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Available online at www.sciencedirect.com

www.elsevier.com/locate/tcm

Atrial fibrillation and dementia Victoria Jacobs, Michael J. Cutler, John D. Day, and T. Jared Bunchn Intermountain Heart Institute, Intermountain Medical Center, Murray, UT

abstract Emerging evidence has shown a consistent association between AF and risk of dementia, including Alzheimer's disease. It is likely that a constellation of various mechanisms combine to cause dementia in AF patients. Both AF and dementia share multiple common risk factors, and as such these may be targets of early prevention strategies to reduce risk. In patients with AF, choices regarding type and duration of anticoagulation as well as rhythm- and rate-control strategies can influence dementia risk. & 2015 Elsevier Inc. All rights reserved.

Atrial fibrillation Atrial fibrillation (AF) is an emerging disease epidemic and is currently affecting approximately 2.3 million people in the United States. This rhythm disorder is predicted to extend its reach to 5.6 million people in the United States by the year 2050 due to the “Baby Boom” (people born between 1946 and 1964) population reaching 85 years and older [1]. Factors that often drive progression of AF are related to age and coexistent cardiovascular disease state. All forms of AF, including paroxysmal AF, can negatively alter left atrial size, substrate, and function. These changes are often characterized by dilatation and contractile dysfunction, which develop very early after arrhythmia diagnosis, and can significantly impact response to therapeutic interventions [2]. These maladaptive changes over time often increase arrhythmia burden and severity and may be responsible for the morbidity and mortality associated with the disease state. They can also specifically impact contractile function of the atrium of left atrial appendage and as a consequence increase risk of macro- and micro-cerebral ischemic events.

abilities. Alzheimer's disease is the most common form of dementia in the United States, accounting for 60–80% of dementia occurrences, while 10–20% are attributable to vascular dementia [3]. Alzheimer's disease afflicts 5.4 million in the United States, with the vast majority of these people being 65 years and older [4]. Similar to AF, the dementia burden is increasing as the “Baby Boom” generation reaches the ages of 65 and older. The number of people affected by Alzheimer's dementia is projected to triple by the year 2050 in the United States [4]. Despite general declines in stroke and cardiovascular mortality and morbidity, the prevalence of dementia has remained relatively stable. The decline in stroke and cardiovascular mortality has been attributed to early recognition, smoking reduction, and early and/or more aggressive treatment of diabetes, hypertension, and dyslipidemia [5]. The lack of simultaneous impact on dementia, despite lower rates of stroke and vascular disease that were felt to increase risk of dementia, suggest that we need to think broadly about risk factors and expand research into novel strategies for disease prevention and treatment.

Dementia

Atrial fibrillation and dementia

Dementia is a condition describing a constellation of symptoms that cause alterations in memory, social functions, and cognitive

There is significant evidence that confirms the association between AF and dementia, including idiopathic or Alzheimer's

Victoria Jacobs, Michael J. Cutler, and John D. Day have nothing to disclose. Thomas Jared Bunch is a minor consultant and is in the advisory board of Boston Scientific. n Correspondence to: Eccles Outpatient Care Center, 5169 Cottonwood St, Suite 510, Murray, UT 84107. Tel.: þ1 801 507 3513; fax: þ1 801 507 3584. E-mail address: [email protected] (T.J. Bunch). http://dx.doi.org/10.1016/j.tcm.2014.09.002 1050-1738/& 2015 Elsevier Inc. All rights reserved.

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dementia (Table). Our group has explored the relationship between AF and dementia in a study of 37,025 patients from the Intermountain Heart Collaborative Study [3]. We included patients with no history of dementia and at least 5 years of follow-up data. Given the large nature of this study, we used ICD9 codes to define dementia. To minimize risk of misclassification, we used ICD-9 codes that were entered by neurology only. Our results showed that AF contributed to the development of all types of dementia. The prevalence of both diseases advances with increasing age and predisposes patients to a rise in the incidence of mortality. Interestingly, in our study the younger group studied (patients o70 years) had the highest relative risk of developing Alzheimer's dementia (odd ratio ¼ 2.30, p ¼ 0.001). This highest relative risk of dementia in the younger AF patients suggests that the association is more than an epiphenomena stemming from disease states that share advancing age as a common risk. However, the Table does highlight some inherent challenges in these types of studies. They are observational and look at dementia that has broad manifestations in presentation and progression. Those with serial cognitive testing are going to be more accurate than those that rely on other methods for dementia diagnosis. Those that are not designed upfront to look at the influence of AF on cognition will have accuracy limitations in diagnosis and understanding of the arrhythmia and the influence of arrhythmia treatment on outcomes. Each disease state shares many common risk factors with the other, many of which are potentially modifiable if disease-based preventative lifestyle changes are started early in life (Fig. 1). Although a common thought is that AF resulted in cognition

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impairment due to stroke, all forms of dementia, including idiopathic variants, are increased in AF patients (Table). The association between AF and dementia is complex. Both disease states share many common risk factors (Fig. 1), and understanding these risk factors may provide clues into the key mechanisms of both disease states. More importantly, many of the shared risk factors are modifiable, and if early preventative lifestyle changes are adopted, the disease states may be avoided altogether. However, given the complexity and variability of both disease states, it is likely that multiple potential mechanisms underlie the association between AF and dementia. Understanding the mechanisms of disease association and then discovering avenues to reduce risk are paramount. In patients with AF, there is also a significant association between dementia onset and total mortality [3]. In our prior study, we found that in patients with AF that develop dementia of any subtype, mortality is significantly increased (HR ¼ 1.46–2.14). Similar to the general association data, the greatest risk of death in those patients with AF and dementia was found in the youngest cohort studied (o70 years, HR across multiple subtypes ¼ 1.55–2.07).

Potential mechanisms underlying dementia in AF patients Repetitive injury from microemboli and/or microbleeds One of the most feared complications of AF is disabling stroke. The majority of strokes in patients with AF are

Table – Longitudinal studies that examine the association of incident dementia and atrial fibrillation. References

Population

Follow-up

Dementia diagnosis

Dementia risk

Rusanen et al. [33]

4 Populations 4midlife n ¼ 1510 Mean age ¼ 67 n ¼ 31,506

425 Years

TD: HR ¼ 2.61 (95% CI: 1.01–6.47) Increased risk if APOE positive

Median age ¼ 74

6.8 Years (mean)

Mini-Mental Status Exam Self-Administered Questionnaire Mini-Mental Status Exam Independent living Assessment Cognitive Abilities Screening Instrument Neuropsychological and clinical assessment ICD-9 Codes entered by neurologists Cognitive test battery Clinical Examination Mini-Mental Status Exam Clinical Examination if MMSE abnormal Mini-Mental Status Exam Clinical Dementia Rating Medical history Mini-Mental Status Exam Clinical Dementia Rating

Marzona et al. [34]

Dublin et al. [35]

56 Months (mean)

n ¼ 3045 Bunch et al. [3] Marengoni (2011) [36] Peters et al. [37]

Mean age ¼ 61 n ¼ 37,025 478 Years n ¼ 685 Mean age ¼ 84 n ¼ 3336

5 Years 4.0 Years (mean) 2.2 Years (mean)

Rastas et al. [38]

Mean age ¼ 88 n ¼ 553

3.5 Years (mean)

Tilvis et al. [39]

Mean age ¼ 80 n ¼ 650

1, 5, and 10 Years

Piguet et al. [40]

Mean age ¼ 81 n ¼ 377

6 Years

Clinical and Neuropsychological Examinations

TD, total dementia; AD, alzheimer dementia; HR, hazard ratio; OR, odds ratio.

TD: HR ¼ 1.30 (95% CI: 1.14–1.49)

TD: HR ¼ 1.38 (95% CI: 1.10–1.73) AD: HR ¼ 1.50 (95% CI: 1.16–1.94) TD: HR ¼ 1.44 (95% CI: 1.23–1.69) AD: HR ¼ 1.06 (95% CI: 0.85–1.33) TD: HR ¼ 0.9 (95% CI: 0.5–1.7) AD: HR ¼ 0.8 (95% CI: 0.4–1.5) TD: HR ¼ 1.03 (95% CI: 0.62–1.72)

TD: 16.4% (AF) vs. 18.6% (no AF)

TD: HR ¼ 2.9 (95% CI: 1.3–6.1) Association only at 5-year followup TD: 35% (AF) vs. 30% (no AF) AD: 13% (AF) vs. 11% (no AF)

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Fig. 1 – The figure displays common risk factors for both atrial fibrillation and dementia. Outside of aging and genetic/ inherited variables, the majority of them are potentially modifiable with early lifestyle changes and disease management.

macroembolic, originating from the left atrial appendage. The presence of multiple strokes in itself can cause dementia. Patients with AF tend to have larger strokes at older ages and as a consequence are at particular risk for cognitive decline that is associated with significant functional deficit and dependency [6]. Although this mechanism helps shed light on the association of AF and multi-infarct dementia, it does not explain the consistent association with idiopathic dementia in which prior stroke(s) are excluded. However, it is possible that the dementia association with AF is a spectrum related to repetitive cerebral injuries that stem from macro-events (multi-infarct dementia) to micro-events (idiopathic dementia with chronic volume loss) (Fig. 2). An autopsy study of 84 patients with Alzheimer's dementia provided evidence in support of this mechanism. The authors found that cerebral microvascular injury was a common root mechanism that stemmed from cerebral atherosclerosis, silent previously undetected lacunar infarcts, and microemboli [7]. Small repetitive vascular injuries are felt to be a common cause of white matter lesions. Cerebral white matter lesions in patients with AF are associated with cognitive impairment [8]. As the brain ages, many of its small vessels become diseased and consequently become predisposed to cerebral microbleeds, especially in the presence of anticoagulation. Microbleeds have also been correlated with hippocampal atrophy and as such may result in volume loss from repetitive injury [9]. Mechanistically, it is plausible that the microbleeds may increase risk of dementia in anticoagulated AF patients, particularly in cognitive domains involving memory. The hippocampus is the most vulnerable area of the brain to develop microbleeds, and damage to this area is also not uncommon in patients with Alzheimer's disease, hypertension, and AF [10].

Confounding the understanding of the role of anticoagulation in AF patients and risk of dementia is that cognitive decline negatively influences safety of anticoagulation. For example, in the “Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events” (ACTIVE-W) trial, 50% of patients had a time in therapeutic rate o65% [11]. Within this trial, those with baseline dementia or those that had lower mini-mental status evaluation scores were more likely to have low percentage times in therapeutic range. In this sense, dementia and anticoagulation for AF become another self-perpetuating problem. In an aging population, the acquisition of additional cardiovascular disease states, frequent drug–drug interactions, and impaired metabolism and clearance pathways make long-term anticoagulation in general challenging. Even novel anticoagulants are not immune, as all require some degree of renal clearance for safety. As such, it is not surprising that higher CHADS2 scores indicate increased risk of both strokes and bleeds [12]. In a similar age- and disease-based pattern, microbleeds also increase over time from a prevalence of 6.5% in individuals 45–50 years of age to 35.7% in those 480 years of age [13]. We sought to understand the role of anticoagulation on long-term risk of dementia in AF patients with no history of dementia. If the above mechanisms increase risk of dementia in AF patients, then patients with poor time in therapeutic range should display an increased risk. We studied 2693 patients that were started on warfarin anticoagulation by the Intermountain Healthcare Clinical Pharmacist Anticoagulation Service (CPAS) trial for atrial fibrillation. The average percentage time in therapeutic range was 62.7 7 22.9%. Longterm dementia outcomes were compared by quartiles. After multivariate adjustment for all baseline demographic risk factors for stroke or bleed, decreasing categories of

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Fig. 2 – Shown are 3 separate cranial images with mechanisms that impact cognition. (A) Diffusion-weighted axial MR images of a patient that developed a large stroke after a cardioversion. A large ischemic injury is noted in the left posterior parietal lobe (yellow arrow). A second injury is also noted on the left (yellow area) consistent with multiple emboli. (B) Axial MR image of a patient with cognitive decline. The ventricles and cortical sulci demonstrate generalized atrophy and resultant enlargement in cerebral spinal fluid spaces (white arrows). Periventricular T2 hyperintensity consistent with white matter disease (yellow arrows). (C) Noncontrast CT scan of an AF patient on warfarin who fell striking her head. Black arrows highlight a subdural hematoma. The yellow arrow highlights intraparenchymal hemorrhage.

percentage TTR were associated with increased dementia risk (vs. 475%; o25%: HR ¼ 4.58, p o 0.0001; 26–50%: HR ¼ 4.14, p o 0.0001; and 51–75%: HR ¼ 2.52, p o 0.001) [14]. Additional insight was obtained in looking at those patients that were consistently over- vs. under- anticoagulated. In both groups, there was a similar increased risk of dementia in support of both microbleeds as well as microemboli as mechanisms.

Microvascular disease manifest by variability in pulse and cerebral vascular perfusion The initial patient that prompted our study into the association of dementia and AF could not be fully explained by repetitive cerebral injury from microbleeds or clots. This patient would speak freely while in sinus rhythm. When his rhythm would change to atrial fibrillation, he would abruptly lose his thought process and look to his wife to complete his sentence. Shortly thereafter, he would say he had a “senior

moment.” The process would repeat each time he transitioned between sinus rhythm and atrial fibrillation. One of the interesting aspects of the previously mentioned autopsy study in 84 patients with Alzheimer's disease was the location of the cerebral vascular disease [7]. The most common form of cerebral vascular atherosclerosis in these patients was found in the Circle of Willis followed by diffuse disease in general. The Circle of Willis is critical for cerebral perfusion, as it creates a means of redundancies and collaterals that provide generalized blood flow throughout the brain even if more proximal atherosclerosis develops. As such, it is likely that people with Circle of Willis atherosclerotic disease, when exposed to beat-by-beat alterations in blood flow during AF (Fig. 3), will not have the same reserve to distribute cerebral blood flow globally compared to those without this type of vascular disease. This type of a mechanism for cognitive decline would explain a patient with abrupt cognitive dysfunction after onset of AF. Hypoperfusion of the brain in patients with AF has also been theorized to be at the core of leukoaraiosis or white matter changes, and the

Fig. 3 – The figure shows the femoral arterial pulse variance in atrial fibrillation (left) compared to sinus rhythm (right) after a spontaneous conversion to sinus rhythm.

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resulting impairment of the flowing blood's ability to remove microemboli from the vessels, which results in embolic infarctions [15]. In a study of 17 patients with persistent medically refractive AF, regional blood flow was examined with brain singlephoton emission computed tomography scanning with comparison to control patients in sinus rhythm. Additional comprehensive neuropsychological testing was performed before and after 3 months following pacemaker implantation and AV node ablation. Patients with AF had significantly lower brain perfusion in all regions compared to control patients. The largest deficits in perfusion were found in the inferior frontal and posterior parietal regions. Cognitive dysfunction was directly proportional to the degree of regional brain perfusion deficit. After AV node ablation, brain perfusion increased in all patients (Fig. 4) to a level statistically identical to controls, and the patients had an immediate and sustained improvement in memory and cognition [16]. In a pooled analysis of long-term AV node ablation studies, there is marked heterogeneity in quality-of-life assessment and scores [17]. In general, symptoms improve after AV node ablation. The inferences that we can gather from these studies in aggregate on the effect of AV node ablation on long-term cognition and dementia risk are modest, given that these were not direct study aims. If variance in R–R interval explains some of the association between AF and dementia, then other disease states that also result in frequent variance in R–R intervals may also impact cognition. We examined the outcomes of 11,723 patients with no history of AF or dementia that underwent 24-h ambulatory monitoring. We quantified dementia risk by percentage ectopy (either premature atrial or ventricular contractions). The dementia risk increased significantly with increased burden of ectopy (r5%: 0.2%; 45% to o25%: 0.9%; and Z25%: 1.3%, p o 0.0001; unpublished data). The data from

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the study by Efimova et al. [16], our index patient, and the ectopy burden all suggest that frequent variance in R–R intervals and cerebral perfusion patterns may explain in part the association of AF and dementia. The data from Efimova et al. [16] suggest that normalizing the R–R intervals and treatment approach can impact risk and improve function.

Atrial fibrillation and dementia are both symptoms of hypertensive vascular disease AF is often the result of hypertensive heart disease that progressively impacts diastolic filling patterns and results in the elevation of end-diastolic pressures and left atrial enlargement. In a recent study involving 30,424 ONTARGET/ TRANSCEND patients over a median follow-up of 4.7 years, hypertension increased risk of new-onset AF by 34%, which then drove the risk of new-onset heart failure, stroke, and death despite contemporary medical therapies [18]. In addition, hypertension increases risk of stroke independent of AF and all of covariates of the CHADS2 risk profile and the combined disease state of AF and hypertension further increases risk [3]. One possibility to explain the association of AF and dementia is that both are the end-stage symptoms of the systemic disease process of hypertension that gradually increases vascular stiffness and impairs end-organ microvascular function. If this is the case, then gradual cognition defects may manifest slowly over time in hypertensive patients with the accumulative burden of these defects resulting in dementia. In a recent study of 3381 patients (aged 18–30 years at study beginning), followed up for 25 years, the impact of development of early hypertension on long-term cognition was evaluated. The accumulative burden of both elevated systolic and diastolic hypertension was an independent

Fig. 4 – The figure shows some of the regional blood flow analysis performed by Efimova et al. [16]. Patients in atrial fibrillation (AF) compared to sinus rhythm (SR) had lower relative regional blood flow. At 3 months after pacemaker implantation and AV node ablation, there was no significant difference in the regional flow patterns in the AF patients compared to the SR patients.

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predictor of declining midlife cognitive performance. Cognitive performance further worsened if the hypertension started in early adulthood (o25 years of age) or if other cardiovascular risk factors or diseases developed [19]. Patients that had blood pressure, lipid, and fasting sugars within American Heart Association guidelines had lower rates of cognitive loss. These latter findings suggest that if treatment is started early enough that dementia risk can be reduced or the disease prevented. Unfortunately, early treatment is essential in the disease process before irreversible changes develop. This point was demonstrated in a recent trial of aggressive blood pressure management and lipid lowering in a cohort of patients with type 2 diabetes. In this study, 2977 patients without baseline cognitive impairment or dementia were randomized to aggressive blood pressure treatment (o120 mmHg vs. o140 mmHg) and to a fibrate to achieve cholesterol levels o5.56 mmol/L. After 40 months, neither intensive blood pressure control nor lipid lowering improved cognitive function. In addition, total brain volume was lower in the intensive blood pressure control group [20]. These findings almost parallel a study looking specifically at aggressive glycemic control to improve cognitive function and brain volume in type 2 diabetics. In this trial, brain volume was better with aggressive glycemic control, but cognition was not influenced [21].

Perpetuation of an inflammatory state It has been proposed that AF triggers and maintains an inflammatory state, resulting in a perpetuation of arrhythmia and concomitant worsening inflammation. In a recent study of C-reactive protein (hs-CRP) among patients with AF, it was determined that the average hs-CRP level was higher in patients with AF compared to those without it [22]. Simultaneously, other inflammatory markers such as prothrombin and interlukin-6 are increased simply by the presence of AF [22]. This promotes additional inflammation and hypercoagulation, predisposing to the formation of thrombi and potentially augmenting risk of stroke and dementia [22]. Multiple inflammatory markers are also independently associated with risk of cognitive dysfunction, Alzheimer's disease, and dementia in general [23].

Shared genetic risk factors Although many of the combined risk factors for AF and dementia have a genetic basis for risk, little is known about which markers may predict risk of dementia in patients with AF. These genetic markers may help explain the paradoxical higher relative risk of idiopathic dementia in the younger cohorts of AF patients. The presence of apolipoprotein E-epsilon 4 allele (ApoE-ε4) exists in approximately 25% of the global population and predisposes those people to an increased risk of early Alzheimer's dementia as well unfavorable disease progression. Moreover, the ApoE-ɛ4 allele has also been shown to predispose patients to a lesser degree of improvement after delirium, contributing to inferior neurological outcomes after traumatic brain injuries as well as poorer outcome results

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following a cerebral hemorrhage [24]. As such, it is possible that the presence of ApoE-ɛ4 allele negatively impacts the brains ability to adapt to injury or stress. If this is the case, then this allele may be associated with dementia risk in patients that develop cerebral vascular stress due to AF. Recently, we found an independent association between the carriage ApoE-ε4 allele and dementia (OR ¼ 1.82; p ¼ 0.017) in a study of 132 AF patients that developed idiopathic dementia [25].

Treatment options may impact dementia risk Previously discussed were the need for very early risk factor modification, particularly high blood pressure and those disease states that are common risk factors for both AF and dementia. Next, many of the disease states that increase risk of adverse outcomes in patients with AF are those that drive risk of the arrhythmia as well. Patients at highest risk for stroke are also those that are at highest risk to develop AF and may benefit from continuous monitoring [26]. Next, anticoagulant therapy must be carefully used. In patients that have low percentage time in therapeutic range, use of a novel agent may be preferable. Also, the use and choice of an anticoagulant must be a dynamic process over time as patients' risks for both stroke and bleed often evolve. Finally, rate and rhythm-control options that minimize R–R and cerebral perfusion variability should be considered. Along these lines, it is likely preferable with rate-control approaches to use more liberal thresholds that minimize long R–R intervals associated with low heart rates. Unfortunately, there are no prospective trials that examine the impact of specific rate-control options or approaches and long-term cognition. Similarly, there are no long-term antiarrhythmic drug trials that examine cognition. Inferences of cognition can be gathered from quality-of-life analysis, but clearly these are not adequate to diagnosis dementia or dementia progression. We recently reported in an abstract that rate-control approach influences dementia in patients with chronic AF. In this study, those patients with lower average heart rates (o75 bpm) on continuous ambulatory monitoring had higher rates of dementia compared to those with higher rates [27]. This study included patients in whom lower heart rates were achieved through rate-control agents and those that were auto-rate controlled. The trial did not provide information on type of rate control and cognitive effects, but it did give insight into the potential need for adequate heart rate to allow cerebral perfusion. Our group has shown that patients undergoing radiofrequency catheter ablation and the long-term clinical treatment to support the ablation for the prevention of AF exhibit a lower risk of stroke regardless of their baseline CHADS2 score [28]. In addition, in low-risk patients with a CHADS2 0-1 managed long-term with aspirin only had very low risk of cerebral ischemic events [29]. In fact, in this analysis of lowrisk patients, all stroke events occurred in those managed with warfarin anticoagulation. These data in aggregate suggest that stroke risk may be favorably modified after ablation or part of the natural disease course of AF altered.

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If ablation is associated with a lower risk of macroembolic events and potentially allows anticoagulants to be discontinued in lower-risk patients, then it may reduce dementia. We studied the long-term outcomes of 4212 consecutive patients who underwent AF ablation that were compared (1:4) to 16,848 age-/gender-matched controls with AF (no ablation) and 16,848 age-/gender-matched controls without AF with at least 3 years of follow-up. AF ablation patients had a lower risk of death and stroke in comparison to AF patients without ablation and similar to patients with no history of AF. Alzheimer's dementia developed in 0.2% of the AF ablation patients vs. 0.9% of the AF no-ablation patients compared to 0.5% of the no AF patients (p o 0.0001). Other forms of dementia were also reduced significantly in those treated with ablation with long-term rates similar to patients without AF [30]. Again, the comparable outcomes in the AF ablation and no AF groups suggest that disease course may be modified with therapeutic approaches. Clearly, our registry data call for cognitive performance testing to be included in prospective randomized trials of catheter ablation. Cognition is an anticipated long-term endpoint being collected in the ongoing CABANA trial. From a cerebral function standpoint, catheter ablation is not without potential risks. Asymptomatic lesions noted on MRI after ablation occur in 10–25% of patients, with occurrence variance somewhat explained by anticoagulation technique and ablation technology. The long-term consequences of these small lesions are largely unknown. After the catheter ablation these injuries may be associated with early cognitive dysfunction notable up to 90 days post-ablation [31]. Fortunately, in one study that included additional MRI studies up to 1 year, the majority of these lesions heal without apparent scarring [32]. Resolution of the lesions and their effects may underlie why we observed lower rates of dementia in our large AF ablation registry. However, it may be that the peri-procedural risks are offset by the long-term improvement in rhythm and rate and lower long-term exposure to anticoagulants and antiarrhythmic and other drugs that impact anticoagulant drug efficacy and safety. Finally, it may be that we select healthier patients that are less like to develop dementia, and in a prospective trial with frequent neurocognitive testing, long-term subtle cognitive deficits may be discovered that do not rise to the level of dementia. A concluding comment regarding ablation is that most trials report 1- and 5-year outcomes. For there to be a durable favorable effect on cognition, there needs to be a durable treatment for AF. In the absence of very long-term data, decisions regarding the use of long-term anticoagulation to reduce stroke risk are based upon pre-ablation demographicbased risk scores. There clearly is a need to perform a study with continuous long-term monitoring to determine if this additional knowledge of the absence of or a very low burden of AF can be used to discontinue anticoagulation in moderate-risk patients safely with no additional risk of cerebral ischemic events at longer than 5 years. Without this information, this subset of AF patients post-ablation remains challenging to manage longterm as their risks evolve. With evolving data regarding the long-term risks of anticoagulation on cognition and significant bleeds with aging in patients that develop comorbid diseases,

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such as renal dysfunction, long-term data to justify permanent anticoagulation are needed.

Conclusion Increasing evidence has demonstrated that AF is associated with a higher risk of dementia. It is likely that a constellation of various mechanisms combine to cause dementia in AF patients. AF and dementia are diseases that affect patients of increased age; however, the arrhythmia paradoxically results in the highest relative risk in younger patients. Microemboli, microbleeds, cerebral perfusion defects in the setting of cerebral vascular disease, and unmasked cerebral microvascular disease are some of the potential mechanisms in which AF increases dementia risk. AF and dementia share multiple common risk factors and as such these may be targets to prevent both diseases. However, any preventative strategies must be started very early in adulthood to maintain cognitive function and preserve brain volume. In patients with AF, choices regarding type and duration of anticoagulation as well as rhythm- and rate-control strategies can influence dementia risk.

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