- Open Access
Cardiovascular risk factors and future risk of Alzheimer’s disease
BMC Medicine volume 12, Article number: 130 (2014)
Alzheimer’s disease (AD) is the most common neurodegenerative disorder in elderly people, but there are still no curative options. Senile plaques and neurofibrillary tangles are considered hallmarks of AD, but cerebrovascular pathology is also common. In this review, we summarize findings on cardiovascular disease (CVD) and risk factors in the etiology of AD. Firstly, we discuss the association of clinical CVD (such as stroke and heart disease) and AD. Secondly, we summarize the relation between imaging makers of pre-clinical vascular disease and AD. Lastly, we discuss the association of cardiovascular risk factors and AD. We discuss both established cardiovascular risk factors and emerging putative risk factors, which exert their effect partly via CVD.
Alzheimer’s disease (AD) is the most common subtype of dementia, and has a large patient and societal burden. AD has a complex and multifactorial etiology that involves senile plaques and neurofibrillary tangles . Increasingly, the role of cardiovascular disease (CVD) is also being recognized as an important etiologic hallmark of AD. Indeed, many studies have shown the importance of vascular pathology in AD -. As CVDs have established therapeutic options and the risk factors of CVD are modifiable, focusing on the association between vascular pathology and AD might provide pathways to prevent or delay AD in elderly individuals ,. In this narrative review, we provide an overview of the current knowledge on the relation between AD and clinical CVDs, imaging markers of pre-clinical CVD, and established and emerging cardiovascular risk factors (Table 1).
CVDs, such as stroke, atrial fibrillation, coronary heart disease (CHD), and heart failure are very common in elderly individuals and have regularly been linked to AD. This association might be due to shared risk factors between CVDs and AD, but there might also be a direct causal association as cardiac disease causes hypoperfusion and microemboli, which have been implicated in the etiology of AD ,. In the following sections, we discuss current evidence relating common CVDs with risk of AD.
Clinical stroke has often been associated with an increased risk of subsequent dementia, but this is by definition then termed `post-stroke dementia’ or `vascular dementia’ . Such terminology hampers thorough investigation of the role of clinical stroke in AD. Therefore, important evidence implicating stroke in the etiology of AD comes from studies investigating asymptomatic or `silent’ stroke, which are often lacunae. Numerous studies have shown that lacunae strongly increase the risk of dementia, including AD -. Moreover, white matter lesions, which also represent ischemic brain damage, are also associated with cognitive impairment and AD ,. These findings suggest that stroke is causally involved in the etiology of dementia. Mechanisms underlying this association include the following. Firstly, stroke causes loss of neuronal tissue, which might enhance the degenerative effect of neuronal tissue loss as a result of amyloid and tau pathology . Secondly, it has been suggested that cerebrovascular disease directly influences amyloid pathology as a result of accelerating amyloid β production or hampering amyloid β clearance ,, although studies on these pathways remain inconsistent ,-.
Several studies have shown that individuals with atrial fibrillation (AF) more often have AD and are at an increased risk of AD -. Because AF causes embolisms that could lead to stroke, the relation between AF and AD might be explained by clinical or silent stroke ,-. Accordingly, a meta-analysis showed that a consistent relation between AF and a higher risk of dementia was restricted to individuals with stroke . However, another study found that stroke-free individuals with AF performed worse on memory and learning tasks, and had a reduced hippocampal volume . Both memory function and hippocampal volume are strongly related to AD, which suggests there might be additional pathways explaining the association between AF and AD . One hypothesis is that cerebral hypoperfusion in AF causes damage to nerve cells, and thereby contributes to the etiology of AD ,-. Another hypothesis is that AF directly influences AD neuropathology, such as senile plaques and neurofibrillary tangles, but evidence for this explanation remains scarce .
Coronary heart disease
CHD is the most common type of heart disease, and one of the major causes of death worldwide . CHD includes angina pectoris, myocardial infarction (MI), and coronary revascularization procedures. The relation between CHD and AD remains difficult to disentangle because of strong competing risks of death; several studies showed that CHD is related to cognitive impairment or AD ,, whereas others found no association ,. The Rotterdam Study showed that unrecognized MI was associated with the risk of AD, whereas recognized MI was not . Explanations linking CHD with AD include shared etiology, as atherosclerosis plays an important role in both CHD and AD ,. This hypothesis is corroborated by findings from the Cardiovascular Health Study, which showed that peripheral artery disease, another manifestation of atherosclerosis, was also strongly associated with an increased risk of AD . Furthermore, CHD might relate to AD through diminished cardiac function, hypoperfusion, and emboli ,-.
Heart failure represents a condition in which the pumping function of the heart is diminished and unable to supply the body with sufficient blood flow. Heart failure has been associated with cognitive impairment and AD -. A Swedish study found that heart failure was related to an increased risk of dementia, including AD . The same study also found that treatment with anti-hypertensive drugs slightly reduced this risk. The Framingham Offspring Study showed that even in individuals without clinical heart failure, lower cardiac function was related to lower brain volume, an important hallmark for dementia . The pathways explaining the role of heart failure in the etiology of AD are similar to those of AF; heart failure results in hypoperfusion of the brain, which leads to hypoxia and damage to nerve cells ,,-. Additionally, heart failure increases the risk of emboli and microvascular pathology, such as white matter lesions and lacunae, which in turn are related to an increased risk of dementia ,-.
Pre-clinical markers of cardiovascular disease
Cardiovascular pathology gradually accumulates over years before manifesting as a clinical event. Similarly, AD pathology also accumulates over decades before clinical symptoms occur. Consequently, several studies have sought to investigate how such pre-clinical pathology relates to cognitive decline and AD.
Pre-clinical markers of large vessel disease
Using various imaging techniques, it is possible to assess markers of pre-clinical large vessel disease. Intima media thickness (IMT) and carotid plaque are measures of atherosclerosis in the carotid artery, which can be obtained via ultrasonography. Both IMT and carotid plaque are more prevalent in patients with dementia and AD than in cognitively healthy individuals . Moreover, both measures are related to increased cognitive decline in patients with AD . Additionally, several population-based studies have shown that individuals with the highest IMT measures have an increased risk of incident dementia, including AD ,,. Carotid plaque scores were also associated with an increased risk of AD in one study, but this association lacked statistical significance . Another marker of pre-clinical large vessel disease is calcification volume in the atherosclerotic plaque, which can be assessed using computed tomography (CT). Although calcification is only part of the plaque, it is a suitable measure of the underlying plaque burden . CT has the disadvantage of radiation exposure, but CT measures of atherosclerotic calcification are more observer-independent than ultrasonography measures. Few studies have investigated the relation between CT-derived atherosclerotic calcification and dementia, but some studies found that larger calcification volumes in the coronary arteries, aortic arch, and carotid arteries relate to worse cognitive performance ,. Moreover, larger calcification volume was associated with smaller brain tissue volumes and worse microstructural integrity of the white matter, which are both factors related to an increased risk of AD . Mechanisms linking carotid large vessel disease to AD include sub-clinical cerebral small vessel disease (see below), hypoperfusion, or shared etiology ,,.
Pre-clinical markers of cerebral small vessel disease
Abundant evidence shows that structural imaging markers of cerebral small vessel disease, such as lacunae and white matter lesions, are related to cognitive impairment or AD -,-. Additionally, brain atrophy, which is an established marker of dementia and AD, is partly influenced by CVD ,,. Cerebral microbleeds (CMBs) are an emerging vascular marker with great promise for AD research. Both amyloid β and vascular pathology are related to the etiology of CMBs, and therefore a link between CMBs and incident AD seems plausible -. However, this association still needs to be confirmed in longitudinal studies. In recent years, it has also become possible to visualize cerebral microinfarcts using high-field magnetic resonance imaging (MRI) scanners, such as 7 T scanners. The role of these microinfarcts in AD remains unclear, but is expected to be the focus of research in coming years ,. Although it is possible to measure markers of cerebral small vessel disease, direct visualization of the small cerebral arterioles in vivo remains difficult. Retinal imaging provides an easy tool to visualize retinal vessels that originate embryologically from the same tissues as cerebral vessels. Thus retinal imaging provides a possibility to study the small vessels of the brain in vivo. Retinal vessel diameter has been associated with white matter lesions, infarcts, brain atrophy, and an increased risk of vascular dementia -. Although a recent case-control study also found a link between AD and retinal microvascular changes , there is currently no evidence relating retinal vessels to an increased risk of AD longitudinally.
Measures of brain connectivity
In recent years, development of newer imaging techniques has allowed quantification of more subtle brain pathology such as changes in brain connectivity. Diffusion tensor imaging (DTI) assesses the microstructural integrity of the white matter, and studies have suggested that DTI markers reflect a very early stage of vascular brain pathology. Consequently, several studies have shown loss of microstructural integrity in early AD or even in mild cognitive impairment (MCI) -. However, longitudinal studies relating DTI markers to incident AD are still largely lacking. Another novel MRI technique is resting-state functional MRI, which measures brain function by functional connectivity at rest. Several studies have shown that functional connectivity is altered in patients with MCI and AD -, but again, robust longitudinal data are still lacking. Moreover, the role of cardiovascular risk factors in functional MRI remains unclear.
Cardiovascular risk factors
In addition to clinical CVDs (see above), risk factors of CVD have also been implicated in AD. The causal pathway of these risk factors might be associated with clinical disease, but there is also evidence directly linking cardiovascular risk factors with AD.
Blood pressure, hypertension, and arterial stiffness
Several studies have related hypertension to brain atrophy, white matter lesions, and neurofibrillary tangles -. Therefore, an association between hypertension and AD is conceivable. Nonetheless, this association is complex and differs with age . Several studies show mid-life hypertension to be related to an increased risk of AD -, whereas other studies failed to find an association between late-life hypertension and dementia. In fact, some studies even suggest low blood pressure might be related to AD . These inconsistencies have yet not been elucidated, but it is suggested that blood pressure decreases in the years before clinical onset of dementia because of reduced physical activity and lowered body weight. Further research is still necessary to verify this hypothesis .
A measure closely related to blood pressure and hypertension is arterial stiffness, which can be measured as increased pulse pressure or elevated pulse wave velocity. The difficulty in investigating arterial stiffness lies in the fact that it can be caused by hypertension as well as leading to hypertension ,. Arterial stiffness results in increased pulsatile pressure, causing damage to the microvascular system of the brain , which in turn causes cognitive decline . Indeed, some studies found a relation between higher pulse pressure or higher pulse wave velocity and an increased prevalence and risk of cognitive decline or AD -; however, others could not demonstrate such an association ,.
Glucose metabolism and diabetes mellitus
Type 2 diabetes mellitus (T2DM) is a complex disorder, in which insulin resistance leads to higher circulating blood glucose levels, which in turn lead to microvascular damage in various organs. In the brain, T2DM has been associated with infarcts and atrophy ,. Accordingly, many studies have confirmed that the risk of dementia and AD is higher in individuals with T2DM . Furthermore, the risk of AD is also increased in individuals with borderline T2DM, that is, pre-diabetes . Besides microvascular damage, other potential mechanisms relating T2DM with AD are direct neurotoxicity due to increased glucose and insulin levels. A higher circulating blood glucose level is toxic to nerve cells, as it causes protein glycation and oxidative stress . Insulin is involved in amyloid β clearance from the brain, and higher levels of insulin could disrupt this metabolism, leading to increased amyloid β burden .
Given the role of cholesterol in the clearance of amyloid β, hypercholesterolemia has been suggested as a risk factor for AD. Support for this hypothesis comes from a recent imaging study showing higher cholesterol levels to be related to higher amyloid β levels . Similarly, apolipoprotein E ε4-carrier status, one of the most important genetic risk factors of AD, is related to increased cholesterol levels . However, results of epidemiological studies on the association between hypercholesterolemia and AD have been inconsistent. Some studies found that hypercholesterolemia in mid-life was associated with an increased risk of AD, whereas in late life there was no association . An explanation is that a high cholesterol level in mid-life is a risk factor of AD, whereas lower cholesterol levels in late life probably reflect pre-clinical disease, as lifestyle and dietary habits change in individuals with sub-clinical dementia.
Various longitudinal studies have established smoking as a risk factor for dementia and AD . Both the Rotterdam Study and the Honolulu-Asia Aging Study found that the risk of dementia in smokers was higher than that in non-smokers ,. Furthermore, the Honolulu-Asia Aging Study found that number of pack-years was related to amyloid burden in the brain in a dose-response manner . Smoking contributes to atherosclerosis, and has been related to cerebral small vessel disease ,. Additionally, tobacco contains many neurotoxins, which might cause direct neuronal damage . However, the exact mechanisms underlying the relation between smoking and dementia require further investigation.
Similar to hypertension and increased cholesterol levels, the association between obesity and risk of dementia and AD changes with age -. Obesity in mid-life is associated with an increased risk of dementia and AD, whereas in older age a higher body weight seems to have a protective effect ,. Individuals with sub-clinical dementia gradually lose body weight due to altered lifestyle and lowered food intake, and thus low body weight might also be an early symptom of dementia -. In contrast, mid-life obesity increases the risk of many chronic diseases, including vascular diseases, and could be related to an increased risk of dementia and AD via those pathways .
Mediterranean diet and physical activity
The Mediterranean diet is characterized by a high intake of vegetables, fruits, cereals, and unsaturated fatty acids, a moderate intake of fish, poultry, eggs, red wine, and dairy products, and a low intake of saturated fats and red, processed meats . Adherence to a Mediterranean diet has shown to reduce vascular disease and vascular risk factors, and to lower inflammation and oxidative stress . Two recent meta-analyses concluded that adherence to a Mediterranean diet might reduce the risk of AD ,. However, the number of studies with long follow-up is limited, and further research is necessary to confirm the potential protective effect of the Mediterranean diet on AD.
Besides dietary habits, another potential modifiable factor to reduce AD risk is physical activity ,. Physical activity is inversely associated with CVD and diabetes, and could therefore also reduce the risk of AD ,. Alternatively, physical activity could have a direct protective effect on the risk of dementia, as it improves cerebral perfusion and increases neurogenesis ,. Several epidemiological studies have associated a higher level of physical activity with a reduced risk of dementia or cognitive decline -. However, most of these studies had relatively short follow-up, and studies with long follow-up periods have yielded inconsistent results ,. For both physical activity levels and the Mediterranean diet, the possibility of reverse causality explaining short-term associations needs to be considered .
Plasma homocysteine levels reflect folate and vitamin B12 status, and are related to renal function. Increased homocysteine levels are associated with vascular disease, and might have an effect on amyloid β and tau phosphorylation. Consequently, high plasma homocysteine levels have been related to an increased risk of AD . Imaging and autopsy studies showed that increased homocysteine levels were associated with brain atrophy and neurofibrillary tangles ,. However, not all studies concur with these results. A recent study found that plasma homocysteine levels were not related to AD, after adjusting for folate or vitamin B12 deficiency and renal dysfunction . Further studies are needed to unravel this association.
Emerging risk factors
In addition to the classic vascular risk factors, there are other emerging risk factors that have been implicated in AD, partly by vascular mechanisms.
Various inflammatory markers have been related to an increased risk of dementia, including AD -. Astrocytes and microglia activate the neuronal immune system in response to pathogens such as infection and vascular pathology ,. Several studies showed that senile plaques in the brains of patients with AD and of AD transgenic mice models were surrounded by an increased number of activated microglia . Amyloid β also activates the neuronal immune system, and might cause a chronic inflammatory reaction that has a toxic effect on nerve cells . Moreover, recent genetic studies have uncovered various genes for inflammation and immune response that seem to be associated with AD . However, there have been no major population-based cohort studies studying inflammation in AD, and trials studying the effect of immunotherapy on AD have not yet been successful . Hence, further studies are required to elucidate the exact role of inflammation in AD.
Chronic kidney disease
In recent years, various studies have focused on the association between chronic kidney disease (CKD) and cognitive decline or AD. Most -, but not all  of these studies found that low kidney function was related to an increased risk of dementia, AD, or cognitive decline. These inconsistencies might be due to methodological discrepancies: different measures of kidney function were used, and there was a large variation across the study populations examined . Mechanisms linking CKD and dementia include shared risk factors (such as hypertension, arterial stiffness, smoking, and obesity) and direct consequences of CKD (such as chronic inflammation, hemodynamic changes, anemia, and uremic toxins) . However, these pathways are not well established, and should be investigated further.
Thyroid hormone is important for brain function, and thyroid dysfunction is a potentially reversible cause of cognitive impairment . Thyroid hormone is involved in amyloid precursor protein (APP) regulation. Animal studies have shown that APP expression is increased in hypothyroidism, which leads to higher amyloid β levels . In addition, thyroid dysfunction is associated with CVD, and could therefore influence AD pathology indirectly . Lastly, thyroid hormone levels alter as a consequence of AD pathology through reduction in thyrotropin releasing hormone secretion . Observational studies have shown both hypothyroidism and hyperthyroidism to be related to AD, but not all studies could establish an association -.
In conclusion, there is abundant and converging evidence showing that CVDs and cardiovascular risk factors play an important role in the etiology of AD. While for some of these factors the mechanisms linking to AD are clear, for others the association with AD is more complex and needs further research to be completely unraveled. Nevertheless, given that these vascular factors are currently the only known modifiable risk factors for AD, the possibility of intervening with these factors to prevent or delay AD merits more dedicated research.
RB and MAI both made substantial contributions to conception and design of the manuscript, and were involved in drafting the manuscript and revising it critically for important intellectual content. Both authors read and approved the final manuscript.
Amyloid precursor protein
Coronary heart disease
Chronic kidney disease
Diffusion tensor imaging
Intima media thickness
Mild cognitive impairment
Magnetic resonance imaging
Type 2 diabetes mellitus
Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E: Alzheimer’s disease. Lancet. 2011, 377: 1019-1031. 10.1016/S0140-6736(10)61349-9.
Jagust W: Untangling vascular dementia. Lancet. 2001, 358: 2097-2098. 10.1016/S0140-6736(01)07230-0.
Iadecola C: The pathobiology of vascular dementia. Neuron. 2013, 80: 844-866. 10.1016/j.neuron.2013.10.008.
de la Torre JC: Is Alzheimer’s disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics. Lancet Neurol. 2004, 3: 184-190. 10.1016/S1474-4422(04)00683-0.
Hachinski V, Munoz DG: Cerebrovascular pathology in Alzheimer’s disease: cause, effect or epiphenomenon?. Ann N Y Acad Sci. 1997, 826: 1-6. 10.1111/j.1749-6632.1997.tb48456.x.
Kelleher RJ, Soiza RL: Evidence of endothelial dysfunction in the development of Alzheimer’s disease: Is Alzheimer’s a vascular disorder?. Am J Cardiovasc Dis. 2013, 3: 197-226.
Hachinski V: Stroke and Alzheimer disease: fellow travelers or partners in crime?. Arch Neurol. 2011, 68: 797-798.
de la Torre JC: Vascular risk factor detection and control may prevent Alzheimer’s disease. Ageing Res Rev. 2010, 9: 218-225. 10.1016/j.arr.2010.04.002.
Middleton LE, Yaffe K: Promising strategies for the prevention of dementia. Arch Neurol. 2009, 66: 1210-1215.
Goldberg I, Auriel E, Russell D, Korczyn AD: Microembolism, silent brain infarcts and dementia. J Neurol Sci. 2012, 322: 250-253. 10.1016/j.jns.2012.02.021.
de la Torre JC: Cardiovascular risk factors promote brain hypoperfusion leading to cognitive decline and dementia. Cardiovasc Psychiatry Neurol. 2012, 2012: 367516.
Leys D, Henon H, Mackowiak-Cordoliani MA, Pasquier F: Poststroke dementia. Lancet Neurol. 2005, 4: 752-759. 10.1016/S1474-4422(05)70221-0.
Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM: Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med. 2003, 348: 1215-1222. 10.1056/NEJMoa022066.
Troncoso JC, Zonderman AB, Resnick SM, Crain B, Pletnikova O, O'Brien RJ: Effect of infarcts on dementia in the Baltimore longitudinal study of aging. Ann Neurol. 2008, 64: 168-176. 10.1002/ana.21413.
Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR: Brain infarction and the clinical expression of Alzheimer disease, the Nun Study. JAMA. 1997, 277: 813-817. 10.1001/jama.1997.03540340047031.
Inaba M, White L, Bell C, Chen R, Petrovitch H, Launer L, Abbott RD, Ross GW, Masaki K: White matter lesions on brain magnetic resonance imaging scan and 5-year cognitive decline: the Honolulu-Asia aging study. J Am Geriatr Soc. 2011, 59: 1484-1489. 10.1111/j.1532-5415.2011.03490.x.
Prins ND, van Dijk EJ, den Heijer T, Vermeer SE, Koudstaal PJ, Oudkerk M, Hofman A, Breteler MM: Cerebral white matter lesions and the risk of dementia. Arch Neurol. 2004, 61: 1531-1534. 10.1001/archneur.61.10.1531.
Garcia-Alloza M, Gregory J, Kuchibhotla KV, Fine S, Wei Y, Ayata C, Frosch MP, Greenberg SM, Bacskai BJ: Cerebrovascular lesions induce transient beta-amyloid deposition. Brain. 2011, 134: 3697-3707. 10.1093/brain/awr300.
Noh Y, Seo SW, Jeon S, Lee JM, Kim JH, Kim GH, Cho H, Yoon CW, Kim HJ, Ye BS, Kim ST, Choe YS, Lee KH, Kim JS, Ewers M, Weiner MW, Lee JH, Werring DJ, Kang DR, Kim CS, Na DL: White matter hyperintensities are associated with amyloid burden in APOE4 non-carriers. J Alzheimers Dis. 2014, 40: 877-886.
Lee MJ, Seo SW, Na DL, Kim C, Park JH, Kim GH, Kim CH, Noh Y, Cho H, Kim HJ, Yoon CW, Ye BS, Chin J, Jeon S, Lee JM, Choe YS, Lee KH, Kim JS, Kim ST, Lee JH, Ewers M, Werring DJ, Weiner MW: Synergistic effects of ischemia and beta-amyloid burden on cognitive decline in patients with subcortical vascular mild cognitive impairment. JAMA Psychiatry. 2014, 71: 412-422. 10.1001/jamapsychiatry.2013.4506.
Launer LJ, Petrovitch H, Ross GW, Markesbery W, White LR: AD brain pathology: vascular origins? Results from the HAAS autopsy study. Neurobiol Aging. 2008, 29: 1587-1590. 10.1016/j.neurobiolaging.2007.03.008.
Ott A, Breteler MM, de Bruyne MC, van Harskamp F, Grobbee DE, Hofman A: Atrial fibrillation and dementia in a population-based study, the Rotterdam Study. Stroke. 1997, 28: 316-321. 10.1161/01.STR.28.2.316.
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. 10.1212/WNL.0b013e31820f2e38.
Bunch TJ, Weiss JP, Crandall BG, May HT, Bair TL, Osborn JS, Anderson JL, Muhlestein JB, Horne BD, Lappe DL, Day JD: Atrial fibrillation is independently associated with senile, vascular, and Alzheimer’s dementia. Heart Rhythm. 2010, 7: 433-437. 10.1016/j.hrthm.2009.12.004.
Muqtadar H, Testai FD, Gorelick PB: The dementia of cardiac disease. Curr Cardiol Rep. 2012, 14: 732-740. 10.1007/s11886-012-0304-8.
Justin BN, Turek M, Hakim AM: Heart disease as a risk factor for dementia. Clin Epidemiol. 2013, 5: 135-145.
Duron E, Hanon O: Vascular risk factors, cognitive decline, and dementia. Vasc Health Risk Manag. 2008, 4: 363-381.
Knecht S, Oelschlager C, Duning T, Lohmann H, Albers J, Stehling C, Heindel W, Breithardt G, Berger K, Ringelstein EB, Kirchhof P, Wersching H: Atrial fibrillation in stroke-free patients is associated with memory impairment and hippocampal atrophy. Eur Heart J. 2008, 29: 2125-2132. 10.1093/eurheartj/ehn341.
Jack CR, Shiung MM, Weigand SD, O'Brien PC, Gunter JL, Boeve BF, Knopman DS, Smith GE, Ivnik RJ, Tangalos EG, Petersen RC: Brain atrophy rates predict subsequent clinical conversion in normal elderly and amnestic MCI. Neurology. 2005, 65: 1227-1231. 10.1212/01.wnl.0000180958.22678.91.
Dublin S, Anderson ML, Heckbert SR, Hubbard RA, Sonnen JA, Crane PK, Montine TJ, Larson EB: Neuropathologic changes associated with atrial fibrillation in a population-based autopsy cohort. J Gerontol A Biol Sci Med Sci. 2013, 69: 609-615. 10.1093/gerona/glt141.
Opie LH, Commerford PJ, Gersh BJ: Controversies in stable coronary artery disease. Lancet. 2006, 367: 69-78. 10.1016/S0140-6736(06)67927-0.
Newman AB, Fitzpatrick AL, Lopez O, Jackson S, Lyketsos C, Jagust W, Ives D, Dekosky ST, Kuller LH: Dementia and Alzheimer’s disease incidence in relationship to cardiovascular disease in the Cardiovascular Health Study cohort. J Am Geriatr Soc. 2005, 53: 1101-1107. 10.1111/j.1532-5415.2005.53360.x.
Roberts RO, Knopman DS, Geda YE, Cha RH, Roger VL, Petersen RC: Coronary heart disease is associated with non-amnestic mild cognitive impairment. Neurobiol Aging. 2010, 31: 1894-1902. 10.1016/j.neurobiolaging.2008.10.018.
Knopman DS, Petersen RC, Cha RH, Edland SD, Rocca WA: Coronary artery bypass grafting is not a risk factor for dementia or Alzheimer disease. Neurology. 2005, 65: 986-990. 10.1212/01.WNL.0000171954.92119.c7.
Petrovitch H, White L, Masaki KH, Ross GW, Abbott RD, Rodriguez BL, Lu G, Burchfiel CM, Blanchette PL, Curb JD: Influence of myocardial infarction, coronary artery bypass surgery, and stroke on cognitive impairment in late life. Am J Cardiol. 1998, 81: 1017-1021. 10.1016/S0002-9149(98)00082-4.
Ikram MA, van Oijen M, de Jong FJ, Kors JA, Koudstaal PJ, Hofman A, Witteman JC, Breteler MM: Unrecognized myocardial infarction in relation to risk of dementia and cerebral small vessel disease. Stroke. 2008, 39: 1421-1426. 10.1161/STROKEAHA.107.501106.
Qiu C, Winblad B, Marengoni A, Klarin I, Fastbom J, Fratiglioni L: Heart failure and risk of dementia and Alzheimer disease: a population-based cohort study. Arch Intern Med. 2006, 166: 1003-1008. 10.1001/archinte.166.9.1003.
Huijts M, van Oostenbrugge RJ, Duits A, Burkard T, Muzzarelli S, Maeder MT, Schindler R, Pfisterer ME, Brunner-La Rocca HP, Investigators T-C: Cognitive impairment in heart failure: results from the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF) randomized trial. Eur J Heart Fail. 2013, 15: 699-707. 10.1093/eurjhf/hft020.
Ganguli M, Fu B, Snitz BE, Hughes TF, Chang CC: Mild cognitive impairment: incidence and vascular risk factors in a population-based cohort. Neurology. 2013, 80: 2112-2120. 10.1212/WNL.0b013e318295d776.
Jefferson AL, Himali JJ, Beiser AS, Au R, Massaro JM, Seshadri S, Gona P, Salton CJ, DeCarli C, O'Donnell CJ, Benjamin EJ, Wolf PA, Manning WJ: Cardiac index is associated with brain aging: the Framingham Heart Study. Circulation. 2010, 122: 690-697. 10.1161/CIRCULATIONAHA.109.905091.
Hofman A, Ott A, Breteler MM, Bots ML, Slooter AJ, van Harskamp F, van Duijn CN, Van Broeckhoven C, Grobbee DE: Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer’s disease in the Rotterdam Study. Lancet. 1997, 349: 151-154. 10.1016/S0140-6736(96)09328-2.
Silvestrini M, Gobbi B, Pasqualetti P, Bartolini M, Baruffaldi R, Lanciotti C, Cerqua R, Altamura C, Provinciali L, Vernieri F: Carotid atherosclerosis and cognitive decline in patients with Alzheimer’s disease. Neurobiol Aging. 2009, 30: 1177-1183. 10.1016/j.neurobiolaging.2007.11.008.
van Oijen M, de Jong FJ, Witteman JC, Hofman A, Koudstaal PJ, Breteler MM: Atherosclerosis and risk for dementia. Ann Neurol. 2007, 61: 403-410. 10.1002/ana.21073.
Wendell CR, Waldstein SR, Ferrucci L, O'Brien RJ, Strait JB, Zonderman AB: Carotid atherosclerosis and prospective risk of dementia. Stroke. 2012, 43: 3319-3324. 10.1161/STROKEAHA.112.672527.
Rumberger JA, Simons DB, Fitzpatrick LA, Sheedy PF, Schwartz RS: Coronary artery calcium area by electron-beam computed tomography and coronary atherosclerotic plaque area, A histopathologic correlative study. Circulation. 1995, 92: 2157-2162. 10.1161/01.CIR.92.8.2157.
Bos D, Vernooij MW, Elias-Smale SE, Verhaaren BF, Vrooman HA, Hofman A, Niessen WJ, Witteman JC, van der Lugt A, Ikram MA: Atherosclerotic calcification relates to cognitive function and to brain changes on magnetic resonance imaging. Alzheimers Dement. 2012, 8: S104-S111. 10.1016/j.jalz.2012.01.008.
Reis JP, Launer LJ, Terry JG, Loria CM, Zeki Al Hazzouri A, Sidney S, Yaffe K, Jacobs DR, Whitlow CT, Zhu N, Carr JJ: Subclinical atherosclerotic calcification and cognitive functioning in middle-aged adults: the CARDIA study. Atherosclerosis. 2013, 231: 72-77. 10.1016/j.atherosclerosis.2013.08.038.
Blum S, Luchsinger JA, Manly JJ, Schupf N, Stern Y, Brown TR, DeCarli C, Small SA, Mayeux R, Brickman AM: Memory after silent stroke: hippocampus and infarcts both matter. Neurology. 2012, 78: 38-46. 10.1212/WNL.0b013e31823ed0cc.
van Dijk EJ, Prins ND, Vrooman HA, Hofman A, Koudstaal PJ, Breteler MM: Progression of cerebral small vessel disease in relation to risk factors and cognitive consequences: Rotterdam Scan study. Stroke. 2008, 39: 2712-2719. 10.1161/STROKEAHA.107.513176.
Jokinen H, Gouw AA, Madureira S, Ylikoski R, van Straaten EC, van der Flier WM, Barkhof F, Scheltens P, Fazekas F, Schmidt R, Verdelho A, Ferro JM, Pantoni L, Inzitari D, Erkinjuntti T, Group LS: Incident lacunes influence cognitive decline: the LADIS study. Neurology. 2011, 76: 1872-1878. 10.1212/WNL.0b013e31821d752f.
Cardenas VA, Reed B, Chao LL, Chui H, Sanossian N, DeCarli CC, Mack W, Kramer J, Hodis HN, Yan M, Buonocore MH, Carmichael O, Jagust WJ, Weiner MW: Associations among vascular risk factors, carotid atherosclerosis, and cortical volume and thickness in older adults. Stroke. 2012, 43: 2865-2870. 10.1161/STROKEAHA.112.659722.
den Heijer T, van der Lijn F, Ikram A, Koudstaal PJ, van der Lugt A, Krestin GP, Vrooman HA, Hofman A, Niessen WJ, Breteler MM: Vascular risk factors, apolipoprotein E, and hippocampal decline on magnetic resonance imaging over a 10-year follow-up. Alzheimers Dement. 2012, 8: 417-425. 10.1016/j.jalz.2011.07.005.
Goos JD, Kester MI, Barkhof F, Klein M, Blankenstein MA, Scheltens P, van der Flier WM: Patients with Alzheimer disease with multiple microbleeds: relation with cerebrospinal fluid biomarkers and cognition. Stroke. 2009, 40: 3455-3460. 10.1161/STROKEAHA.109.558197.
Goos JD, Henneman WJ, Sluimer JD, Vrenken H, Sluimer IC, Barkhof F, Blankenstein MA, Scheltens PH, van der Flier WM: Incidence of cerebral microbleeds: a longitudinal study in a memory clinic population. Neurology. 2010, 74: 1954-1960. 10.1212/WNL.0b013e3181e396ea.
Vernooij MW, van der Lugt A, Ikram MA, Wielopolski PA, Niessen WJ, Hofman A, Krestin GP, Breteler MM: Prevalence and risk factors of cerebral microbleeds: the Rotterdam Scan Study. Neurology. 2008, 70: 1208-1214. 10.1212/01.wnl.0000307750.41970.d9.
van Rooden S, Goos JD, van Opstal AM, Versluis MJ, Webb AG, Blauw GJ, van der Flier WM, Scheltens P, Barkhof F, van Buchem MA, van der Grond J: Increased number of microinfarcts in Alzheimer disease at 7-T MR imaging. Radiology. 2014, 270: 205-211. 10.1148/radiol.13130743.
van Veluw SJ, Zwanenburg JJ, Engelen-Lee J, Spliet WG, Hendrikse J, Luijten PR, Biessels GJ: In vivo detection of cerebral cortical microinfarcts with high-resolution 7 T MRI. J Cereb Blood Flow Metab. 2013, 33: 322-329. 10.1038/jcbfm.2012.196.
de Jong FJ, Schrijvers EM, Ikram MK, Koudstaal PJ, de Jong PT, Hofman A, Vingerling JR, Breteler MM: Retinal vascular caliber and risk of dementia: the Rotterdam study. Neurology. 2011, 76: 816-821. 10.1212/WNL.0b013e31820e7baa.
Ikram MK, De Jong FJ, Van Dijk EJ, Prins ND, Hofman A, Breteler MM, De Jong PT: Retinal vessel diameters and cerebral small vessel disease: the Rotterdam Scan Study. Brain. 2006, 129: 182-188. 10.1093/brain/awh688.
Ikram MK, de Jong FJ, Vernooij MW, Hofman A, Niessen WJ, van der Lugt A, Klaver CC, Ikram MA: Retinal vascular calibers associate differentially with cerebral gray matter and white matter atrophy. Alzheimer Dis Assoc Disord. 2013, 27: 351-355. 10.1097/WAD.0b013e31829344ed.
Cheung CY, Ong YT, Ikram MK, Ong SY, Li X, Hilal S, Catindig JA, Venketasubramanian N, Yap P, Seow D, Chen CP, Wong TY: Microvascular network alterations in the retina of patients with Alzheimer’s disease. Alzheimers Dement. 2014, 10: 135-142. 10.1016/j.jalz.2013.06.009.
Sexton CE, Kalu UG, Filippini N, Mackay CE, Ebmeier KP: A meta-analysis of diffusion tensor imaging in mild cognitive impairment and Alzheimer’s disease. Neurobiol Aging. 2011, 32: 2322 e2325-2318. 10.1016/j.neurobiolaging.2010.05.019.
Wang JH, Lv PY, Wang HB, Li ZL, Li N, Sun ZY, Zhao BH, Huang Y: Diffusion tensor imaging measures of normal appearing white matter in patients who are aging, or have amnestic mild cognitive impairment, or Alzheimer’s disease. J Clin Neurosci. 2013, 20: 1089-1094. 10.1016/j.jocn.2012.09.025.
Scola E, Bozzali M, Agosta F, Magnani G, Franceschi M, Sormani MP, Cercignani M, Pagani E, Falautano M, Filippi M, Falini A: A diffusion tensor MRI study of patients with MCI and AD with a 2-year clinical follow-up. J Neurol Neurosurg Psychiatry. 2010, 81: 798-805. 10.1136/jnnp.2009.189639.
Binnewijzend MA, Schoonheim MM, Sanz-Arigita E, Wink AM, van der Flier WM, Tolboom N, Adriaanse SM, Damoiseaux JS, Scheltens P, van Berckel BN, Barkhof F: Resting-state fMRI changes in Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging. 2012, 33: 2018-2028. 10.1016/j.neurobiolaging.2011.07.003.
Greicius MD, Srivastava G, Reiss AL, Menon V: Default-mode network activity distinguishes Alzheimer’s disease from healthy aging: evidence from functional MRI. Proc Natl Acad Sci U S A. 2004, 101: 4637-4642. 10.1073/pnas.0308627101.
Rombouts SA, Barkhof F, Goekoop R, Stam CJ, Scheltens P: Altered resting state networks in mild cognitive impairment and mild Alzheimer’s disease: an fMRI study. Hum Brain Mapp. 2005, 26: 231-239. 10.1002/hbm.20160.
Sheline YI, Raichle ME: Resting state functional connectivity in preclinical Alzheimer’s disease. Biol Psychiatry. 2013, 74: 340-347. 10.1016/j.biopsych.2012.11.028.
Kenny ER, O'Brien JT, Firbank MJ, Blamire AM: Subcortical connectivity in dementia with Lewy bodies and Alzheimer’s disease. Br J Psychiatry. 2013, 203: 209-214. 10.1192/bjp.bp.112.108464.
van Dijk EJ, Breteler MM, Schmidt R, Berger K, Nilsson LG, Oudkerk M, Pajak A, Sans S, de Ridder M, Dufouil C, Fuhrer R, Giampaoli S, Launer LJ, Hofman A: The association between blood pressure, hypertension, and cerebral white matter lesions: cardiovascular determinants of dementia study. Hypertension. 2004, 44: 625-630. 10.1161/01.HYP.0000145857.98904.20.
den Heijer T, Launer LJ, Prins ND, van Dijk EJ, Vermeer SE, Hofman A, Koudstaal PJ, Breteler MM: Association between blood pressure, white matter lesions, and atrophy of the medial temporal lobe. Neurology. 2005, 64: 263-267. 10.1212/01.WNL.0000149641.55751.2E.
Petrovitch H, White LR, Izmirilian G, Ross GW, Havlik RJ, Markesbery W, Nelson J, Davis DG, Hardman J, Foley DJ, Launer LJ: Midlife blood pressure and neuritic plaques, neurofibrillary tangles, and brain weight at death: the HAAS. Honolulu-Asia aging Study. Neurobiol Aging. 2000, 21: 57-62.
Qiu C, Winblad B, Fratiglioni L: The age-dependent relation of blood pressure to cognitive function and dementia. Lancet Neurol. 2005, 4: 487-499. 10.1016/S1474-4422(05)70141-1.
Launer LJ, Ross GW, Petrovitch H, Masaki K, Foley D, White LR, Havlik RJ: Midlife blood pressure and dementia: the Honolulu-Asia aging study. Neurobiol Aging. 2000, 21: 49-55. 10.1016/S0197-4580(00)00096-8.
Whitmer RA, Sidney S, Selby J, Johnston SC, Yaffe K: Midlife cardiovascular risk factors and risk of dementia in late life. Neurology. 2005, 64: 277-281. 10.1212/01.WNL.0000149519.47454.F2.
Kivipelto M, Helkala EL, Laakso MP, Hanninen T, Hallikainen M, Alhainen K, Iivonen S, Mannermaa A, Tuomilehto J, Nissinen A, Soininen H: Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Ann Intern Med. 2002, 137: 149-155. 10.7326/0003-4819-137-3-200208060-00006.
Joas E, Backman K, Gustafson D, Ostling S, Waern M, Guo X, Skoog I: Blood pressure trajectories from midlife to late life in relation to dementia in women followed for 37 years. Hypertension. 2012, 59: 796-801. 10.1161/HYPERTENSIONAHA.111.182204.
Kaess BM, Rong J, Larson MG, Hamburg NM, Vita JA, Levy D, Benjamin EJ, Vasan RS, Mitchell GF: Aortic stiffness, blood pressure progression, and incident hypertension. JAMA. 2012, 308: 875-881. 10.1001/2012.jama.10503.
Gepner AD, Korcarz CE, Colangelo LA, Hom EK, Tattersall MC, Astor BC, Kaufman JD, Liu K, Stein JH: Longitudinal effects of a decade of aging on carotid artery stiffness: the multiethnic study of atherosclerosis. Stroke. 2014, 45: 48-53. 10.1161/STROKEAHA.113.002649.
O'Rourke MF, Safar ME: Relationship between aortic stiffening and microvascular disease in brain and kidney: cause and logic of therapy. Hypertension. 2005, 46: 200-204. 10.1161/01.HYP.0000168052.00426.65.
Hanon O, Haulon S, Lenoir H, Seux ML, Rigaud AS, Safar M, Girerd X, Forette F: Relationship between arterial stiffness and cognitive function in elderly subjects with complaints of memory loss. Stroke. 2005, 36: 2193-2197. 10.1161/01.STR.0000181771.82518.1c.
Waldstein SR, Rice SC, Thayer JF, Najjar SS, Scuteri A, Zonderman AB: Pulse pressure and pulse wave velocity are related to cognitive decline in the Baltimore Longitudinal Study of Aging. Hypertension. 2008, 51: 99-104. 10.1161/HYPERTENSIONAHA.107.093674.
Qiu C, Winblad B, Viitanen M, Fratiglioni L: Pulse pressure and risk of Alzheimer disease in persons aged 75 years and older: a community-based, longitudinal study. Stroke. 2003, 34: 594-599. 10.1161/01.STR.0000060127.96986.F4.
Poels MM, van Oijen M, Mattace-Raso FU, Hofman A, Koudstaal PJ, Witteman JC, Breteler MM: Arterial stiffness, cognitive decline, and risk of dementia: the Rotterdam study. Stroke. 2007, 38: 888-892. 10.1161/01.STR.0000257998.33768.87.
Dhoat S, Ali K, Bulpitt CJ, Rajkumar C: Vascular compliance is reduced in vascular dementia and not in Alzheimer’s disease. Age Ageing. 2008, 37: 653-659. 10.1093/ageing/afn158.
Schmidt R, Launer LJ, Nilsson LG, Pajak A, Sans S, Berger K, Breteler MM, de Ridder M, Dufouil C, Fuhrer R, Giampaoli S, Hofman A, Consortium C: Magnetic resonance imaging of the brain in diabetes: the Cardiovascular Determinants of Dementia (CASCADE) Study. Diabetes. 2004, 53: 687-692. 10.2337/diabetes.53.3.687.
Peila R, Rodriguez BL, Launer LJ, Honolulu-Asia Aging S: Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: the Honolulu-Asia Aging Study. Diabetes. 2002, 51: 1256-1262. 10.2337/diabetes.51.4.1256.
Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P: Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol. 2006, 5: 64-74. 10.1016/S1474-4422(05)70284-2.
Xu W, Qiu C, Winblad B, Fratiglioni L: The effect of borderline diabetes on the risk of dementia and Alzheimer’s disease. Diabetes. 2007, 56: 211-216. 10.2337/db06-0879.
Reed B, Villeneuve S, Mack W, Decarli C, Chui HC, Jagust W: Associations between serum cholesterol levels and cerebral amyloidosis. JAMA Neurol. 2014, 71: 195-200. 10.1001/jamaneurol.2013.5390.
Eichner JE, Dunn ST, Perveen G, Thompson DM, Stewart KE, Stroehla BC: Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. Am J Epidemiol. 2002, 155: 487-495. 10.1093/aje/155.6.487.
Anstey KJ, Lipnicki DM, Low LF: Cholesterol as a risk factor for dementia and cognitive decline: a systematic review of prospective studies with meta-analysis. Am J Geriatr Psychiatry. 2008, 16: 343-354. 10.1097/01.JGP.0000310778.20870.ae.
Anstey KJ, von Sanden C, Salim A, O'Kearney R: Smoking as a risk factor for dementia and cognitive decline: a meta-analysis of prospective studies. Am J Epidemiol. 2007, 166: 367-378. 10.1093/aje/kwm116.
Reitz C, den Heijer T, van Duijn C, Hofman A, Breteler MM: Relation between smoking and risk of dementia and Alzheimer disease: the Rotterdam Study. Neurology. 2007, 69: 998-1005. 10.1212/01.wnl.0000271395.29695.9a.
Tyas SL, White LR, Petrovitch H, Webster Ross G, Foley DJ, Heimovitz HK, Launer LJ: Mid-life smoking and late-life dementia: the Honolulu-Asia Aging Study. Neurobiol Aging. 2003, 24: 589-596. 10.1016/S0197-4580(02)00156-2.
Messner B, Bernhard D: Smoking and cardiovascular disease: mechanisms of endothelial dysfunction and early atherogenesis. Arterioscler Thromb Vasc Biol. 2014, 34: 509-515. 10.1161/ATVBAHA.113.300156.
Treweek JB, Dickerson TJ, Janda KD: Drugs of abuse that mediate advanced glycation end product formation: a chemical link to disease pathology. Acc Chem Res. 2009, 42: 659-669. 10.1021/ar800247d.
Besser LM, Gill DP, Monsell SE, Brenowitz W, Meranus DH, Kukull W, Gustafson DR: Body mass index, weight change, and clinical progression in mild cognitive impairment and Alzheimer disease. Alzheimer Dis Assoc Disord. 2014, 28: 36-43. 10.1097/WAD.0000000000000005.
Gu Y, Scarmeas N, Cosentino S, Brandt J, Albert M, Blacker D, Dubois B, Stern Y: Change in body mass index before and after Alzheimer’s disease onset.Curr Alzheimer Res. in press.
Tolppanen AM, Ngandu T, Kareholt I, Laatikainen T, Rusanen M, Soininen H, Kivipelto M: Midlife and late-life body mass index and late-life dementia: results from a prospective population-based cohort. J Alzheimers Dis. 2014, 38: 201-209.
Xu WL, Atti AR, Gatz M, Pedersen NL, Johansson B, Fratiglioni L: Midlife overweight and obesity increase late-life dementia risk: a population-based twin study. Neurology. 2011, 76: 1568-1574. 10.1212/WNL.0b013e3182190d09.
Trichopoulou A, Costacou T, Bamia C, Trichopoulos D: Adherence to a Mediterranean diet and survival in a Greek population. N Engl J Med. 2003, 348: 2599-2608. 10.1056/NEJMoa025039.
Frisardi V, Panza F, Seripa D, Imbimbo BP, Vendemiale G, Pilotto A, Solfrizzi V: Nutraceutical properties of Mediterranean diet and cognitive decline: possible underlying mechanisms. J Alzheimers Dis. 2010, 22: 715-740.
Psaltopoulou T, Sergentanis TN, Panagiotakos DB, Sergentanis IN, Kosti R, Scarmeas N: Mediterranean diet, stroke, cognitive impairment, and depression: a meta-analysis. Ann Neurol. 2013, 74: 580-591. 10.1002/ana.23944.
Singh B, Parsaik AK, Mielke MM, Erwin PJ, Knopman DS, Petersen RC, Roberts RO: Association of mediterranean diet with mild cognitive impairment and Alzheimer’s disease: a systematic review and meta-analysis. J Alzheimers Dis. 2014, 39: 271-282.
Hamer M, Chida Y: Physical activity and risk of neurodegenerative disease: a systematic review of prospective evidence. Psychol Med. 2009, 39: 3-11. 10.1017/S0033291708003681.
Berlin JA, Colditz GA: A meta-analysis of physical activity in the prevention of coronary heart disease. Am J Epidemiol. 1990, 132: 612-628.
Helmrich SP, Ragland DR, Leung RW, Paffenbarger RS: Physical activity and reduced occurrence of non-insulin-dependent diabetes mellitus. N Engl J Med. 1991, 325: 147-152. 10.1056/NEJM199107183250302.
van Praag H, Christie BR, Sejnowski TJ, Gage FH: Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci U S A. 1999, 96: 13427-13431. 10.1073/pnas.96.23.13427.
Pereira AC, Huddleston DE, Brickman AM, Sosunov AA, Hen R, McKhann GM, Sloan R, Gage FH, Brown TR, Small SA: An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci U S A. 2007, 104: 5638-5643. 10.1073/pnas.0611721104.
Buchman AS, Boyle PA, Yu L, Shah RC, Wilson RS, Bennett DA: Total daily physical activity and the risk of AD and cognitive decline in older adults. Neurology. 2012, 78: 1323-1329. 10.1212/WNL.0b013e3182535d35.
Scarmeas N, Luchsinger JA, Schupf N, Brickman AM, Cosentino S, Tang MX, Stern Y: Physical activity, diet, and risk of Alzheimer disease. JAMA. 2009, 302: 627-637. 10.1001/jama.2009.1144.
Barnes DE, Blackwell T, Stone KL, Goldman SE, Hillier T, Yaffe K: Cognition in older women: the importance of daytime movement. J Am Geriatr Soc. 2008, 56: 1658-1664. 10.1111/j.1532-5415.2008.01841.x.
Middleton LE, Manini TM, Simonsick EM, Harris TB, Barnes DE, Tylavsky F, Brach JS, Everhart JE, Yaffe K: Activity energy expenditure and incident cognitive impairment in older adults. Arch Intern Med. 2011, 171: 1251-1257. 10.1001/archinternmed.2011.277.
Rovio S, Kareholt I, Helkala EL, Viitanen M, Winblad B, Tuomilehto J, Soininen H, Nissinen A, Kivipelto M: Leisure-time physical activity at midlife and the risk of dementia and Alzheimer’s disease. Lancet Neurol. 2005, 4: 705-711. 10.1016/S1474-4422(05)70198-8.
Morgan GS, Gallacher J, Bayer A, Fish M, Ebrahim S, Ben-Shlomo Y: Physical activity in middle-age and dementia in later life: findings from a prospective cohort of men in Caerphilly, South Wales and a meta-analysis. J Alzheimers Dis. 2012, 31: 569-580.
de Bruijn RF, Schrijvers EM, de Groot KA, Witteman JC, Hofman A, Franco OH, Koudstaal PJ, Ikram MA: The association between physical activity and dementia in an elderly population: the Rotterdam Study. Eur J Epidemiol. 2013, 28: 277-283. 10.1007/s10654-013-9773-3.
Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, Wilson PW, Wolf PA: Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med. 2002, 346: 476-483. 10.1056/NEJMoa011613.
den Heijer T, Vermeer SE, Clarke R, Oudkerk M, Koudstaal PJ, Hofman A, Breteler MM: Homocysteine and brain atrophy on MRI of non-demented elderly. Brain. 2003, 126: 170-175. 10.1093/brain/awg006.
Hooshmand B, Polvikoski T, Kivipelto M, Tanskanen M, Myllykangas L, Erkinjuntti T, Makela M, Oinas M, Paetau A, Scheltens P, van Straaten EC, Sulkava R, Solomon A: Plasma homocysteine, Alzheimer and cerebrovascular pathology: a population-based autopsy study. Brain. 2013, 136: 2707-2716. 10.1093/brain/awt206.
Nilsson K, Gustafson L, Hultberg B: Elevated plasma homocysteine level is not primarily related to Alzheimer’s disease. Dement Geriatr Cogn Disord. 2012, 34: 121-127. 10.1159/000342612.
Engelhart MJ, Geerlings MI, Meijer J, Kiliaan A, Ruitenberg A, van Swieten JC, Stijnen T, Hofman A, Witteman JC, Breteler MM: Inflammatory proteins in plasma and the risk of dementia: the Rotterdam Study. Arch Neurol. 2004, 61: 668-672. 10.1001/archneur.61.5.668.
van Oijen M, van der Meer IM, Hofman A, Witteman JC, Koudstaal PJ, Breteler MM: Lipoprotein-associated phospholipase A2 is associated with risk of dementia. Ann Neurol. 2006, 59: 139-144. 10.1002/ana.20721.
van Oijen M, Witteman JC, Hofman A, Koudstaal PJ, Breteler MM: Fibrinogen is associated with an increased risk of Alzheimer disease and vascular dementia. Stroke. 2005, 36: 2637-2641. 10.1161/01.STR.0000189721.31432.26.
Ferreira ST, Clarke JR, Bomfim TR, De Felice FG: Inflammation, defective insulin signaling, and neuronal dysfunction in Alzheimer’s disease. Alzheimers Dement. 2014, 10: S76-S83. 10.1016/j.jalz.2013.12.010.
Serpente M, Bonsi R, Scarpini E, Galimberti D: Innate immune system and inflammation in Alzheimer’s disease: from pathogenesis to treatment. Neuroimmunomodulation. 2014, 21: 79-87.
Liu L, Chan C: The role of inflammasome in Alzheimer’s disease. Ageing Res Rev. 2014, 15: 6-15. 10.1016/j.arr.2013.12.007.
Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, DeStafano AL, Bis JC, Beecham GW, Grenier-Boley B, Russo G, Thorton-Wells TA, Jones N, Smith AV, Chouraki V, Thomas C, Ikram MA, Zelenika D, Vardarajan BN, Kamatani Y, Lin CF, Gerrish A, Schmidt H, Kunkle B, Dunstan ML, Ruiz A, Bihoreau MT, Choi SH, Reitz C, Pasquier F, et al: Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet. 2013, 45: 1452-1458. 10.1038/ng.2802.
Bugnicourt JM, Godefroy O, Chillon JM, Choukroun G, Massy ZA: Cognitive disorders and dementia in CKD: the neglected kidney-brain axis. J Am Soc Nephrol. 2013, 24: 353-363. 10.1681/ASN.2012050536.
Miwa K, Tanaka M, Okazaki S, Furukado S, Yagita Y, Sakaguchi M, Mochizuki H, Kitagawa K: Chronic kidney disease is associated with dementia independent of cerebral small-vessel disease. Neurology. 2014, 82: 1051-1057. 10.1212/WNL.0000000000000251.
Cheng KC, Chen YL, Lai SW, Mou CH, Tsai PY, Sung FC: Patients with chronic kidney disease are at an elevated risk of dementia: a population-based cohort study in Taiwan. BMC Nephrol. 2012, 13: 129-10.1186/1471-2369-13-129.
Etgen T, Chonchol M, Forstl H, Sander D: Chronic kidney disease and cognitive impairment: a systematic review and meta-analysis. Am J Nephrol. 2012, 35: 474-482. 10.1159/000338135.
Sasaki Y, Marioni R, Kasai M, Ishii H, Yamaguchi S, Meguro K: Chronic kidney disease: a risk factor for dementia onset: a population-based study, the Osaki-Tajiri Project. J Am Geriatr Soc. 2011, 59: 1175-1181. 10.1111/j.1532-5415.2011.03477.x.
Helmer C, Stengel B, Metzger M, Froissart M, Massy ZA, Tzourio C, Berr C, Dartigues JF: Chronic kidney disease, cognitive decline, and incident dementia: the 3C Study. Neurology. 2011, 77: 2043-2051. 10.1212/WNL.0b013e31823b4765.
Tan ZS, Vasan RS: Thyroid function and Alzheimer’s disease. J Alzheimers Dis. 2009, 16: 503-507.
Tan ZS, Beiser A, Vasan RS, Au R, Auerbach S, Kiel DP, Wolf PA, Seshadri S: Thyroid function and the risk of Alzheimer disease: the Framingham Study. Arch Intern Med. 2008, 168: 1514-1520. 10.1001/archinte.168.14.1514.
Forti P, Olivelli V, Rietti E, Maltoni B, Pirazzoli G, Gatti R, Gioia MG, Ravaglia G: Serum thyroid-stimulating hormone as a predictor of cognitive impairment in an elderly cohort. Gerontology. 2012, 58: 41-49. 10.1159/000324522.
de Jong FJ, Masaki K, Chen H, Remaley AT, Breteler MM, Petrovitch H, White LR, Launer LJ: Thyroid function, the risk of dementia and neuropathologic changes: the Honolulu-Asia aging study. Neurobiol Aging. 2009, 30: 600-606. 10.1016/j.neurobiolaging.2007.07.019.
de Jong FJ, den Heijer T, Visser TJ, de Rijke YB, Drexhage HA, Hofman A, Breteler MM: Thyroid hormones, dementia, and atrophy of the medial temporal lobe. J Clin Endocrinol Metab. 2006, 91: 2569-2573. 10.1210/jc.2006-0449.
Kalmijn S, Mehta KM, Pols HA, Hofman A, Drexhage HA, Breteler MM: Subclinical hyperthyroidism and the risk of dementia, the Rotterdam study. Clin Endocrinol (Oxf). 2000, 53: 733-737. 10.1046/j.1365-2265.2000.01146.x.
MAI was supported by the Netherlands Heart Foundation (2012-T008), Internationale Stichting Alzheimer Onderzoek (grant number 12533), Erasmus MC Fellowship 2013, and MRACE grant from Erasmus MC.
The authors declare that they have no competing interests.
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de Bruijn, R.F., Ikram, M.A. Cardiovascular risk factors and future risk of Alzheimer’s disease. BMC Med 12, 130 (2014). https://doi.org/10.1186/s12916-014-0130-5
- Cardiovascular disease
- Imaging markers
- Risk factors
- Alzheimer’s disease