, imaging was performed for suspected stroke. Silent cerebral infarction was present in 36.7% of patients (95% CI 14.8–58.7, I2 = 97.7%) with AF, and 22.9% (95% CI 16.6–29.3, I2 = 96.6%) without AF. Overall, AF was associated with 2.11-fold increased risk of SCI (OR = 2.11, 95% CI 1.58–2.64, I2 = 0.0%) (Figure 5).

Figure 5.

Figure 5

Open in a new tab

AF and silent cerebral infarction. AF, atrial fibrillation.

Cerebral microbleeds in patients with atrial fibrillation

A total of 11 studies reported on association of CMB and AF. Supplementary material online, Table S3 provides the study characteristics and baseline parameters and anticoagulation status of subjects in the studies. Cerebral microbleeds were present in 30.1% of patients (95% CI 23.5–36.7, I2 = 57.6%) with AF, and 26.5% (95% CI 21.2–31.9, I2 = 91.4%) without AF. Eight, consisting of 3698 patients, demonstrated a 38% increased likelihood of CMB (OR = 1.38, 95% CI 1.11–1.73, I2 = 0.0) (Figure 6) in patients with AF.52,55–61 Of these, six examined ischaemic stroke cohorts, one haemorrhagic stroke, and only one evaluated patients with AF undergoing MRI for a neurological indication.

Figure 6.

Figure 6

Open in a new tab

AF and cerebral microbleeds. AF, atrial fibrillation.

Three studies examined the prognostic role of CMB in AF patients.62–64 Overall, presence of CMB at baseline was associated with a 1.7-fold increased risk of composite all-cause death and all-cause stroke at follow-up (n = 3, HR = 1.70, 95% CI 1.0–2.403, I2 = 38.0%).62–64

Study quality and publication bias

All included studies fulfilled the Newcastle Ottawa Score for being representative of the relevant cohort and having adequate sample size. There was low risk of detection and information biases in all studies. Supplementary material online, Table S4 provides the modified Newcastle Ottawa Score for the included studies. Funnel plots and egger test revealed no significant publication bias in any of the statistical analyses (Supplementary material online, Figure S1).

Discussion

Atrial fibrillation is associated with serious complications ranging from heart failure to debilitating stroke and death. Our systematic review and meta-analyses provide compelling evidence for association of AF with cognitive impairment (Graphical abstract). The meta-analyses included only prospective observational studies, which enabled the measurement of events in temporal sequence, providing reliable results. The major findings were

Graphical Abstract.

Graphical Abstract

Open in a new tab

  1. The presence of AF is associated with a 39% increased risk of cognitive impairment with a lead time of years to decade(s). The association persisted even after exclusion of patients with previous history of stroke. Furthermore, the presence of AF results in early and 2.7-fold increased risk of cognitive impairment after acute stroke.

  2. Atrial fibrillation is associated with increased risk of cerebral small vessel disease, such as white matter lesions, SCI, CMB, and reduced cerebral volume which may represent the plausible link between AF and cognitive impairment.

  3. Atrial fibrillation is associated with 38% increased risk of CMB. When present, CMB are associated with increased risk of death and recurrent stroke in patients with AF.

Atrial fibrillation and cognitive impairment

The Rotterdam Study was the first to describe the association between AF and cognitive impairment.71 Although some small studies or studies in elderly cohorts have not shown this association, larger cross-sectional and prospective longitudinal studies have confirmed high risk of cognitive impairment in patients with AF.6,33 The risk of cognitive decline has also been noted to be dependent on the duration of exposure or when AF is diagnosed earlier than the eighth decade.6,9,16 However, this association is confounded by the presence of shared cardiovascular risk factors, such as hypertension, diabetes mellitus, heart failure, and excess alcohol intake. Some studies have shown a lower risk of dementia in patients with AF on oral anticoagulation providing evidence in favour of the causal association of AF and dementia.72,73 Similarly, patients managed with rhythm control by catheter ablation may have a lower risk of dementia.74 The current meta-analysis restricted itself to prospective studies that had adjusted risk for cardiovascular risk factors, providing strength to the association between AF and cognitive impairment. The lengthy follow-up of prospective studies also suggests a long lead time in absence of clinical stroke. However, the cognitive impairment was more common and accelerated to occur within months to years after acute stroke. The association between AF and progression of cognitive impairment did not achieve significance and may represent lack of adequate power of the analysis.

Link between atrial fibrillation and cognitive impairment

Atrial fibrillation is an established risk factor for stroke, accounting for up to one-third of the stroke cases in elderly patients. The presence of AF has been associated with large ischaemic lesions secondary to macro-embolism from the left atrium.66,68 These lesions increase the risk of developing large vessel dementia.65 Even in absence of clinical stroke, several mechanisms have been proposed to explain the increased risk of cognitive impairment in patients with AF.

This meta-analysis comprehensively presents the various neuropathological changes associated with AF that could represent a plausible link between AF and cognitive impairment. Silent micro-emboli secondary to thrombogenic and inflammatory state in AF have been proposed to result in not only silent cortical33–45,75 and but also silent sub-cortical infarction.33–35,46,47 However, associated small vessel disease may contribute to silent sub-cortical infarction. Hypoperfusion secondary to variability in cerebral blood flow and cerebral vascular rhythm may result in ischaemia or impairment of flowing blood’s ability to remove micro emboli from the vessels which results in embolic infarction.76 In addition, the burden of cerebral small vessel disease, such as white matter lesions, increases with a chronic reduction in cerebral blood flow secondary to persistent AF.36 Although certain studies suggest an association with Alzheimer’s disease, autopsy, and positron emission tomography (PET) imaging have demonstrated an absence of neuritic plaques,66 neurofibrillary tangles,68 and Alzheimer’s disease pattern.35 Furthermore, decreased cerebral perfusion54 may explain reduction in cerebral volume in patients with AF, even after adjustment for infarction35,49,50 and ApoEε4.35,49 The meta-analysis also confirmed that CMB, a marker of cerebral small vessel disease, are seen more often in patients with AF. Recent data suggest that novel oral anticoagulants may not increase risk of CMB as they do not cross the blood brain barrier.77 CMB have been shown to be associated with greater risk of cerebral haemorrhage and stroke. The risk for recurrent ischaemic stroke is greater than the risk for cerebral haemorrhage even in patients on oral anticoagulants.62 Our meta-analysis confirmed that CMB are associated with increased risk of death and all-cause stroke in patients with AF.

To summarize, cerebral small vessel disease, clinical, and subclinical infarction are associated with AF. We hypothesize that these changes when superimposed on the concomitant cerebral small vessel disease associated with comorbid conditions such as hypertension and diabetes predispose patients to cognitive impairment (Graphical abstract).

Strengths and limitations

The results of the current study were compiled using meta-analysis of primarily observational data. However, the technique of meta-analysis is well accepted in the literature to aggregate results from observational data, to facilitate synthesis of available evidence and the infarction were also heterogenous in the included studies. Although previous meta-analyses have shown similar association with cognitive function,78,79 this updated meta-analyses included only prospective longitudinal studies only and demonstrated a robust relationship despite adjusting for cardiovascular risk factors. In addition, this meta-analysis highlights the potential timeline of cognitive impairment based on the length of follow-up. The study also systematically reviews the association of gamut of neuropathological changes in patients with AF. The impact of oral anticoagulation on cognitive impairment in patients with AF was not evaluated as it way beyond the scope of the meta-analyses. This meta-analysis provides important information that will be useful to estimate sample size and design further prospective studies to inform on measures that may reduce risk of cognitive impairment due to AF.

Conclusion

Atrial fibrillation is associated with increased risk of cognitive impairment. Clinical and silent brain infarction, cerebral small vessel disease, and cerebral atrophy secondary to cardioembolism and cerebral hypoperfusion may represent the plausible link in absence of clinical stroke. Further prospective randomized control trials are essential to further the understanding of the mechanisms of cognitive impairment and to develop strategies to prevent cognitive impairment in patients with AF.

Supplementary material

Supplementary material is available at Europace online.

 

Funding

D.A.M. was supported by the Post-doctoral Research Fellowship from the University of Adelaide. A.D.E. was supported by an Early Career fellowship from the National Heart Foundation (NHF). D.L. was supported by a Beacon Research Fellowship from the University of Adelaide. D.H.L. was supported by the Robert J. Craig Lectureship from the University of Adelaide. R.M. was supported by the Mid-Career Fellowship from the Hospital Research Fund. This study was supported by funds from the University of Adelaide. Several of the authors are employees of the University of Adelaide. The sponsor has had no direct involvement in the management or outcomes of the study.

Supplementary Material

euac003_Supplementary_Data
Click here for additional data file. (5.9MB, docx)

Contributor Information

Yu Han Koh, The University of Adelaide, Adelaide, Australia.

Leslie Z W Lew, The University of Adelaide, Adelaide, Australia.

Kyle B Franke, The University of Adelaide, Adelaide, Australia.

Adrian D Elliott, The University of Adelaide, Adelaide, Australia.

Dennis H Lau, The University of Adelaide, Adelaide, Australia; Royal Adelaide Hospital, Adelaide, Australia.

Anand Thiyagarajah, Royal Adelaide Hospital, Adelaide, Australia.

Dominik Linz, The University of Adelaide, Adelaide, Australia.

Margaret Arstall, The University of Adelaide, Adelaide, Australia; Lyell McEwin Hospital, Adelaide, Australia.

Phillip J Tully, The University of Adelaide, Adelaide, Australia.

Bernhard T Baune, Department of Psychiatry, University of Melbourne, Melbourne, Australia; The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia; Department of Psychiatry, University of Münster, Münster, Germany.

Dian A Munawar, The University of Adelaide, Adelaide, Australia; Royal Adelaide Hospital, Adelaide, Australia; Department of Cardiology and Vascular Medicine, University of Indonesia, Jakarta, Indonesia.

Rajiv Mahajan, The University of Adelaide, Adelaide, Australia; Lyell McEwin Hospital, Adelaide, Australia.

Data Availability

Data are available on request to the corresponding author.

References

  • 1. Chugh SS, Havmoeller R, Narayanan K, Singh D, Rienstra M, Benjamin EJet al. . Worldwide epidemiology of atrial fibrillation: a global burden of disease 2010 study. Circulation 2014;129:837–47. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. Dagres N, Chao T-F, Fenelon G, Aguinaga L, Benhayon D, Benjamin EJet al. . European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) expert consensus on arrhythmias and cognitive function: what is the best practice?. Europace 2018;20:1399–421. 10.1093/europace/euy046. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. Cheng G, Huang C, Deng H, Wang H.. Diabetes as a risk factor for dementia and mild cognitive impairment: a meta-analysis of longitudinal studies. Intern Med J 2012;42:484–91. [DOI] [PubMed] [Google Scholar]
  • 4. Elias MF, Wolf PA, D'Agostino RB, Cobb J, White LR.. Untreated blood pressure level is inversely related to cognitive functioning: the Framingham Study. Am J Epidemiol 1993;138:353–64. [DOI] [PubMed] [Google Scholar]
  • 5. Vogels RL, Scheltens P, Schroeder-Tanka JM, Weinstein HC.. Cognitive impairment in heart failure: a systematic review of the literature. Eur J Heart Fail 2007;9:440–9. [DOI] [PubMed] [Google Scholar]
  • 6. Bunch TJ, Weiss JP, Crandall BG, May HT, Bair TL, Osborn JSet al. . Atrial fibrillation is independently associated with senile, vascular, and Alzheimer's dementia. Heart Rhythm 2010;7:433–7. [DOI] [PubMed] [Google Scholar]
  • 7. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie Det al. . Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000;283:2008–12. [DOI] [PubMed] [Google Scholar]
  • 8. Borenstein M, Hedges L, Higgins J, Rothstein H. Comprehensive meta-analysis version 2. 2005.
  • 9. de Bruijn RF, Heeringa J, Wolters FJ, Franco OH, Stricker BH, Hofman Aet al. . Association between atrial fibrillation and dementia in the general population. JAMA Neurol 2015;72:1288–94. [DOI] [PubMed] [Google Scholar]
  • 10. Dublin S, Anderson ML, Haneuse SJ, Heckbert SR, Crane PK, Breitner JCet al. . Atrial fibrillation and risk of dementia: a prospective cohort study. J Am Geriatr Soc 2011;59:1369–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Haring B, Leng X, Robinson J, Johnson KC, Jackson RD, Beyth Ret al. . Cardiovascular disease and cognitive decline in postmenopausal women: results from the Women's Health Initiative Memory Study. J Am Heart Assoc 2013;2:e000369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Liao JN, Chao TF, Liu CJ, Wang KL, Chen SJ, Tuan TCet al. . Risk and prediction of dementia in patients with atrial fibrillation–a nationwide population-based cohort study. Int J Cardiol 2015;199:25–30. [DOI] [PubMed] [Google Scholar]
  • 13. Marengoni A, Qiu C, Winblad B, Fratiglioni L.. Atrial fibrillation, stroke and dementia in the very old: a population-based study. Neurobiol Aging 2011;32:1336–7. [DOI] [PubMed] [Google Scholar]
  • 14. Marzona I, O'Donnell M, Teo K, Gao P, Anderson C, Bosch Jet al. . Increased risk of cognitive and functional decline in patients with atrial fibrillation: results of the ONTARGET and TRANSCEND studies. CMAJ 2012;184:E329–36. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15. Marzona I, Baviera M, Vannini T, Tettamanti M, Cortesi L, Riva Eet al. . Risk of dementia and death in patients with atrial fibrillation: a competing risk analysis of a population-based cohort. Int J Cardiol 2016;220:440–4. [DOI] [PubMed] [Google Scholar]
  • 16. Singh-Manoux A, Fayosse A, Sabia S, Canonico M, Bobak M, Elbaz Aet al. . Atrial fibrillation as a risk factor for cognitive decline and dementia. Eur Heart J 2017;38:2612–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Rydén L, Zettergren A, Seidu NM, Guo X, Kern S, Blennow Ket al. . Atrial fibrillation increases the risk of dementia amongst older adults even in the absence of stroke. J Intern Med 2019;286:101–10. [DOI] [PubMed] [Google Scholar]
  • 18. Kim D, Yang PS, Lip GYH, Joung B.. Atrial fibrillation increases the risk of early-onset dementia in the general population: data from a population-based cohort. J Clin Med 2020;9:3665–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Rusanen M, Kivipelto M, Levälahti E, Laatikainen T, Tuomilehto J, Soininen Het al. . Heart diseases and long-term risk of dementia and Alzheimer's disease: a population-based CAIDE study. J Alzheimers Dis 2014;42:183–91. [DOI] [PubMed] [Google Scholar]
  • 20. Ding M, Fratiglioni L, Johnell K, Santoni G, Fastbom J, Ljungman Pet al. . Atrial fibrillation, antithrombotic treatment, and cognitive aging: a population-based study. Neurology 2018;91:e1732–40. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. Chen LY, Norby FL, Gottesman RF, Mosley TH, Soliman EZ, Agarwal SKet al. . Association of atrial fibrillation with cognitive decline and dementia over 20 years: the ARIC-NCS (Atherosclerosis Risk in Communities Neurocognitive Study). J Am Heart Assoc 2018;7:e007301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Bailey MJ, Soliman EZ, McClure LA, Howard G, Howard VJ, Judd SEet al. . Relation of atrial fibrillation to cognitive decline (from the REasons for Geographic and Racial Differences in Stroke [REGARDS] Study). Am J Cardiol 2021;148:60–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Forti P, Maioli F, Pisacane N, Rietti E, Montesi F, Ravaglia G.. Atrial fibrillation and risk of dementia in non-demented elderly subjects with and without mild cognitive impairment (MCI). Arch Gerontol Geriatr 2007;44(Suppl 1):155–65. [DOI] [PubMed] [Google Scholar]
  • 24. Barba R, Martínez-Espinosa S, Rodríguez-García E, Pondal M, Vivancos J, Del Ser T.. Poststroke dementia: clinical features and risk factors. Stroke 2000;31:1494–501. [DOI] [PubMed] [Google Scholar]
  • 25. Altieri M, Di Piero V, Pasquini M, Gasparini M, Vanacore N, Vicenzini Eet al. . Delayed poststroke dementia: a 4-year follow-up study. Neurology 2004;62:2193–7. [DOI] [PubMed] [Google Scholar]
  • 26. Chander RJ, Lim L, Handa S, Hiu S, Choong A, Lin Xet al. . Atrial fibrillation is independently associated with cognitive impairment after ischemic stroke. J Alzheimers Dis 2017;60:867–75. [DOI] [PubMed] [Google Scholar]
  • 27. Inzitari D, Di Carlo A, Pracucci G, Lamassa M, Vanni P, Romanelli Met al. . Incidence and determinants of poststroke dementia as defined by an informant interview method in a hospital-based stroke registry. Stroke 1998;29:2087–93. [DOI] [PubMed] [Google Scholar]
  • 28. Zhou DH, Wang JY, Li J, Deng J, Gao C, Chen M.. Study on frequency and predictors of dementia after ischemic stroke: the Chongqing stroke study. J Neurol 2004;251:421–7. [DOI] [PubMed] [Google Scholar]
  • 29. Al Fawal B, Ibrahim A, Abd Elhamed M.. Post-stroke dementia: frequency, predictors, and health impact. Egyptian J Neurol Psychiatr Neurosurg 2021;57. [Google Scholar]
  • 30. Cacciatore F, Testa G, Langellotto A, Galizia G, Della-Morte D, Gargiulo Get al. . Role of ventricular rate response on dementia in cognitively impaired elderly subjects with atrial fibrillation: a 10-year study. Dement Geriatr Cogn Disord 2012;34:143–8. [DOI] [PubMed] [Google Scholar]
  • 31. Li J, Wang YJ, Zhang M, Xu ZQ, Gao CY, Fang CQet al. ; Chongqing Ageing Study Group . Vascular risk factors promote conversion from mild cognitive impairment to Alzheimer disease. Neurology 2011;76:1485–91. [DOI] [PubMed] [Google Scholar]
  • 32. Ravaglia G, Forti P, Maioli F, Martelli M, Servadei L, Brunetti Net al. . Conversion of mild cognitive impairment to dementia: predictive role of mild cognitive impairment subtypes and vascular risk factors. Dement Geriatr Cogn Disord 2006;21:51–8. [DOI] [PubMed] [Google Scholar]
  • 33. Chen LY, Lopez FL, Gottesman RF, Huxley RR, Agarwal SK, Loehr Let al. . Atrial fibrillation and cognitive decline–the role of subclinical cerebral infarcts: the ARIC study. Stroke 2014;45:2568–74. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34. Ezekowitz MD, James KE, Nazarian SM, Davenport J, Broderick JP, Gupta SRet al. . Silent cerebral infarction in patients with nonrheumatic atrial fibrillation. The Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. Circulation 1995;92:2178–82. [DOI] [PubMed] [Google Scholar]
  • 35. Graff-Radford J, Madhavan M, Vemuri P, Rabinstein AA, Cha RH, Mielke MMet al. . Atrial fibrillation, cognitive impairment, and neuroimaging. Alzheimers Dement 2016;12:391–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. Gaita F, Corsinovi L, Anselmino M, Raimondo C, Pianelli M, Toso Eet al. . Prevalence of silent cerebral ischemia in paroxysmal and persistent atrial fibrillation and correlation with cognitive function. J Am Coll Cardiol 2013;62:1990–7. [DOI] [PubMed] [Google Scholar]
  • 37. Kempster PA, Gerraty RP, Gates PC.. Asymptomatic cerebral infarction in patients with chronic atrial fibrillation. Stroke 1988;19:955–7. [DOI] [PubMed] [Google Scholar]
  • 38. Petersen P, Madsen EB, Brun B, Pedersen F, Gyldensted C, Boysen G.. Silent cerebral infarction in chronic atrial fibrillation. Stroke 1987;18:1098–100. [DOI] [PubMed] [Google Scholar]
  • 39. Wang Z, Van Veluw SJ, Wong A, Liu W, Shi L, Yang Jet al. . Risk factors and cognitive relevance of cortical cerebral microinfarcts in patients with ischemic stroke or transient ischemic attack. Stroke 2016;47:2450–5. [DOI] [PubMed] [Google Scholar]
  • 40. Das RR, Seshadri S, Beiser AS, Kelly-Hayes M, Au R, Himali JJet al. . Prevalence and correlates of silent cerebral infarcts in the Framingham offspring study. Stroke 2008;39:2929–35. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41. Guidotti M, Tadeo G, Zanasi S, Pellegrini G.. Silent cerebral ischemia in patients with chronic atrial fibrillation–a case-control study. Ir J Med Sci 1990;159:96–7. [DOI] [PubMed] [Google Scholar]
  • 42. Kim MH, Moon JS, Park SY, An SA, Kim OJ, Kim NKet al. . Different risk factor profiles between silent brain infarction and symptomatic lacunar infarction. Eur Neurol 2011;65:250–6. [DOI] [PubMed] [Google Scholar]
  • 43. Kobayashi A, Iguchi M, Shimizu S, Uchiyama S.. Silent cerebral infarcts and cerebral white matter lesions in patients with nonvalvular atrial fibrillation. J Stroke Cerebrovasc Dis 2012;21:310–7. [DOI] [PubMed] [Google Scholar]
  • 44. Marfella R, Sasso FC, Siniscalchi M, Cirillo M, Paolisso P, Sardu Cet al. . Brief episodes of silent atrial fibrillation predict clinical vascular brain disease in type 2 diabetic patients. J Am Coll Cardiol 2013;62:525–30. [DOI] [PubMed] [Google Scholar]
  • 45. Zito M, Muscari A, Marini E, Di Iorio A, Puddu GM, Abate G.. Silent lacunar infarcts in elderly patients with chronic non valvular atrial fibrillation. Aging (Milano) 1996;8:341–6. [DOI] [PubMed] [Google Scholar]
  • 46. Raiha I, Tarvonen S, Kurki T, Rajala T, Sourander L.. Relationship between vascular factors and white matter low attenuation of the brain. Acta Neurol Scand 1993;87:286–9. [DOI] [PubMed] [Google Scholar]
  • 47. de Leeuw FE, de Groot JC, Oudkerk M, Kors JA, Hofman A, van Gijn Jet al. . Atrial fibrillation and the risk of cerebral white matter lesions. Neurology 2000;54:1795–801. [DOI] [PubMed] [Google Scholar]
  • 48. Lazarus R, Prettyman R, Cherryman G.. White matter lesions on magnetic resonance imaging and their relationship with vascular risk factors in memory clinic attenders. Int J Geriatr Psychiatry 2005;20:274–9. [DOI] [PubMed] [Google Scholar]
  • 49. Piers RJ, Nishtala A, Preis SR, DeCarli C, Wolf PA, Benjamin EJet al. . Association between atrial fibrillation and volumetric magnetic resonance imaging brain measures: Framingham Offspring Study. Heart Rhythm 2016;13:2020–4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50. Stefansdottir H, Arnar DO, Aspelund T, Sigurdsson S, Jonsdottir MK, Hjaltason Het al. . Atrial fibrillation is associated with reduced brain volume and cognitive function independent of cerebral infarcts. Stroke 2013;44:1020–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51. Alonso A, Knopman DS, Gottesman RF, Soliman EZ, Shah AJ, O'Neal WTet al. . Correlates of dementia and mild cognitive impairment in patients with atrial fibrillation: the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). J Am Heart Assoc 2017;6:e006014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52. Zand R, Shahjouei S, Tsivgoulis G, Singh M, McCormack M, Noorbakhsh-Sabet Net al. . Cerebral microbleeds are associated with higher mortality among ischemic stroke patients. J Stroke Cerebrovasc Dis 2018;27:3036–42. [DOI] [PubMed] [Google Scholar]
  • 53. Alosco ML, Spitznagel MB, Sweet LH, Josephson R, Hughes J, Gunstad J.. Atrial fibrillation exacerbates cognitive dysfunction and cerebral perfusion in heart failure. Pacing Clin Electrophysiol 2015;38:178–86. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54. Lavy S, Stern S, Melamed E, Cooper G, Keren A, Levy P.. Effect of chronic atrial fibrillation on regional cerebral blood flow. Stroke 1980;11:35–8. [DOI] [PubMed] [Google Scholar]
  • 55. Horstmann S, Mohlenbruch M, Wegele C, Rizos T, Laible M, Rauch Get al. . Prevalence of atrial fibrillation and association of previous antithrombotic treatment in patients with cerebral microbleeds. Eur J Neurol 2015;22:1355–62. [DOI] [PubMed] [Google Scholar]
  • 56. Heo SH, Lee D, Kwon YC, Kim BJ, Lee KM, Bushnell CDet al. . Cerebral microbleeds in the patients with acute stroke symptoms. Front Neurol 2018;9:988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57. Ovbiagele B, Saver JL, Sanossian N, Salamon N, Villablanca P, Alger JRet al. . Predictors of cerebral microbleeds in acute ischemic stroke and TIA patients. Cerebrovasc Dis 2006;22:378–83. [DOI] [PubMed] [Google Scholar]
  • 58. Saito T, Kawamura Y, Tanabe Y, Asanome A, Takahashi K, Sawada Jet al. . Cerebral microbleeds and asymptomatic cerebral infarctions in patients with atrial fibrillation. J Stroke Cerebrovasc Dis 2014;23:1616–22. [DOI] [PubMed] [Google Scholar]
  • 59. Yang K, Feng Y, Mu J, Fu N, Chen S, Fu Y.. The presence of previous cerebral microbleeds has a negative effect on hypertensive intracerebral hemorrhage recovery. Front Aging Neurosci 2017;9:49. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60. Soo Y, Abrigo J, Leung KT, Tsang SF, Ip V, Ma Ket al. . Stroke risk prediction with cortical microinfarcts in patients with atrial fibrillation. Eur Stroke J 2018;3:461–2. [Google Scholar]
  • 61. Thijs V, Lemmens R, Schoofs C, Görner A, Van Damme P, Schrooten Met al. . Microbleeds and the risk of recurrent stroke. Stroke 2010;41:2005–9. [DOI] [PubMed] [Google Scholar]
  • 62. Hert L, Polymeris AA, Schaedelin S, Lieb J, Seiffge DJ, Traenka Cet al. . Small vessel disease is associated with an unfavourable outcome in stroke patients on oral anticoagulation. Eur Stroke J 2020;5:63–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63. Wang J, Zhang J, Shen Y, Xu X.. The safety of antithrombotic therapy in patients with cerebral microbleeds and cardiogenic cerebral embolism due to nonvalvular atrial fibrillation. BMC Cardiovasc Disord 2019;19:77. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64. Wilson D, Ambler G, Shakeshaft C, Brown MM, Charidimou A, Al-Shahi Salman Ret al. ; CROMIS-2 collaborators . Cerebral microbleeds and intracranial haemorrhage risk in patients anticoagulated for atrial fibrillation after acute ischaemic stroke or transient ischaemic attack (CROMIS-2): a multicentre observational cohort study. Lancet Neurol 2018;17:539–47. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65. Andin U, Gustafson L, Passant U, Brun A.. A clinico-pathological study of heart and brain lesions in vascular dementia. Dement Geriatr Cogn Disord 2005;19:222–8. [DOI] [PubMed] [Google Scholar]
  • 66. Dublin S, Anderson ML, Heckbert SR, Hubbard RA, Sonnen JA, Crane PKet al. . Neuropathologic changes associated with atrial fibrillation in a population-based autopsy cohort. J Gerontol A Biol Sci Med Sci 2014;69:609–15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67. Erkinjuntti T, Haltia M, Palo J, Sulkava R, Paetau A.. Accuracy of the clinical diagnosis of vascular dementia: a prospective clinical and post-mortem neuropathological study. J Neurol Neurosurg Psychiatry 1988;51:1037–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68. Rastas S, Verkkoniemi A, Polvikoski T, Juva K, Niinisto L, Mattila Ket al. . Atrial fibrillation, stroke, and cognition: a longitudinal population-based study of people aged 85 and older. Stroke 2007;38:1454–60. [DOI] [PubMed] [Google Scholar]
  • 69. Ferro D, van den Brink H, Amier R, van Buchem M, de Bresser J, Bron Eet al. ; Heart-Brain Connection Consortium . Cerebral cortical microinfarcts: a novel MRI marker of vascular brain injury in patients with heart failure. Int J Cardiol 2020;310:96–102. [DOI] [PubMed] [Google Scholar]
  • 70. Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne Ret al. ; STandards for ReportIng Vascular changes on nEuroimaging (STRIVE v1) . Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 2013;12:822–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71. Ott A, Breteler MM, de Bruyne MC, van Harskamp F, Grobbee DE, Hofman A.. Atrial fibrillation and dementia in a population-based study. The Rotterdam Study. Stroke 1997;28:316–21. [DOI] [PubMed] [Google Scholar]
  • 72. Barber M, Tait RC, Scott J, Rumley A, Lowe GD, Stott DJ.. Dementia in subjects with atrial fibrillation: hemostatic function and the role of anticoagulation. J Thromb Haemost 2004;2:1873–8. [DOI] [PubMed] [Google Scholar]
  • 73. Jacobs V, Woller SC, Stevens S, May HT, Bair TL, Anderson JLet al. . Time outside of therapeutic range in atrial fibrillation patients is associated with long-term risk of dementia. Heart Rhythm 2014;11:2206–13. [DOI] [PubMed] [Google Scholar]
  • 74. Bunch TJ, Crandall BG, Weiss JP, May HT, Bair TL, Osborn JSet al. . Patients treated with catheter ablation for atrial fibrillation have long-term rates of death, stroke, and dementia similar to patients without atrial fibrillation. J Cardiovasc Electrophysiol 2011;22:839–45. [DOI] [PubMed] [Google Scholar]
  • 75. Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM.. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 2003;348:1215–22. [DOI] [PubMed] [Google Scholar]
  • 76. Thacker EL, McKnight B, Psaty BM, Longstreth WT Jr, Sitlani CM, Dublin Set al. . Atrial fibrillation and cognitive decline. Neurology 2013;81:119–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77. Soo Y, Abrigo J, Leung KT, Liu W, Lam B, Tsang SFet al. . Correlation of non-vitamin K antagonist oral anticoagulant exposure and cerebral microbleeds in Chinese patients with atrial fibrillation. J Neurol Neurosurg Psychiatry 2018;89:680–6. [DOI] [PubMed] [Google Scholar]
  • 78. Islam MM, Poly TN, Walther BA, Yang HC, Wu CC, Lin MCet al. . Association between atrial fibrillation and dementia: a meta-analysis. Front Aging Neurosci 2019;11:305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79. Kalantarian S, Stern TA, Mansour M, Ruskin JN.. Cognitive impairment associated with atrial fibrillation: a meta-analysis. Ann Intern Med 2013;158:338–46. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

euac003_Supplementary_Data
Click here for additional data file. (5.9MB, docx)

Data Availability Statement

Data are available on request to the corresponding author.

Articles from Europace are provided here courtesy of Oxford University Press

RESOURCES