Abstract
Objective:
Levothyroxine treatment is common among older adults as is atrial fibrillation (AF), yet less is known about its potential effects on the development of dementia.
Methods:
The study population included all adults with diagnosed AF (n=156,104) aged ≥45 years in Sweden without an earlier recorded diagnosis of dementia. Individuals with a dispensed prescription of levothyroxine on two or more occasions between July 1 2005 and December 31 2006 in Sweden were considered exposed (n=12,978; 8.3%), and were compared to all other patients with AF without this treatment. Cox regression with hazard ratios (HRs) and 95% confidence interval (95% CI), with outcome defined as dementia of all causes between January 1, 2007 and December 31, 2015, was used in the analysis. Adjustments were made for socio-demographic factors (age, immigration status, marital status, educational level, neighborhood socio-economic status), co-morbidity (cardiovascular disease, obesity, diabetes, COPD, depression, anxiety and alcohol related diagnoses), and cardiovascular medications.
Results:
During follow-up, a total of 9,054 patients with AF were diagnosed with dementia (5.8%). We found no significant association of levothyroxine treatment and incident dementia, fully adjusted HR 1.03 (95% CI 0.96–1.11), neither among men and women, nor in different age-groups or subgroups of dementia.
Conclusion:
We found no significant association of levothyroxine treatment and incident dementia among patients with AF, which contrasts some earlier findings.
Keywords: Atrial fibrillation, Alzheimer’s disease, dementia, gender, drug treatment, levothyroxine
There are conflicting results on the association between thyroid function and incident dementia. An increased risk of dementia in patients with hypothyroidism has been found in some studies. For example, one study of patients with Alzheimer’s dementia (AD) found hypothyroidism to be overrepresented among those patients with dementia [1], while another study did not find hypothyroidism to be associated with AD pathology but instead with cerebrovascular diseases and thus with vascular dementia (VaD) [2].
However, there are possible mechanisms supporting the association between hypothyroidism, thyroid hormones and dementia. Thyroid hormones certainly are involved in the development and maturation of the brain in early life, and the lack of thyroid hormones have deleterious effects on the brain in congenital hypothyroidism [3, 4]. Thyroid hormones could also exert an effect on the adult brain, e.g. showing a positive effect on memory in euthyroid men [5], and thyroid hormones showing improvement in hippocampus function [6], and an augmentation of cholinergic activity [7].
Atrial Fibrillation (AF) is increasingly common with age and has also been shown to be associated with a higher dementia risk [8–10], where the most important factor is the increased risk of cardio-embolic stroke [10]. In accordance with this, anticoagulant treatment has been shown to be associated with a lower risk of dementia in patients with AF in observational studies [11, 12]. To use a population of patients with AF as they are generally prescribed many cardiovascular drugs is also a way to test if levothyroxine may effect development of dementia in patients with complex cardiovascular pharmacotherapies. For example, antihypertensive drugs have been shown to reduce the risk of dementia, such as thiazides in combination with a RAS-blocker (ACE-inhibitor or angiotensin receptor blockers, ARBs) in patients with AF [13], and calcium channel blockers and ARBs in older people [14].
The relation between hypothyroidism, levothyroxine, and mortality has been elucidated in earlier research, where hypothyroidism and levothyroxine treatment was associated with a lower cardiovascular risk and mortality [15], even if the potential mechanism explaining the association between levothyroxine treatment and mortality is unknown.
Women are known to exhibit a higher prevalence of hypothyroidism and thus of levothyroxine treatment than men [16]. Besides, women with AF are also found to have a higher relative risk of stroke than men [17]. Hence, men and women should be analysed separately.
The primary aim was to study the association between levothyroxine treatment and dementia among patients with AF in Sweden.
Methods
We examined information on individuals from Swedish population-based registers with national coverage. These registers were linked using each person’s unique identification number replaced by a serial number to preserve confidentiality. The study population was defined from the Swedish Total Population Register at Statistics Sweden who also delivered the individual socioeconomic variables, Inpatient Register, the Swedish Prescribed Drug Register and the Swedish Cause-of-Death Register were from The National Board of Health and Welfare. These registers contains individual-level data on age, gender, education, hospital admissions, mortality and cause-of-death for all residents registered in Sweden. Ethical approvals were obtained from regional boards at Karolinska Institutet and the University of Lund.
The study included all patients with diagnosed AF, identified by the presence of the ICD-10 code (10th version of the WHO’s International Classification of Diseases) for atrial fibrillation (I48) in the Swedish Hospital register from January 1 1998 until December 31 2006.
We excluded individuals with a diagnosis of dementia during January 1 1998 until December 31 2006; a new diagnosis of hypothyroidism between January 1 2007 and December 31 2015; a diagnosis of hyperthyroidism or thyroid cancer during January 1 1998 until December 31 2006, and with dispensed prescription of levothyroxine on two or more occasions during July 1 2005 until December 31 2006; individuals below 45 years of age at January 1 2007; and individuals with a dispensed prescription of levothyroxine on only one occasion during July 1 2005 until December 31 2006. In total, 156,104 individuals (89,251 men and 66,853 women), aged ≥45 years were included (see Supplementary Figure 1!).
The exposition was at least two dispensed prescription of levothyroxine (H03AA01) during July 1 2005 until December 31 2006, aged 45 years of age or above and alive at January 1 2007. Individuals without a dispensed prescription were used as reference group.
The outcome was defined as a diagnosis of dementia according to ICD-10 classification in electronic patient records from hospitals, or from the Death register, was used as primary outcome (F00 Alzheimer’s dementia, F01 Vascular dementia, F02 Dementia in other diseases classified elsewhere, F03 Unspecified dementia, F10.7A Alcohol dementia, F10.97Alcohol use, unspecified with alcohol-induced persisting dementia or G30 Alzheimer’s disease).We categorized dementia as Alzheimer’s dementia (AD; F00 and G30), vascular dementia (VaD; F01) or other types of dementia (remaining diagnoses as listed above). For the primary outcome, time to diagnosis of dementia from between January 1 2007 and December 31 2015 was registered. Individuals were also divided into the following pre-specified age groups 45–64, 65–84, and ≥85 years. Individuals <45 years of age were excluded. Educational level was categorized according to pre-specification as ≤9 years (partial or complete compulsory schooling), 10–12 years (partial or complete secondary schooling) and >12 years (college and/or university studies). Country of birth was classified as born in Sweden or foreign-born. Marital status was classified as married, unmarried, divorced or widowed. The neighborhood socioeconomic status (SES) areas were categorized into three groups according the neighborhood index: > one standard deviation (SD) below the mean (high SES or low deprivation level), > one SD above the mean (low SES or high deprivation level), and within one SD of the mean (middle SES or deprivation level).
The following related disorders were used as covariates (with ICD-10 codes): hypertension (I10–15); coronary heart disease (CHD; I20–25); congestive heart failure (CHF; I50 or I110); cerebrovascular diseases (CVD; I60–69); obesity (E65-E68); diabetes mellitus (E10–14); chronic obstructive pulmonary disease (COPD; J40-J47); depression (F32–F34, F38–F39); anxiety disorders (F40–41); and alcoholism and related disorders (F10 and K70).
Cardiovascular medication was recorded, with at least two dispensed prescription of the following drugs : Loop diuretics (C03C), thiazides (C03A, C03B, C03E, C09B and C09DA), potassium-saving agents (C03D), beta-1-selective beta-blockers (C07AB and C07FB), non-selective beta-blockers (C07AA and C07AG), heart-active calcium channel blockers (C08DA), vessel-active calcium channel blockers (C08CA and C08DB), ACE inhibitors (C09AA and C09BA), angiotensin-receptor blockers (ARBs; C09CA, C09DA and C09DB), statins (C10AA) and anticoagulants (B01AA).
Descriptive data were shown as numbers and percentages, and with differences between individuals with incident dementia vs those without dementia shown as p-values obtained from Chi square test. Cox regression with hazard ratios (HRs) and 95% confidence interval (95% CI), using time to dementia as the outcome, was used in follow-up analyses for patients with levothyroxine treatment compared to those without this, for all individuals and also categorized by sex. We used the following regression models: Model 1 adjusted for age; model 2 adjusted for age, educational level, immigrant status, marital status, and neighborhood deprivation; Model 3 as Model 2 + comorbidities; and Model 4 as Model 3 + cardiovascular medication. In subgroup analyses, we analyzed dementia diagnosed as AD, VaD or other types of dementia. Furthermore, as risk factors for dementia differs over age, we also analyzed patients in the following age strata: 45–64 years of age, 65–84 years of age, and 85 years of age and above.
A two-sided p-value of <0.01 was considered statistically significant for variables at baseline owing to multiple testing, and <0.05 for variables in the regression analyses. All analyses were performed in SAS 9.4.
Results
Characteristics of the study population (n=156,104 individuals; 89,251 men and 66,853 women) are shown in Table 1. In total, 9,054 dementia diagnoses were recorded (5.8%), 4486 among men (5.0%) and 4568 (6.8%) among women. Mean follow-up was 5.4 years in the total sample, in the age-group 45–64 years 7.4 years, in the age-group 65–84 years 5.7 years, and in the age-group 85 years and above 3.0 years. Total person-years were in the whole sample 836,270 years, and, in the age-groups 45–64, 65–84 and 85 years and above 199,429, 525,186 and 111,655 years, respectively. Among individuals with dementia there were more women. Individuals with dementia were also older, had lower educational level, were less often married, had more often registered diagnoses of CHD, stroke, and depression, less often registered diagnoses of obesity and COPD, and were less often treated with anticoagulants. There were only small differences in regard to dispensed cardiovascular drugs, with higher rate of loop diuretics and lower rate of ARBs among dementia patients (Supplementary Table 1).
Table 1.
Baseline data of patients with atrial fibrillation and with or without levothyroxine treatment, and number of incident cases of dementia during follow-up
| Population | Dementia events | Without dementia | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| No. | % | No | % | No | % | P-value* | ||||
| Total population | 156104 | 9054 | 147050 | |||||||
| Exposition | <0.001 | |||||||||
| Levothyroxine treatment | 12978 | 8.3 | 878 | 9.7 | 12100 | 8.2 | ||||
| No levothyroxine treatment | 143126 | 91.7 | 8176 | 90.3 | 134950 | 91.8 | ||||
| Gender | <0.001 | |||||||||
| Males | 89251 | 57.2 | 4486 | 49.5 | 84765 | 57.6 | ||||
| Females | 66853 | 42.8 | 4568 | 50.5 | 62285 | 42.4 | ||||
| Age (years) | <0.001 | |||||||||
| 45–64 | 26919 | 17.2 | 209 | 2.3 | 26710 | 18.2 | ||||
| 65–84 | 91732 | 58.8 | 6175 | 68.2 | 85557 | 58.2 | ||||
| ≥ 85 | 37453 | 24.0 | 2670 | 29.5 | 34783 | 23.7 | ||||
| Educational level | <0.001 | |||||||||
| ≤ 9 | 76264 | 48.9 | 4719 | 52.1 | 71545 | 48.7 | ||||
| 10–12 | 36017 | 23.1 | 2023 | 22.3 | 33994 | 23.1 | ||||
| > 12 | 43823 | 28.1 | 2312 | 25.5 | 41511 | 28.2 | ||||
| Immigrant status | 0.2674 | |||||||||
| Born in Sweden | 140224 | 89.8 | 8102 | 89.5 | 132122 | 89.8 | ||||
| Foreign born | 15880 | 10.2 | 952 | 10.5 | 14928 | 10.2 | ||||
| Marital status | <0.001 | |||||||||
| Married | 85474 | 54.8 | 4322 | 47.7 | 81152 | 55.2 | ||||
| Not married | 70630 | 45.2 | 4732 | 52.3 | 65898 | 44.8 | ||||
| Neighborhood deprivation | <0.001 | |||||||||
| Low | 17347 | 11.1 | 966 | 10.7 | 16381 | 11.1 | ||||
| Middle | 78938 | 50.6 | 4306 | 47.6 | 74632 | 50.8 | ||||
| High | 18670 | 12.0 | 1085 | 12.0 | 17585 | 12.0 | ||||
| Unknown | 41149 | 26.4 | 2697 | 29.8 | 38452 | 26.1 | ||||
| Hospital diagnosis | ||||||||||
| Hypertension | 43854 | 28.1 | 2592 | 28.6 | 41262 | 28.1 | 0.2428 | |||
| CHD | 43111 | 27.6 | 2646 | 29.2 | 40465 | 27.5 | <0.001 | |||
| Heart failure | 40502 | 25.9 | 2294 | 25.3 | 38208 | 26.0 | 0.1734 | |||
| Stroke | 25610 | 16.4 | 1808 | 20.0 | 23802 | 16.2 | <0.001 | |||
| Obesity | 1454 | 0.9 | 31 | 0.3 | 1423 | 1.0 | <0.001 | |||
| Diabetes | 17623 | 11.3 | 1012 | 11.2 | 16611 | 11.3 | 0.7289 | |||
| COPD | 10998 | 7.0 | 555 | 6.1 | 10443 | 7.1 | <0.001 | |||
| Depression | 3505 | 2.2 | 314 | 3.5 | 3191 | 2.2 | <0.001 | |||
| Anxiety | 2172 | 1.4 | 148 | 1.6 | 2024 | 1.4 | 0.0418 | |||
| Alcoholism and related disorders | 2932 | 1.9 | 182 | 2.0 | 2750 | 1.9 | 0.3407 | |||
CHD: Coronary heart disease; COPD: Chronic obstructive pulmonary disease
P-value was calculated based on Chi-square test.
Tables 2–4 show Cox regression models for incident dementia for subjects with levothyroxine treatment vs. subjects without treatment, categorized by sex and also for men and women combined. Table 2 shows results in four models, while in Tables 3 and 4 only fully adjusted models are shown. Table 3 is categorized by age-groups, and Table 4 is categorized by type of dementia. We did not observe any association of levothyroxine therapy with incident dementia.
Table 2.
Cox regression of dementia diagnosis among men (n=89,251) and women (n=66,853) with atrial fibrillation HR and with or without Levothyroxine treatment
| Model 1 | Model 2 | Model 3 | Model 4 | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| HR | 95% CI | HR | 95% CI | HR | 95% CI | HR | 95% CI | ||||
| Men | |||||||||||
| Levothyroxine treatment | 1.04 | 0.89 – 1.22 | 1.03 | 0.87 – 1.20 | 1.01 | 0.86–1.19 | 1.01 | 0.86–1.19 | |||
| No treatment | ref | ref | ref | ref | |||||||
| Women | |||||||||||
| Levothyroxine treatment | 1.07 | 0.98 – 1.16 | 1.04 | 0.96 – 1.14 | 1.04 | 0.96–1.13 | 1.04 | 0.95–1.13 | |||
| No treatment | ref | ref | ref | ref | |||||||
| All* | |||||||||||
| Levothyroxine treatment | 1.07 | 0.99 – 1.15 | 1.04 | 0.97 – 1.12 | 1.03 | 0.96 – 1.12 | 1.03 | 0.96 – 1.11 | |||
| No treatment | ref | ref | ref | ref | |||||||
Model 1: Adjusted for age; Model 2: Adjusted for age, educational level, immigrant status, marital status, and neighborhood deprivation; Model 3: Model 2 + comorbidities; Model 4: Model 3 + cardiovascular medications.
Gender was added in the Model 2, Model 3, and Model 4.
Table 4.
Cox regression of dementia diagnosis among men (n=89,251) and women (n=66,853) with atrial fibrillation HR and with or without Levothyroxine treatment in different dementia groups in fully adjusted model
| Alzheimer’s disease | Vascular dementia | Others | ||||||
|---|---|---|---|---|---|---|---|---|
| HR | 95% CI | HR | 95% CI | HR | 95% CI | |||
| Men | ||||||||
| Levothyroxine treatment | 1.05 | 0.78–1.43 | 1.21 | 0.92–1.61 | 0.87 | 0.68–1.12 | ||
| No treatment | ref | ref | ref | |||||
| Women | ||||||||
| Levothyroxine treatment | 1.04 | 0.88–1.23 | 1.03 | 0.86–1.24 | 1.05 | 0.93–1.18 | ||
| No treatment | ref | ref | ref | |||||
| All* | ||||||||
| Levothyroxine treatment | 1.05 | 0.91–1.21 | 1.08 | 0.93–1.26 | 1.01 | 0.91–1.12 | ||
| No treatment | ref | ref | ref | |||||
Full Model: Adjusted for age, educational level, immigrant status, marital status, neighborhood deprivation, comorbidities, and cardiovascular medications.
Gender was added in the fully adjusted model.
Table 3.
Cox regression of dementia diagnosis among men (n=89,251) and women (n=66,853) with atrial fibrillation HR and with or without Levothyroxine treatment in different age-groups in fully adjusted model
| Aged 45–64 years | Aged 65–84 years | Aged 85+ years | ||||||
|---|---|---|---|---|---|---|---|---|
| HR | 95% CI | HR | 95% CI | HR | 95% CI | |||
| Men | ||||||||
| Levothyroxine treatment | 1.84 | 0.68–5.00 | 1.01 | 0.84–1.22 | 0.97 | 0.71–1.34 | ||
| No treatment | ref | ref | ref | |||||
| Women | ||||||||
| Levothyroxine treatment | 0.71 | 0.26–1.95 | 1.06 | 0.95–1.18 | 0.99 | 0.86–1.14. | ||
| No treatment | ref | ref | ref | |||||
| All* | ||||||||
| Levothyroxine treatment | 1.05 | 0.51–2.15 | 1.05 | 0.95–1.15 | 0.99 | 0.87–1.13 | ||
| No treatment | ref | ref | ref | |||||
Full Model: Adjusted for age, educational level, immigrant status, marital status, neighborhood deprivation, comorbidities, and cardiovascular medications.
Gender was added in the fully adjusted model.
Discussion
The main finding of this study was that levothyroxine treatment in AF patients was not associated with different risk of incident dementia. This was true for men and women and also when divided by age-groups and type of dementia.
Our results seem to confirm the conclusion in an earlier review that there is no association between cognitive disturbances and dementia due to thyroid dysfunction [18]. However, there are studies challenging this conclusion. In a study of AF patients in Swedish primary care, a lower risk of dementia was found in women with hypothyroidism and levothyroxine treatment, while no such association was found in men and women with levothyroxine treatment but without a diagnosis of hypothyroidism [19]. Besides, in animal models as an association between treatment with thyroid hormones and an improved brain function has been shown [6, 7]. In contrast, there are other studies showing an increased risk of cerebrovascular diseases associated with treated hypothyroidism [1, 2]. The reason for this discrepancy between studies is unclear, even if differences in methodology used, and populations included, could contribute to this. However, more studies on this topic are needed, including studies with levels of thyroid hormones.
In regard to co-morbidities, individuals with incident dementia have been shown to more often be registered with some diagnoses, also known as risk factors for dementia, i.e. CHD [20], stroke [21], diabetes [22, 23], and depression [24, 25]. Some cardiovascular drugs, including anticoagulant treatment and some antihypertensive drugs, have also been shown to be associated with a lower risk of dementia among AF patients [26, 27]. However, adjusting for these factors only changed the HR estimates marginally.
There are several limitations of this study which must be kept in mind when interpreting the results. We did not have access to levels of thyroid hormones in the study, which could be of importance in further studies. Thus, we could not identify patients with over- or under-treatment with levothyroxine. As this is an observational study there may be residual confounding present, and the result may be affected by biases such as competing risks, i.e. patients may die due to other causes before getting a dementia diagnosis, or survival treatment selection bias [28]. Besides, as dementia develops over a period of many years the results the setting of the diagnosis in relation to time may differ. We included patients with AF registered in hospital care, however, both from in-patient clinics and open care. Another study showed that 12% of all registered AF patients in Stockholm County were only registered with a diagnosis in primary health care, and 9% in ambulatory specialist care, including hospital out-patient clinics [29]. Clinical diagnoses were taken from hospital care, why most diagnosis, i.e. hypertension, diabetes, COPD, depression and anxiety, will be underrepresented as most patients are cared for these diseases in primary care [30]. We included patients with levothyroxine treatment recorded on at least two occasions, to ensure that this was a long-term treatment. However, we had neither data on levothyroxine treatment before 2005, nor on treatment duration. Our intention was to study patients with levothyroxine treatment with and without a diagnosis of hypothyroidism, but as most patients with this diagnosis are cared for in primary care only, a smaller part were identified with this diagnosis (1,711 individuals or 13.8% of all with levothyroxine treatment). In the present study, we only had access to diagnoses of hypothyroidism in the Inpatient Register, while no diagnoses from primary care are included, and we had no possibility to identify patients with levothyroxine treatment without a diagnosis of hypothyroidism. In an earlier, smaller study (n=12,057) of AF patients in primary care, as much as 35% of the patients could not be identified with a diagnosis of hypothyroidism [19]. Furthermore, we did not have access to levels of thyroid hormones. Moreover, AF could not be classified as paroxysmal, persistent or permanent and heart rhythm could not be classified as sinus rhythm or fibrillation rhythm. Additionally, we had not access to data on kidney function. Besides, we have chosen not to report results of co-morbidities and cardiovascular medications used for adjustment, as we are analyzing these factors in other sub-studies, and including them here would go far beyond the main topic of the actual study.
In conclusion, we found no significant differences in incident dementia among AF patients with or without levothyroxine treatment. However, as previous studies show divergent results, it is of interest to perform further studies within this area. Furthermore, it would also be of interest to study the general potential effect of levothyroxine in relation to incident dementia, and not restrict future studies to patients with AF only. Yet, levothyroxine seems to be safe regarding dementia in patients with AF and also in combination with many cardiovascular pharmacotherapies.
Supplementary Material
Key messages.
Use of levothyroxine was not associated with risk of dementia among patients with AF
No association with incident dementia were seen in subgroups of age, as well as in any subgroups of dementia
Funding
This work was supported by ALF funding awarded to Jan Sundquist and Kristina Sundquist and by grants from the Swedish Research Council (awarded to Kristina Sundquist and to Jan Sundquist), and the National Heart, Lung, And Blood Institute of the National Institutes of Health under Award Number R01HL116381 to Kristina Sundquist.
Footnotes
Disclosures
The authors have no conflict of interest to declare.
References
- 1.Landin K, Blennow K, Wallin A, Gottfries CG (1993) Low blood pressure and blood glucose levels in Alzheimer’s disease. Evidence for a hypometabolic disorder? J Intern Med 233 (4): 357–363 [DOI] [PubMed] [Google Scholar]
- 2.Brenowitz WD, Han F, Kukull WA, Nelson PT (2018) Treated hypothyroidism is associated with cerebrovascular disease but not Alzheimer’s disease pathology in older adults. Neurobiol Aging 62: 64–71 DOI S0197-4580(17)30343-3 [pii] 10.1016/j.neurobiolaging.2017.10.004 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Rovet JF (2014) The role of thyroid hormones for brain development and cognitive function. Endocr Dev 26: 26–43 DOI 10.1159/000363153 000363153 [pii] [DOI] [PubMed] [Google Scholar]
- 4.Kollati Y, Ambati RR, Reddy PN, Kumar NSS, Patel RK, Dirisala VR (2017) Congenital Hypothyroidism: Facts, Facets & Therapy. Curr Pharm Des 23 (16): 2308–2313 DOI 10.2174/1381612823666170206124255 CPD-EPUB-81537 [pii] [DOI] [PubMed] [Google Scholar]
- 5.Prinz PN, Scanlan JM, Vitaliano PP, Moe KE, Borson S, Toivola B, Merriam GR, Larsen LH, Reed HL (1999) Thyroid hormones: positive relationships with cognition in healthy, euthyroid older men. J Gerontol A Biol Sci Med Sci 54 (3): M111–116 [DOI] [PubMed] [Google Scholar]
- 6.Rivas M, Naranjo JR (2007) Thyroid hormones, learning and memory. Genes Brain Behav 6 Suppl 1: 40–44 DOI GBB321 [pii] 10.1111/j.1601-183X.2007.00321.x [DOI] [PubMed] [Google Scholar]
- 7.Smith JW, Evans AT, Costall B, Smythe JW (2002) Thyroid hormones, brain function and cognition: a brief review. Neurosci Biobehav Rev 26 (1): 45–60 DOI S0149763401000379 [pii] [DOI] [PubMed] [Google Scholar]
- 8.Aldrugh S, Sardana M, Henninger N, Saczynski JS, McManus DD (2017) Atrial fibrillation, cognition and dementia: A review. J Cardiovasc Electrophysiol 28 (8): 958–965 DOI 10.1111/jce.13261 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Jacobs V, Cutler MJ, Day JD, Bunch TJ (2015) Atrial fibrillation and dementia. Trends Cardiovasc Med 25 (1): 44–51 DOI 10.1016/j.tcm.2014.09.002 S1050–1738(14)00127–3 [pii] [DOI] [PubMed] [Google Scholar]
- 10.Shah AD, Merchant FM, Delurgio DB (2016) Atrial Fibrillation and Risk of Dementia/Cognitive Decline. J Atr Fibrillation 8 (5): 1353 DOI 10.4022/jafib.1353 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Graves KG, May HT, Jacobs V, Bair TL, Stevens SM, Woller SC, Crandall BG, Cutler MJ, Day JD, Mallender C, Osborn JS, Peter Weiss J, Jared Bunch T (2017) Atrial fibrillation incrementally increases dementia risk across all CHADS2 and CHA2DS2VASc strata in patients receiving long-term warfarin. Am Heart J 188: 93–98 DOI S0002-8703(17)30066-2 [pii] 10.1016/j.ahj.2017.02.026 [DOI] [PubMed] [Google Scholar]
- 12.Viscogliosi G, Ettorre E, Chiriac IM (2017) Dementia correlates with anticoagulation underuse in older patients with atrial fibrillation. Arch Gerontol Geriatr 72: 108–112 DOI S0167-4943(16)30315-6 [pii] 10.1016/j.archger.2017.05.014 [DOI] [PubMed] [Google Scholar]
- 13.Wandell P, Carlsson AC, Sundquist J, Sundquist K (2018) Antihypertensive drugs and relevant cardiovascular pharmacotherapies and the risk of incident dementia in patients with atrial fibrillation. Int J Cardiol DOI S0167-5273(18)32760-8 [pii] 10.1016/j.ijcard.2018.07.106 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.van Middelaar T, van Vught LA, Moll van Charante EP, Eurelings LSM, Ligthart SA, van Dalen JW, van den Born BJH, Richard E, van Gool WA (2017) Lower dementia risk with different classes of antihypertensive medication in older patients. J Hypertens 35 (10): 2095–2101 DOI 10.1097/HJH.0000000000001411 [DOI] [PubMed] [Google Scholar]
- 15.Wandell P, Carlsson AC, Holzmann MJ, Arnlov J, Sundquist J, Sundquist K (2017) Comparison of Mortality and Nonfatal Cardiovascular Events in Adults With Atrial Fibrillation With Versus Without Levothyroxine Treatment. Am J Cardiol 120 (11): 1974–1979 DOI S0002-9149(17)31383-8 [pii] 10.1016/j.amjcard.2017.08.013 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Virta LJ, Eskelinen SI (2011) Prevalence of hypothyroidism in Finland--a nationwide prescription study. Eur J Clin Pharmacol 67 (1): 73–77 DOI 10.1007/s00228-010-0884-4 [DOI] [PubMed] [Google Scholar]
- 17.Michelena HI, Powell BD, Brady PA, Friedman PA, Ezekowitz MD (2010) Gender in atrial fibrillation: Ten years later. Gend Med 7 (3): 206–217 DOI S1550-8579(10)00056-2 [pii] 10.1016/j.genm.2010.06.001 [DOI] [PubMed] [Google Scholar]
- 18.SBU (2008) Dementia – Etiology and epidemiology. In: ed.
- 19.Wandell P, Carlsson AC, Sundquist J, Sundquist K (2019) Effect of Levothyroxine Treatment on Incident Dementia in Adults with Atrial Fibrillation and Hypothyroidism. Clin Drug Investig 39 (2): 187–195 DOI 10.1007/s40261-018-0740-3 10.1007/s40261-018-0740-3 [pii] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Deckers K, Schievink SHJ, Rodriquez MMF, van Oostenbrugge RJ, van Boxtel MPJ, Verhey FRJ, Kohler S (2017) Coronary heart disease and risk for cognitive impairment or dementia: Systematic review and meta-analysis. PLoS One 12 (9): e0184244 DOI 10.1371/journal.pone.0184244 PONE-D-17–05997 [pii] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Pendlebury ST, Rothwell PM (2009) Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis. Lancet Neurol 8 (11): 1006–1018 DOI 10.1016/S1474-4422(09)70236-4 S1474–4422(09)70236–4 [pii] [DOI] [PubMed] [Google Scholar]
- 22.Biessels GJ, Strachan MW, Visseren FL, Kappelle LJ, Whitmer RA (2014) Dementia and cognitive decline in type 2 diabetes and prediabetic stages: towards targeted interventions. Lancet Diabetes Endocrinol 2 (3): 246–255 DOI 10.1016/S2213-8587(13)70088-3 S2213–8587(13)70088–3 [pii] [DOI] [PubMed] [Google Scholar]
- 23.Zhang J, Chen C, Hua S, Liao H, Wang M, Xiong Y, Cao F (2017) An updated meta-analysis of cohort studies: Diabetes and risk of Alzheimer’s disease. Diabetes Res Clin Pract 124: 41–47 DOI S0168-8227(16)31537-6 [pii] 10.1016/j.diabres.2016.10.024 [DOI] [PubMed] [Google Scholar]
- 24.Bennett S, Thomas AJ (2014) Depression and dementia: cause, consequence or coincidence? Maturitas 79 (2): 184–190 DOI 10.1016/j.maturitas.2014.05.009 S0378–5122(14)00161–3 [pii] [DOI] [PubMed] [Google Scholar]
- 25.Wiberg P, Waern M, Billstedt E, Ostling S, Skoog I (2013) Secular trends in the prevalence of dementia and depression in Swedish septuagenarians 1976–2006. Psychol Med 43 (12): 2627–2634 DOI 10.1017/S0033291713000299 S0033291713000299 [pii] [DOI] [PubMed] [Google Scholar]
- 26.Friberg L, Rosenqvist M (2018) Less dementia with oral anticoagulation in atrial fibrillation. Eur Heart J 39 (6): 453–460 DOI 10.1093/eurheartj/ehx579 4560111 [pii] [DOI] [PubMed] [Google Scholar]
- 27.Wandell P, Carlsson AC, Sundquist J, Sundquist K (2018) Antihypertensive drugs and relevant cardiovascular pharmacotherapies and the risk of incident dementia in patients with atrial fibrillation. Int J Cardiol 272: 149–154 DOI S0167-5273(18)32760-8 [pii] 10.1016/j.ijcard.2018.07.106 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Delgado-Rodriguez M, Llorca J (2004) Bias. J Epidemiol Community Health 58 (8): 635–641 DOI 10.1136/jech.2003.008466 58/8/635 [pii] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Forslund T, Wettermark B, Wandell P, von Euler M, Hasselstrom J, Hjemdahl P (2013) Risk scoring and thromboprophylactic treatment of patients with atrial fibrillation with and without access to primary healthcare data: experience from the Stockholm health care system. Int J Cardiol 170 (2): 208–214 DOI 10.1016/j.ijcard.2013.10.063 S0167–5273(13)01907–4 [pii] [DOI] [PubMed] [Google Scholar]
- 30.Carlsson AC, Wandell P, Osby U, Zarrinkoub R, Wettermark B, Ljunggren G (2013) High prevalence of diagnosis of diabetes, depression, anxiety, hypertension, asthma and COPD in the total population of Stockholm, Sweden - a challenge for public health. BMC Public Health 13: 670 DOI 10.1186/1471-2458-13-670 1471-2458-13-670 [pii] [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.