Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice. The prevalence of AF is on the rise as the population ages globally. The fact that people are now living longer with cardiovascular diseases and other risk factors for AF further augments age-based disease risk.

Dementia is characterized by impairment of memory and at least one additional cognitive domain and can have devastating effects on quality of life. Age is a significant risk factor for dementia, in particular Alzheimer's disease, with estimated age-based annual incidences of Alzheimer's disease of 0.6-1.0% (65-74 years), 2.0-3.3% (75-84 years), and 8.4% (>85 years).¹ Similar to AF, in the setting of an aging population the prevalence of dementia has increased.

We previously asked the question if AF and dementia were associated. We studied 37,025 patients with a mean age of 60.6±17.9 years that had a minimum of five years of follow-up. We found an increase incidence of dementia in general and all dementia subtypes in those patients with AF versus those without AF (Nonspecific: 1.3% (355) versus 3.3% (333), p<0.0001, Alzheimer's: 0.7% (199) versus 1.5% (148), p<0.0001, Senile: 0.6% (161) versus 1.6% (160), p<0.0001, and Vascular: 0.3% (89) versus 0.9% (90), p<0.0001). In contrast to what may be a perceived epiphenomena, we found that the strongest association of AF and dementia was in the youngest cohort studied (patients ≤ 70 years).² Our findings were strengthened by the subsequent publishing of three robust meta-analysis studies.^3-5 In all of these studies there was a pervasive risk of dementia in patients with AF, although all were limited in general by study heterogeneity and/or confounding variables introduced by observational and other study designs.

One notable challenge in examining prior studies as well as the pooled data from the meta-analyses is the variance of cognitive decline diagnosis. Ideally to fully elucidate the risk association of AF and dementia, the diagnosis of dementia would be made in a prospective manner, with a battery of neurocognitive tests, and by a neurologist. There exist many small or cross-sectional studies that have used neurocognitive testing to better define cognitive decline in AF patients.^6-8 However, in the absence of an ideal analysis, additional studies are required. Recently, Thacker et al.⁹ performed a large community-based longitudinal analysis in the Cardiovascular Health Study of 5,888 men and women aged 65 years and older. Only patients without a history of AF or stroke were included. AF diagnosis was made by a routine annual ECG or hospital discharge summary. Cognitive tests included the modified mini-mental state examination with was administered annually up to nine times. This test is used to sample a broad variety of cognitive functions, including memory.¹⁰ Also, the digit symbol substitution test was administered annually up to ten times which was additive to the mini-mental state examination in that it provided insight into information processing and attention.¹¹ Over the study period, 10.7% developed AF. The authors found that cognitive decline was more rapid after incident AF in both neurocognitive tests. In specific, in patients 75 years and older the modified mini-mental state examination scores decline on average three points faster per five years than in patients without AF. In patients 70 years and older, the digit symbol substitution test scores declined two points faster per five years than in non-AF patients. These results remained significant when accounting for multiple base demographics including coronary disease, hypertension, diabetes, gender, race, education level, smoking history, etc. These data clearly add to the growing body of evidence of the detriment of AF on cognitive function over time.

The underlying mechanisms behind the association are unknown. We have postulated that the risk of dementia may stem from chronic exposure to microembolism or microbleeds, unmasking cerebral microvascular dysfunction, regional variance in cerebral perfusion, genetic susceptibilities, declining physical function, or a combination to various degrees of any of these.¹² The study by Thacker et al.⁹ clearly gives additional incentive to begin studies to examine the mechanisms behind the consistently demonstrated association of cognitive decline after incident AF. These mechanistic studies are necessary so therapeutic approaches can be developed to decrease risk of cognitive decline in an ever increasing population of patients that develop AF.

References

1. Hebert LE, Scherr PA, Beckett LA, et al. Age-specific incidence of Alzheimer's disease in a community population. JAMA 1995;273:1354-1359.
2. Bunch TJ, Weiss JP, Crandall BG, et al. Atrial fibrillation is independently associated with senile, vascular, and Alzheimer's dementia. Heart Rhythm 2010;7:433-7.
3. Kalantarian S, Stern TA, Mansour M, Ruskin JN. Cognitive impairment associated with atrial fibrillation: a meta-analysis. Ann Intern Med 2013; 158(5 Pt 1):338-346.
4. Santangeli P, Di Biase L, Bai R, et al. Atrial fibrillation and the risk of incident dementia: a meta-analysis. Heart Rhythm 2012;9:1761-1768.
5. Kwok CS, Loke YK, Hale R, Potter JF, Myint PK. Atrial fibrillation and incidence of dementia: a systematic review and meta-analysis. Neurology 2011; 76:914-922.
6. Kilander L, Andren B, Nyman H, Lind L, Boberg M, Lithell H. Atrial fibrillation is an independent determinant of low cognitive function: a cross-sectional study in elderly men. Stroke 1998;29:1816-1820.
7. Park H, Hildreth A, Thomson R, O'Connell J. Non-valvular atrial fibrillation and cognitive decline: a longitudinal cohort study. Age Ageing 2007;36:157-163.
8. Elias MF, Sullivan LM, Elias PK, et al. Atrial fibrillation is associated with lower cognitive performance in the Framingham offspring men. J Stroke Cerebrovasc Dis 2006;15:214-222.
9. Thacker EL, McKnight B, Psaty BM, Longstreth WT, Jr., Sitlani CM, Dublin S, Arnold AM, Fitzpatrick AL, Gottesman RF, Heckbert SR. Atrial fibrillation and cognitive decline: A longitudinal cohort study. Neurology 2013; [Epub Ahead of Print].
10. Teng EL, Chui HC. The Modified Mini-Mental State (3MS) examination. J Clin Psychiatry 1987;48:314-318.
11. Fabrigoule C, Rouch I, Taberly A, et al. Cognitive process in preclinical phase of dementia. Brain 1998;121(Pt 1):135-141.
12. Bunch TJ, Crandall BG, Weiss JP, Osborn JS, Johnson DL, Day JD. Expanding the Evaluation and Treatment of Patients with Atrial Fibrillation to Minimize the Risk of Dementia. J Innov Card Rhythm Manag 2012;3:855-863.

Keywords: Alzheimer Disease, Atrial Fibrillation, Coronary Disease, Cross-Sectional Studies, Dementia, Hypertension, Smoking, Stroke

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