October 19, 2015
Written by Jared Bunch MD

Atrial fibrillation is the most common sustained arrhythmia observed in clinical practice. It increases in prevalence with age, sleep apnea, obesity, inactivity and sedentary lifestyles, hypertension, and other acquired cardiovascular diseases. Dementia has emerged as a significant source of morbidity and mortality in developed countries and shares the many risk factors listed for atrial fibrillation. We studied a potential disease association in an analysis of 37,025 patients with at least 5 years of follow-up. In this retrospective analysis, 27% developed atrial fibrillation.¹ In those patients who developed atrial fibrillation, we observed a significant risk for all forms of dementia, including Alzheimer’s disease. Since both disease states are associated with aging, it was plausible that the observed risk was an epiphenomenon. In contrast to this possibility was our observation that the highest risk of dementia was in the youngest group studied (<70 years of age), with a multivariate adjusted hazard ratio of 2.30 (P = .001) for Alzheimer’s disease, 3.34 (P <.0001) for senile dementia, and 2.22 (P = .004) for vascular dementia.¹

In a recent study by de Brujin and colleagues,² the question of whether or not atrial fibrillation raises risk of dementia was again studied. In this analysis of 6514 patients, 318 developed atrial fibrillation, and 994 developed dementia over 79,003 person-years of follow-up. The authors found a significantly increased risk of dementia in those patients with atrial fibrillation (HR, 1.23) that persisted even when censoring for incident stroke. Similar to our study, the authors found the highest risk in the younger group, with a hazard ratio of 1.81 for those younger than 67 years of age compared with 1.12 for those older than 65 years. Their results provided new insight to our study in that they found that atrial fibrillation duration significantly increased dementia risk. They also found that the risk was independent of apolipoprotein E ε4 allele, a general marker of increased risk of dementia. The lack of the association with apolipoprotein E ε4 allele suggests that atrial fibrillation is not necessarily a “second hit” to a predisposed dementia state. We have also found lack of association of apolipoprotein E ε4 allele when exploring genetic variants that underlie the association of atrial fibrillation and dementia.³

An interesting finding in the study by Brujin et al was that use of anticoagulation was significantly higher in the group that developed dementia compared with the group that did not (27.4% vs 22.4%; P < .001). This finding may reflect patient treatment bias or the actual treatment itself. In patients with atrial fibrillation, the most common anticoagulant used worldwide is warfarin. Although this therapy may lower risk of macro events such as stroke in patients with atrial fibrillation, as time in therapeutic range falls the risk of dementia significantly increases, and the therapy that is used to protect cerebral function can impair it.⁴

A recent review explored the disease association and potential underlying mechanisms.⁵ This review highlights two recent meta-analysis studies that found the risk of dementia was 2 to 2.5 times greater in patients with atrial fibrillation. The review proposes potential mechanisms including embolic or hemorrhagic (macro and micro), low perfusion, oxidative stress, and proinflammatory or thrombotic status. Many of these mechanisms can result in neuronal and synaptic loss and cerebral amyloid angiopathy, the histologic hallmarks of Alzheimer’s dementia. Of these proposed mechanisms, we have therapies that may potentially alter their impact; for example: (1) improving anticoagulation efficacy with direct oral anticoagulants; (2) minimizing exposure to aspirin, particularly in those without a need for the therapy or those already on an anticoagulant;⁶ (3) minimizing hypotension and bradycardia to enhance cerebral perfusion and minimize exposure to periods of hypoperfusion; and (4) preventing atrial fibrillation altogether or in those with disease development, restoring the rhythm early to minimize disease-related comorbidities. As pointed out in the review, all of these therapies need to be studied in a randomized, prospective manner.

References:

1. Bunch TJ, Weiss JP, Crandall BG, et al. Atrial fibrillation is independently associated with senile, vascular, and Alzheimer’s dementia. Heart Rhythm. 2010;7(4):433-437.
2. de Bruijn RF, Heeringa J, Wolters FJ, et al. Association between atrial fibrillation and dementia in the general population [published online September 21, 2015]. JAMA Neurol. doi: 10.1001/jamaneurol.2015.2161.
3. Rollo J, Knight S, May HT, et al. Incidence of dementia in relation to genetic variants at PITX2, ZFHX3, and ApoE epsilon4 in atrial fibrillation patients. Pacing Clin Electrophysiol. 2015;38(2):171-177.
4. Jacobs V, Woller SC, Stevens S, et al. Time outside of therapeutic range in atrial fibrillation patients is associated with long-term risk of dementia. Heart Rhythm. 2014;11(12):2206-2213.
5. Poggesi A, Inzitari D, Pantoni L. Atrial fibrillation and cognition: Epidemiological data and possible mechanisms [published online September 22, 2015]. Stroke. doi: 10.1161/STROKEAHA.115.008225.
6. Jacobs V, Woller SC, Stevens SM, et al. Percent time with a supratherapeutic INR in atrial fibrillation patients also using an antiplatelet agent is associated with long-term risk of dementia [published online August 13, 2015]. J Cardiovasc Electrophysiol.

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