Archief Roodbont

Discussion

In this population-based study of older adults, AF was associated with a 40% to 50% higher risk of AD and all-cause dementia, independent of stroke. This higher risk persisted after adjustment for many cardiovascular risk factors and diseases and in numerous sensitivity analyses. Because participants were followed prospectively and screened routinely for cognitive impairment, and dementia was ascertained using sensitive and valid methods, the findings provide more-rigorous information than many prior studies of this question. Considerable efforts were made to identify and account for clinically recognized stroke, so the estimates reflect the associations between AF and dementia beyond its known association with clinical stroke.

Several biological mechanisms may underlie the association between AF and dementia and AD. First, AF leads to incomplete atrial emptying, which may lead to thrombus formation in the left atrial appendage. This can result in systemic embolization, including to the brain. In addition to clinically recognized stroke, people with AF experience silent cerebral emboli.^[15] It has previously been reported that cerebral microinfarcts are an important neuropathological predictor of clinical dementia.^[32] It is not known whether AF increases the risk of cerebral microinfarcts. Second, AF is associated with greater beat-to-beat heart rate variability, which may lead to cerebral hypoperfusion.^[13] Either or both of these mechanisms may be associated with other neuropathological entities associated with dementia, such as neurofibrillary tangles, Lewy bodies, and hippocampal sclerosis. These findings are consistent with Fortuhi's "dynamic polygon" hypothesis,^[33] which posits that multiple processes and risk factors act together to produce late-life dementia. People with late-life dementia and AD commonly have multiple neuropathological findings (e.g., vascular pathology or Lewy bodies in addition to AD lesions).^[34] It may be that, in people with levels of AD pathology insufficient to produce dementia on their own, additional insults from AF decrease cognitive reserves and hasten the onset of dementia or AD.

In addition to the mechanisms described above, there are other possible explanations for the association observed between AF and dementia. First, AF and dementia may share underlying risk factors or pathophysiological processes, such as inflammation. It may be that despite efforts to control for cardiovascular risk factors and clinical cardiovascular disease, AF serves as a marker for the overall burden of cardiovascular disease. Second, subtle changes in the brain may affect autonomic input to the heart, changing cardiac conduction and leading to AF. However, the outcome of incident dementia was studied, so autonomic changes should have been minimal in these cases with early AD.

These findings are consistent with those of prior cross-sectional studies^[4,35] and with some^[6–8] but not all^[16–20] longitudinal studies. (For more information, please see summary table provided as Appendix S1.) Three of eight longitudinal studies reported that participants with AF were at higher risk of dementia than those without,^[6–8] although one study found this association only in participants with mild cognitive impairment,^[7] and another found an association at 5 years of follow-up but not 1 or 10 years.^[8] Five longitudinal studies found no association.^[16–20] In general, the studies that found an association examined a younger population than those that found no association, but there were other important differences. The methods used to detect AF and dementia varied widely. Only one prior study^[6] presented data about AF diagnosed during follow-up; other studies ascertained AF only at baseline. Because the current study identified AF diagnosed during follow-up, it is likely that it had more-complete ascertainment than most prior studies, improving its accuracy and power. Some studies used measures of dementia that have poor sensitivity or specificity, such as ICD-9 codes from administrative data^[6] or Mini-Mental State Examination scores less than 24.^[16] The current study included the largest number of dementia cases identified using sensitive and rigorous methods of any study to date. Only one prior study included more dementia cases,^[6] but it relied purely on administrative data to identify dementia, which likely led to substantial misclassification. This probably led to bias, the direction of which cannot be predicted.

This study has limitations. Diagnoses of dementia and AD were based on clinical criteria, and although neuroimaging studies were available for many dementia cases, research-quality neuroimaging was not performed. Cases of vascular or mixed dementia may have been misclassified as AD. It is not likely that this detracts from the findings, because prior work has established that in late-life dementia, people who meet neuropathological criteria for AD commonly have additional coexisting neuropathological findings, often vascular lesions.^[34] The association between AF and AD remained present when the outcome was limited to participants with probable AD, a group that is likely to meet neuropathological criteria for AD.^[34]

It is likely that some cases of AF that did not come to clinical attention were missed, particularly those that were transitory or asymptomatic. It is difficult to predict how this misclassification would have affected the results. If this misclassification was nondifferential, the true association between AF and dementia may be stronger than was observed. Information about AF duration and persistence was lacking, so these aspects of AF could not be examined in relation to dementia. The timing of dementia onset and the onset of self-reported CHD, stroke, and CHF were subject to error because the exact date of onset was not known, so it was estimated as occurring halfway between ACT visits. Covariates including CHD and CHF were measured from self-report, which may be inaccurate. Information about valvular heart disease or echocardiographic findings such as left atrial dilation and impaired systolic function, which are associated with development of AF, was not available.^[10] All of these limitations could have led to residual confounding. The study population was predominantly white and well educated, which may limit generalizability. Participants who died or withdrew from ACT may have differed from those who remained in the study in terms of their likelihood of having AF and of developing dementia, which may have led to bias.

The findings have important clinical implications. AF is common, and its prevalence is increasing.^[36] It is not known whether specific treatments for AF could modify the greater risk of dementia observed. If such treatment could delay the onset of dementia by even a few years, this could have a substantial effect on the burden of dementia in the population. Although one recent observational study reported that participants with AF who underwent catheter ablation had a lower risk of dementia than those who did not,^[37] these results may have been biased because treatment was not randomly assigned. Additional research is needed to examine the relationship between various treatments for AF and cognitive outcomes. Clinical trials and comparative effectiveness studies examining AF treatments will surely continue to study stroke and mortality but should also use sensitive and rigorous measures to ascertain cognitive decline and incident dementia so that these important outcomes can be evaluated. Future research seeking ways to avert the increasing burden of dementia should aim to determine the extent to which AF might be a modifiable risk factor.