Does atrial fibrillation lead to cognitive decline and dementia?

This editorial refers to ‘Atrial fibrillation as a risk factor for cognitive decline and dementia’†, by A. Singh-Manoux et al., on page 2612. Both atrial fibrillation (AF) and dementia are diseases of elderly people. The incidence of AF and cognitive decline increases with age. The coincidence of the two frequent conditions might be simply explained by a common factor, namely increasing age. Recent research, however, provided evidence that vascular risk factors and vascular disease contribute not only to vascular dementia but also to degenerative dementias such as Alzheimer’s disease.1 AF increases the risk of stroke by a factor of five, and stroke is an important risk factor and predictor of cognitive decline and dementia. A number of studies indicated that AF might increase the risk of faster cognitive decline and dementia even in patients without prior stroke. Most of these studies were retrospective in nature. Therefore, results from prospective long-term studies are needed. Singh-Manoux et al., in their study published in this issue of the journal, used prospectively collected data from the Whitehall II study. A total of 10 308 persons aged 33–45 years were recruited into the study between 1985 and 1988 and followed until 2013.2 Vascular diseases and vascular events were recorded. Cognitive test batteries were introduced in 1997 and repeated four times until 2013. Cognitive test results were available for 7014 persons without AF and 414 patients with AF aged 45–69 years in 1995. Patients with a 5-, 10-, or 15-year history of AF had a faster cognitive decline after adjustment for socio-demographic and behavioural factors, and chronic diseases. Incident dementia was more frequent in patients with AF compared with persons without AF [hazard ratio (HR) 1.87, 95% confidence inerval (CI) 1.37–2.55]. This was also true for patients without stroke. These robust data complement the results of the Rotterdam study.3 In this prospective study, 6514 dementia-free participants were followed from 1989 to 2010. At baseline, 318 of 6514 participants (4.9%) had prevalent AF, and during 81 483 person-years of follow-up, 994 participants (15.3%) developed incident dementia. Prevalent AF was related to an increased risk of dementia (HR 1.33, 95% CI 1.02–1.73). Among 6196 participants without prevalent AF during 79 003 person-years of follow-up, 723 participants (11.7%) developed incident AF and 932 individuals (15.0%) developed incident dementia. Incident AF was associated with an increased risk of dementia in younger participants (<67 years). The relationship between AF, cognitive impairment, and dementia was also shown in two recent meta-analyses. Kalantarian et al.4 identified 21 studies with 89 907 participants and investigated the association of AF with cognitive decline and dementia. AF was significantly associated with a higher risk of cognitive impairment independent of a history of stroke [relative risk (RR) 1.34, 95% CI 1.13–1.58]. The risk of dementia was also significantly increased (RR 1.38, 95% CI 1.22–1.56). A second meta-analysis included 46 637 participants from 15 studies and showed that AF was associated with a significant increase in dementia (odds ratio 2.0, 95% CI 1.4–2.7) with a strong contribution of patients with previous stroke.5 What are the possible mechanisms leading to cognitive decline and dementia in patients with AF? (Figure 1). (i) AF results in decreased cardiac output and may result in chronic cerebral hypoperfusion.6 Cerebral hypoperfusion may lead to leucoaraiosis and cognitive decline and also promote Alzheimer’s disease.7 (ii) AF increases the risk of stroke and therefore increases the risk of cognitive decline and dementia. (iii) AF may result in silent strokes. Silent strokes are associated with cognitive decline and dementia.8 (iv) AF may result in microemboli leading to asymptomatic small lacunar defects or cerebral microbleeds. Mechanisms of AF leading to cognitive decline or dementia. How might treatment of AF decrease the risk of cognitive decline and dementia? Cardioversion or AF ablation might result in sinus rhythm and improve cardiac output and cerebral perfusion. Optimal anticoagulation reduces the risk of ischaemic stroke, silent infarcts, and possibly the occurrence of microemboli. The randomized studies investigating non vitamin-K oral anticoagulants (NOACs) vs. warfarin showed in aggregate a reduction in the risk of stroke.9 They would have been too short to show an impact on cognition. Prospective trials investigating the potential benefit of rhythm control or anticoagulation in AF would need to run for 10 years to show an impact on cognitive decline and dementia, and would require many thousands of patients. Therefore it is unlikely that these trials will ever be funded. We are restricted at the moment with analyses from large databases in Denmark, Sweden, or the UK which are underway. In conclusion, AF is associated with cognitive decline and dementia. It is very likely that treatment of AF and anticoagulation may prevent or delay cognitive decline and dementia. Conflict of interest: H.C.D. received honoraria for participation in clinical trials, contribution to advisory boards, or oral presentations from: Abbott, Achelios, Allergan, AstraZeneca, Bayer Vital, BMS, Boehringer Ingelheim, CoAxia, Corimmun, Covidien, Daiichi-Sankyo, D-Pharm, Fresenius, GlaxoSmithKline, Janssen-Cilag, Johnson & Johnson, Knoll, Lilly, MSD, Medtronic, MindFrame, Neurobiological Technologies, Novartis, Novo-Nordisk, Paion, Parke-Davis, Pfizer, Sanofi-Aventis, Schering-Plough, Servier, Solvay, St. Jude, Syngis, Talecris, Thrombogenics, WebMD Global, Wyeth, and Yamanouchi. Financial support for research projects was provided by AstraZeneca, GSK, Boehringer Ingelheim, Lundbeck, Novartis, Janssen-Cilag, Sanofi-Aventis, Syngis, and Talecris. The Department of Neurology at the University Duisburg-Essen received research grants from the German Research Council (DFG), German Ministry of Education and Research (BMBF), European Union, NIH, Bertelsmann Foundation, and Heinz-Nixdorf Foundation. H.C.D. has no ownership interest and does not own stocks of any pharmaceutical company. Within the past year, HCD served as editor of Aktuelle Neurologie, Arzneimitteltherapie, Kopfschmerznews, Stroke News, as co-editor of Cephalalgia, and on the editorial board of Lancet Neurology, Stroke, European Neurology, and Cerebrovascular Disorders. H.C.D. chairs the Treatment Guidelines Committee of the German Society of Neurology and contributed to the EHRA and ESC guidelines for the treatment of AF.