The Atrial Fibrillation-Dementia Connection: Current Knowledge and Future Directions
Scroll to the end of the article to see video commentary by author Linda Moulton, RN, MS!
The presence of atrial fibrillation (AF) has been associated with a higher risk of developing Alzheimers disease (AD) and all forms of dementia.1-4 The risk of dementia in AF has been found to be 34%-40% higher than for those without AF.5-6 This is true independent of the presence of stroke.7 The relationship is also seen to be stronger for those who develop AF at an earlier age, and therefore, have AF for a longer duration.7-10
The following will review the risk factors for cardiovascular disease (CVD) and mental decline, the proposed mechanisms or causes for this relationship, proposed treatments/preventive measures, and possible screening measures to detect mental decline in AF patients, with the goal of acting earlier to slow or stop the progression of both diagnoses.
Risk Factors for AF and Dementia
There are various risk factors for coronary artery disease that are also seen as risks for dementia.11 Hypertension is often seen with AF. One theory on why this is true is the belief that hypertension is often undertreated.1 Wiseman et al12 found that older individuals with moderate hypertension who are nonimpaired have associated smaller whole brain volumes and an increased burden of subcortical and periventricular white matter hyperintensities (WMH). Diabetes mellitus is an independent risk factor for AF.13,14 Diabetes is linked to reduced total brain and gray matter volumes.15 Smoking leads to increased AF susceptibility due to reduced oxygen-carrying capacity, promotion of coronary vasoconstriction, and the acceleration of atherosclerosis.16
Obstructive sleep apnea (OSA) is also a factor. Mehra et al17 found that those with sleep-disordered breathing had 2-4 higher odds of having complex arrhythmias. This is of importance due to the risk for ventricular tachycardia and sudden cardiac death. OSA is also associated with hypertension, diabetes, congestive heart failure, and myocardial infarction. One-third of those with AF have OSA. Leuenberger et al18 proposed a mechanism for the role of OSA, noting that surges of sympathetic activity induced by hypoxia and the chemoreflex, near the end of an apneic episode, lead to transient blood pressure rises.
Additional cofactors include obesity, increased age, prior stroke, large and small vessel disease, and alcoholism. Other possible factors receiving more attention are inflammation, chronic kidney disease, and thyroid function.
Proposed Mechanisms
Identifying the exact cause of dementia in the AF patient is a complex subject. Many of the findings seen in AF patients are now known due to use of magnetic resonance imaging (MRI). The following includes many of the changes that have been found or proposed.
Cerebral small vessel disease has been related to cognitive decline, vascular dementia, and stroke. The primary causes of this small vessel disease are thought to be cerebral amyloid angiopathy, microemboli, and hypoperfusion.19 Cerebral amyloid angiopathy is theorized to occur because the reduced cardiac blood flow due to AF can lead to hypoxia and may impair clearance of amyloid-β (Aβ) peptides. This causes cerebral amyloid angiopathy and the onset of AD.20 Proteins of Aβ, thrombin, and fibrin are seen as key drivers in triggering vascular changes and the neurodegenerative changes seen in AD.21
Cerebral microemboli cause microinfarcts or small ischemic lesions. These lesions cause disruptions to structural brain connections. Some individuals have hundreds to thousands of these emboli.19 The microinfarcts lead to brain atrophy.22 WMH have been associated with chronic cerebral microinfarcts and small vessel disease.23 Increased WMH volume can lead to a decline in executive function, sensorimotor function, and mobility.24 Song et al25 reported that an increased number of cerebral microbleeds leads to higher CHA2DS2-VASc scores.
Cerebral hypoperfusion or reduced cerebral blood flow can occur due to beat-to-beat variation in stroke volume. This can result in a reduction in gray and white matter volume, and especially gray matter, which has a higher metabolic demand.22 Jefferson et al found that cardiac index (CI) was associated with brain volume and proposed that reductions in CI and CI in the low end of normal range may be implicated in accelerating age-related changes in the brain.26 They also found a stronger relationship for those <60 years (true even in absence of CVD).27 Reduced cerebral perfusion was proposed as the mechanism for the changes.
Silent brain infarcts, transient ischemic attacks (TIAs), and strokes also play a role. Lobar microbleeds are associated with a decline in executive functions, information processing, and memory function. Microbleeds in other brain regions are associated with a decline in information processing and motor speed.28 Using MRI, Gaita et al29 found that paroxysmal and persistent AF patients had a higher prevalence and number of areas of silent cerebral ischemia than controls and worse cognitive performance. Those with persistent AF were worse than paroxysmal AF. Visual-spatial ability was also worse with persistent AF; visual-spatial ability is a function of the frontal subcortical circuit.
Brain atrophy has also been found in AF patients. Knecht et al30 reported that in patients with AF and no stroke history, there was a trend toward worse performance in learning and memory tasks in chronic/persistent vs paroxysmal AF patients. Hippocampal volumes were also reduced. In another MRI study of 4251 patients without dementia, of the 330 who were diagnosed with AF, lower brain volumes were seen with a significantly stronger relationship for this in persistent/permanent AF, and with increased time from first diagnosis.22 There was a lower volume of gray and white matter, but not more WMHs. AF patients also scored lower on memory tests. These results were not related to current warfarin therapy or cerebral infarcts.22
Both AF and dementia can be caused by vascular inflammation. Inflammation plays a role in the genesis and perpetuation of AF and contributes to hypercoagulability, the development of thrombus, and an increasing risk of strokes. The inflammatory markers C-reactive protein (CRP) and IL-6 are elevated with AF and dementia.31,32 In a meta-analysis, Jia et al33 found that when increased levels of IL-6 were present, there was a significant association with stroke and all-cause mortality in patients with AF. IL-6 is a circulatory cytokine produced by monocytes, T lymphatics, and epithelial cells. IL-6 increases platelet production and platelet sensitivity to thrombin, stimulates transcription of fibrinogen, and is linked to endothelial cell activation and damage.34 Aryal35 proposed that the flow disturbances caused by AF lead to a disruption of the blood-brain barrier, thus making the brain more vulnerable and leading to dementia. This disruption could be causing activation of inflammatory immune cells and lead to neuronal injury.
A recent study from Switzerland reported on baseline cerebral infarcts found at study enrollment and subsequent findings over 2 years of prospective data collection.36 In this study of 1227 participants with AF, 235 (19.2%) had a history of stroke or TIA. At 2-year follow-up, there were 10 new overt infarcts and 58 silent infarcts. Cognitive assessment of these patients compared to baseline testing found a decline with most infarct patients. Lesions included small noncortical infarcts and large noncortical or cortical infarcts. There was a decrease in efficiency of cognitive operations; semantic memory, language production, and mental flexibility decreased. Macroembolic and microembolic events both seem to have an impact on cognition.
Treatment/Prevention Approaches
Treatment of cardiac and vascular risk factors may help to slow or prevent some dementia. Treatment with anticoagulants, statins, ablation, rhythm control, and lifestyle modifications will be discussed.
Anticoagulants
The use of anticoagulants with AF has been shown to decrease the risk of dementia, especially if started within 1 year of initial diagnosis.37-39 However, with the use of warfarin, there is difficulty keeping the drug at a therapeutic level. Those with lower time in therapeutic range (TTR) percentages have a higher incidence of dementia or lower cognition. Also, the longer period on warfarin, the more likely cognition is reduced, probably owing to periods of underanticoagulation and times of overanticoagulation when bleeding occurs.40
Many have proposed that the use of direct oral anticoagulants (DOACs) may be an improvement due to the steadier anticoagulation levels that can be obtained. Cadogan et al41 reviewed medical records of 39,200 first-time oral anticoagulant users from 2012-2018 (53% warfarin, 47% DOACs). Those on DOACs for AF were less likely to be diagnosed with dementia and mild cognitive impairment than those on warfarin (16% reduction rate). This result was supported by other database studies and a meta-analysis.42-44 The combination of DOACs and sinus rhythm maintenance has also been suggested as a way to reduce cognitive decline.37,44
Reflecting the results of much of this research, European AF guidelines from 2020 recommended the following for patients on warfarin with low TTR (<70%): either switch to a DOAC but also ensure good adherence and persistence; or improve the efficacy of warfarin through education, counseling, and more frequent international normalized ratio measurements.45
A couple of recently reported, smaller, randomized, prospective trials have not supported the superiority of DOACs over warfarin. The GIRAF trial enrolled 200 AF or atrial flutter patients of 70+ years and randomized them to warfarin or dabigatran. At 2-year follow-up, there were no group differences in cognitive outcomes.46 The CAF trial also randomized AF patients to warfarin or dabigatran and followed them for 24 months. There was also no significant difference between groups on cognitive assessment instruments.47
The literature on AD is also suggesting that AD patients, even without AF, may benefit from the use of anticoagulants. Grossmann21 hypothesized that anticoagulants, especially DOACs, would have a beneficial effect on the changes seen with AD. Anticoagulants could counteract the formation of inflammatory thrombin and fibrin, and the deposition of degradation-resistant Aβ-containing fibrin clots in cerebral blood vessels of cerebral amyloid angiopathy and in brain parenchyma.21 He proposed the need for further study.
The use of statins could be helpful for both AF and dementia due to their antiinflammatory properties.48 Lappegård et al49 reported that statins could modify the deterioration of neurocognition. They found a reduction of high-sensitivity CRP and a trend toward decreased white matter lesions in patients on statins. Calcium channel blockers (CCBs) also show some treatment promise. Lovell et al50 reported on a study of patients on nifedipine who showed a significant decrease in level of Aβ peptides, suggesting that CCBs may diminish the rate of progression to dementia.
The onset of AF with fluctuating heart rates and resultant loss of AV synchrony help to promote poor cerebral perfusion. Multiple studies have found that those who undergo ablation for AF have a lower risk for dementia than AF patients not undergoing ablation.51-53 Efimova et al54 studied patients with AF and rapid ventricular rates refractory to medical therapy. Many patients had brain hypoperfusion and impaired cognitive function. After receiving a pacemaker and undergoing atrioventricular nodal ablation, there was a significant improvement in perfusion and cognitive function at 3-month follow-up. This was attributed to the benefit of a consistent heart rate, with improved left ventricular systolic function and improved blood pressure.
Bunch proposed a model incorporating the mechanisms seen with AF and cognitive decline (Figure, available at www.eplabdigest.com).55 The model demonstrates 2 events that may be occurring simultaneously: issues with the use and efficacy of anticoagulation, and factors related to rhythm, rate, and cerebral perfusion. Anticoagulation issues may lead to microemboli and macroemboli/bleeds, which lead to disruption of the blood-brain barrier and cytotoxicity, leading to cellular apoptosis, cytotoxicity, and brain volume loss. Rhythm and cerebral perfusion issues lead to cerebral hypoperfusion, leading to arteriolar hypotension and capillary hypertension, and also leading to cellular apoptosis, cytotoxicity, and brain volume loss.
Aldrugh et al56 proposed a model in which AF and cognitive decline are linked via cerebral hypoperfusion, vascular inflammation, brain atrophy, and cerebral small vessel disease (Table 2). Both models are an attempt to clarify these interlocking processes.
Lifestyle modification has been proposed as an approach to improve memory performance in older adults, including the following recommendations: physical exercise equivalent to 13,000 kcal energy expenditure per week; a diet rich in fruits, vegetables, whole grain, and low in fat; maintenance of weight below a body mass index of 22; no smoking; and limiting alcohol consumption to 4-10 drinks per week.57 These recommendations fit with healthy lifestyle goals for the AF patient as well.
Screening/Detection
Greater emphasis is being placed on cognition screening/detection for those diagnosed with AF. Screening suggestions include the use of the Mini-Mental State Exam, multidimensional geriatric evaluation, and CHA2DS2- VASc at baseline and periodically, especially for those of advanced age.5,58-60 In addition, it has been proposed that measurement of dementia progression should be an independent outcome assessed in clinical trials.5,22,60
Of particular interest is a study by Graves et al,61 who used the Intermountain Mortality Risk Scores (IMRS) tool plus CHA2DS2-VASc to test whether these tools could jointly stratify dementia risk. The IMRS tool uses commonly performed blood tests such as a complete blood count and basic metabolic profile. The investigators’ rationale for the IMRS being valuable is that the tests identify processes that may be occurring in other areas of the body, which could forewarn of processes also taking place in the heart and brain. These processes include: (1) inflammation, which has a role in AF and dementia in a majority of cardiovascular disorders, brain neurodegeneration, and AD; and (2) macrovascular and microvascular dysfunction, which lead to progressive end-organ injury contributing to AF, unmasked by R-R interval variance. These factors promote cranial injury risk. Patients in this study were followed for 5 years (those with dementia and cognitive decline were excluded). The scores obtained were independently associated with dementia incidence. The blood tests performed as well as the CHA2DS2-VASc helped to predict those at high risk for AF and AD.
Summary
The incidence of AF and dementia are increasing as the population ages. More of our health care resources will continue to flow into research on these conditions and the care of those affected. Finding ways to slow down these processes will benefit all of us.
Disclosure: The author has completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Ms Moulton has no conflicts of interest to report regarding the content herein.
Linda Moulton, RN, MS, comments on her article published in the July 2022 issue of EP Lab Digest.
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