EpidemiologyVascular risk factors for Alzheimer’s disease:: An epidemiologic perspective
Introduction
Alzheimer’s disease is a heterogeneous and multifactorial disorder. Its frequency increases strongly with age, from less than 1% in people aged 65 years to over 25% in those who are aged 85 years or over. Reliable age- and gender-specific estimates of the incidence of Alzheimer’s disease exist only for subjects over the age of 60. Gender-specific incidence rates are quite similar until the age of 85 years, after which the incidence rates seem higher for women than for men [33], [69]. One in eight men, and almost one in four women, will suffer at least some of their lifetime from Alzheimer’s disease. Over the last decade, epidemiologic evidence is accumulating that, particularly in elderly subjects, vascular risk factors and indicators of vascular disease are associated with cognitive impairment and Alzheimer’s disease [13], [40], and that presence of cerebrovascular disease intensifies the presence and severity of the clinical symptoms of Alzheimer’s disease [86]. In this paper, current epidemiological evidence for a relation between vascular risk factors and Alzheimer’s disease will be reviewed. The focus will be on ‘classical’ vascular risk factors, including hypertension, diabetes mellitus, cholesterol, presence of atherosclerosis, atrial fibrillation, and cigarette smoking. In addition, more recently identified vascular risk factors will be reviewed, including APOE genotype, serum homocysteine concentration, relative abnormalities in the hemostatic and thrombotic systems, inflammation, and alcohol consumption.
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Hypertension
Hypertension is one of the most important risk factors for stroke and coronary heart disease, and it is an important risk factor for vascular dementia. The relation with Alzheimer’s disease is less unequivocal. In a longitudinal study reported by Skoog et al, both systolic and diastolic blood pressure was increased 10 to 15 years before the onset of AD [84]. In that study, the risk of developing dementia between the ages of 80 and 85 increased with increasing blood pressure at the age of 70.
Diabetes mellitus
Some older cross-sectional case-control studies showed diabetes mellitus to be positively associated with vascular dementia, but inversely with Alzheimer’s disease [17], [50], [59], [62], [98]. However, these studies were based on selected patients and controls, the presence of diabetes mellitus was assessed from medical records and not actually screened for, and subjects with any indication of vascular disease were rigorously excluded from the patient series. More recent studies, both
Cholesterol
The relation between plasma cholesterol levels and Alzheimer’s disease is of interest. The ϵ4 allele of the apolipoprotein E (APOE) gene (APOE∗4) is associated with Alzheimer’s disease (AD) and also with increased plasma cholesterol, low-density lipoprotein levels, atherosclerosis and cardiovascular disease [27], [93]. Besides, Sparks et al. reported dose-dependent amyloid accumulations in the brains of rabbits that were fed a high-cholesterol diet [87]. There have been only few epidemiologic
Existing cardiovascular disease
Clinical (cardio)vascular disease has hardly been studied in relation to Alzheimer’s disease. Because of the diagnostic criteria for Alzheimer’s disease, patients with clinical vascular disease are less likely to be diagnosed as Alzheimer patients [14]. However, Aronson et al. reported that coronary artery disease is common among women developing Alzheimer’s disease [4]. In a study among 4971 subjects, those with overt or clinically silent vascular disease performed worse on cognitive tests
Atrial fibrillation
Cardiac dysrythmias have long been suspected to aggravate or precipitate dementia [2], yet studies on cognitive performance or risk of dementia in patients with atrial fibrillation are rare. Recently, two studies reported worse cognitive performance in nondemented subjects with as compared to subjects without atrial fibrillation [46], [66]. In the Rotterdam Study, atrial fibrillation as assessed in standard 12-lead ECGs, was significantly more frequent among subjects with dementia (age- and
Smoking
The relation between smoking and Alzheimer’s disease is much disputed. A meta-analysis on case-control studies conducted before 1990 suggested an inverse association between Alzheimer’s disease and history of smoking [36]. Studies conducted since then showed no relation [[3], [31], [39], [97],99], an inverse relation [12], [54], or a positive relation [75]. Another meta-analysis yielded again an inverse relation between smoking history and Alzheimer’s disease [52]. There are some biologically
Apolipoprotein E
APOE has been studied in relation to vascular disease because of its central role in lipid metabolism [56]. The ϵ4 allele is associated with increased serum total cholesterol levels, and with increased risk of atherosclerosis and coronary artery disease [25], [93]. The relation of APOE with cerebrovascular disease is controversial. Much more is known about the relation between APOE genotype and Alzheimer’s disease. Since the first reports of a link between APOE∗4 and Alzheimer’s disease in 1993
Homocysteine
There is increasing evidence that a raised blood level of homocysteine is a risk factor for cardiovascular disease [24] as well as cerebrovascular disease and stroke [10], [73]. Plasma levels of vitamin B12 and folate are important determinants of plasma homocysteine concentration, and homocysteine concentration is a sensitive marker for vitamin B12 and folate deficiency. It is generally recommended to routinely determine serum vitamin B12 levels as part of the screening of demented patients,
Thrombosis
Thrombosis plays a central role in the pathogenesis of vascular disease. This raises the question whether hemostatic status is also of importance for the development of dementia. A low anticoagulant response of plasma to activated protein C (APC), or APC resistance, is an abnormality of the coagulation system that increases the risk of venous thrombosis as well as stroke [49], [91]. A low APC response is frequently due to the factor V Leiden mutation [5]; however, no association between factor
Inflammation
Inflammatory factors play a role in Alzheimer’s disease, and beta amyloid induces a local inflammatory reaction that contributes to the progression of the disease [27], [57], [75]. Epidemiologic studies have reported lower risk of Alzheimer’s disease in subjects that used nonsteroid antiinflammatory drugs [1], [11]. Although these studies can be criticized on methodological grounds, and may be biased, they lend some support to a possible relation between chronic inflammation and Alzheimer’s
Alcohol
The relation between alcohol intake and the risk of vascular diseases, including stroke, is J-shaped: Moderate alcohol consumption protects from vascular disease, but with increasing alcohol intake the risk gradually increases. Most studies reported no evidence for an altered risk of Alzheimer’s disease in people with moderate alcohol intake [3], [12], [36], but alcohol abuse has been reported to significantly increase the risk of dementia or Alzheimer’s disease [32], [81]. Recently, the Paquid
Conclusion
It is relatively novel that etiological research in Alzheimer’s disease also focuses on vascular risk factors, and available evidence is still limited. Evidence is accumulating though that vascular risk factors and vascular disease increase the risk of dementia, including Alzheimer’s disease. Findings from other research areas corroborate the epidemiological reports of involvement of vascular disease processes in Alzheimer’s disease. It is as yet unclear what underlies the associations between
Acknowledgements
This paper was previously published as a chapter in the book “Cerebrovascular Amyloidosis (CAA) in Alzheimer’s Disease and Related Disorders”; Verbeek MM, Vinters HV, de Waal RMW (eds.) Wolters Kluwer Academic Publishers, Dordrecht, The Netherlands, 2000.
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