Cognitive Decline and Dementia in Patients with Atrial Fibrillation: Risk Factors and Treatment Targets

Atrial fibrillation (AF) is the most common sustained arrhythmia we encounter in clinical practice.¹ As risk factors of the arrhythmia increase, so does the incidence, which has increased globally in both developed and developing countries.² In most people, AF is a risk marker of a vascular disease state driven by hypertension, diabetes, obesity, sleep apnea, and aging.³ The most feared complication of atrial fibrillation is stroke, because strokes associated with AF tend to be more disabling and result in higher rates of mortality.⁴ 

Atrial Fibrillation and Dementia

Multiple strokes or those in key locations can result in severe cognitive decline and vascular dementia. Atrial fibrillation is also associated with other forms of dementia, including senility and Alzheimer’s disease. In our population-based study, the relative risk of dementia in atrial fibrillation was found in younger patients. Specifically, the youngest AF group studied in our population (<70 years of age) had an adjusted hazard ratio of 2.30 (P=0.001) for Alzheimer’s disease, 3.34 (P<0.0001) for senile dementia, and 2.22 (P=0.004) for vascular dementia.⁵ Other groups have subsequently described the association of atrial fibrillation and dementia, including finding a relatively higher risk of AF in younger patients.^6,7 

Mechanisms of Atrial Fibrillation and Dementia

As multiple groups have reported an association between atrial fibrillation and dementia, the next step is to explore mechanisms. One possibility is that the association reflects the epiphenomena of two diseases associated with aging. However, in our experience and in others, the highest risk in young AF patients is in opposition of this possibility.^5,6 Given the complexities of these diseases, their association is likely the manifestation of multiple mechanisms.

At the core of this association between the two diseases are the multiple shared risk factors (Figure 1). The risk factors used in the CHADS₂ and CHA₂DS₂-VASc scores can often predict the incidence of both atrial fibrillation and dementia. When AF is added to the model, it adds risk for dementia across all CHADS₂ and CHA₂DS₂-VASc strata.³ It remains to be defined whether atrial fibrillation is a marker of more severe vascular disease that drives this risk, or is an additive risk factor. 

It is also plausible that dementia is a spectrum of cranial injury in atrial fibrillation patients. Atrial fibrillation and its management are commonly associated with stroke and intracranial bleeds. Dementia may be the end manifestation from recurrent subclinical cranial ischemic events from microbleeds or microclots. If this mechanism is a dominant driver of atrial fibrillation and dementia, then the initiation and efficacy of anticoagulation will matter and influence cognitive risk.

A common symptom in patients with atrial fibrillation is a sense of mental slowing or feeling “less sharp” with arrhythmia onset. This type of acute change in cognition cannot be explained by the above mechanisms. With onset of atrial fibrillation, multiple mechanisms immediately develop. These include loss of atrial contractility as well as loss of atrial-ventricular coordination, both of which can impact ventricular filling and output, particularly in those patients with diastolic dysfunction.⁸ In addition, ventricular conduction becomes more random, leading to marked variation of R-R intervals. This leads to variance in perfusion pressure of organs, in addition to that lost due to failure of atrial systolic and atrial-ventricular coordination. This concept was recently modeled in an experiment by Anselmino and colleagues.⁹ They found AF triggered a higher variability of the cerebral hemodynamic variables expressed toward the distal circulation of microvasculature. This variability resulted in 303 critical hypoperfusion events at the arteriolar level and 387 hypertensive events at the capillary level. This variability resolved in sinus rhythm. Loss of cardiac output in atrial fibrillation coupled with variance in organ perfusion can unmask cranial microvascular dysfunction, leading to cognitive change. 

Therapeutic Targets to Lower Risk of Dementia in AF Patients

Working within the construct of these discussed mechanisms, multiple potential therapeutic targets can be considered. Foremost is to identify the multiple shared risk factors. Many of these disease states can be avoided or lowered in risk by making changes such as incorporating exercise, following a healthy diet, and avoiding a sedentary lifestyle. These risk factors include high blood pressure, metabolic syndrome, obesity, diabetes, vascular disease, and sleep apnea. As both dementia and atrial fibrillation become epidemic disease states, true prevention will start with targeting the shared risks.

Next is to improve anticoagulation use and efficiency. We have found that patients with poor times in therapeutic range on warfarin experience much lower rates of dementia compared to those with high times in therapeutic range. The risk is observed in people that are both consistently under- and over-anticoagulated with warfarin consistent with repetitive injury from both microemboli and bleed as a mechanism.¹⁰ We have also found that for patients on antiplatelet agents, the risk of dementia with frequent exposure to over-anticoagulation is magnified.¹¹ Aspirin use is required in some AF patients, but in others, the long-term use may be due to a perception of heart health or benefit that is not supported.

With regard to anticoagulation as a therapeutic target, the next step is to determine if novel or direct oral anticoagulants, which are more predictable and have been shown to lower risk of macrocranial injuries of stroke and bleeding in AF patients, can lower risk of dementia. We examined this question in a population-based study, and found that patients taking novel or direct oral anticoagulation were 43% less likely to develop stroke/transient ischemia attack/dementia (hazard ratio 0.57 [CI 0.17, 1.97]; P=0.38) than those taking warfarin.¹² When specifically considering dementia as an independent endpoint, there remained a significantly lower risk in those treated with direct oral anticoagulants. Two randomized studies will prospectively look at this question. The Cognitive Impairment Related to Atrial Fibrillation Prevention Trial (GIRAF) and the Impact of Anticoagulation Therapy on the Cognitive Decline and Dementia in Patients With Non-Valvular Atrial Fibrillation (CAF) trial will evaluate if dabigatran compared to warfarin will improve cognitive function (ClinicalTrials.gov: NCT01994265, NCT03061006). The CAF trial will also include an MRI substudy to quantify the anatomic and characteristic changes such as microclots, microbleeds, and brain volume, and associate these with incident cognitive changes. 

Finally, if heart rate variability and cardiac output are potential mechanisms of cognitive dysfunction in AF patients, then restoration of sinus rhythm or improving the heart rate variance may improve outcomes. In a small study, it was shown that patients with atrial fibrillation have marked signs of cerebral hypoperfusion and impaired cognitive functioning. Following AV node ablation and permanent pacemaker implantation, an improvement in both cognitive functioning and cerebral blood flow was observed.¹³ Regarding rhythm control, in a study of 37,908 patients, 0.2% of the AF ablation patients compared to 0.9% of the AF (no ablation) patients and 0.5% of the no atrial fibrillation patients (P<0.0001) developed Alzheimer’s. Long-term rates of stroke and general dementia were also found to be similar in AF ablation patients and patients with no history of atrial fibrillation.¹⁴ 

A summary of potential treatment strategies is shown in Figure 2. Early treatment of shared risks will likely become the cornerstone of therapeutic approaches to truly reduce disease incidence. However, along the temporal course of disease progression, multiple additional approaches can be considered as risk factors for dementia in atrial fibrillation continue to be defined. It is important to recognize that once the combined disease state develops, mortality risk significantly increases.⁵ Unfortunately, current pharmacologic therapies have not shown significant benefit at this disease stage, and of those used, such as anticoagulation therapies, safety and efficacy are unfavorably altered. 

Disclosure: Dr. Bunch has no conflicts of interest to report regarding the content herein. Outside the submitted work, he reports grants from Boehringer Ingelheim.  

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