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https://doi.org/10.47803/rjc.2020.30.1.12

Márta Germán-Salló1,2, Mónika Szabó1,3, Zoltán Preg1,2, Enikő Nemes-Nagy4, Dalma Bálint-Szentendrey1,2, Tünde Pál5

1 George Emil Palade” University of Medicine, Pharmacy, Science and Technology, Targu Mures, Romania
2 Department of Cardiovascular Rehabilitation, Emergency Clinical County Hospital, Targu Mures, Romania
3 Department of Diabetes, Nutrition and Metabolic Diseases, Emergency Clinical County Hospital, Targu Mures, Romania
4 Department of Fundamental Pharmaceutical Sciences, „George Emil Palade” University of Medicine, Pharmacy, Science and Technology, Targu Mures, Romania
5 Emergency Institute for Cardiovascular Diseases and Transplantation, Targu Mures, Romania

Abstract: Dementia represents a major health problem in elderly people. Several lifestyle-related and cardiovascular risk factors contribute to cognitive dysfunction, some of them can be counteracted, thus reducing the prevalence of dementia. Hypertension causes brain damage inducing micro- and macrovascular modifi cations, which can develop silently. Diabetes mellitus represents a major risk factor for cognitive decline due to hyperglycaemia, insulin resistance and chronic inflamma-tion. Smoking increases the risk of dementia inducing vascular modifications and neurotoxicity. Midlife obesity is another risk factor for dementia, being associated with brain atrophy and having influence on other cardiovascular risk factors. Hyper-cholesterolemia, especially increased LDL-cholesterol might contribute to the development of dementia, but the results are controversial. Physical exercise has a protective effect on neuro-degenerative processes, especially the combination of aerobic and resistance exercise seems to have the best impact on cognitive function. These risk factors represent targets for intervention in preventing cognitive dysfunction, and screening can be helpful in the early diagnosis of this disease. Keywords: cognitive dysfunction, dementia, modifiable risk factors, hypertension, type 2 diabetes.

Rezumat: Demenţa reprezintă o problemă majoră de sănătate la vârstnici. Există câţiva factori de risc cardiovascular legaţi de stilul de viaţă, care pot contribui la declinul funcţiilor cognitive. Unii dintre aceştia pot fi influenţaţi prin măsuri de prevenţie, făcând astfel posibilă reducerea prevalenţei demenţei. Hipertensiunea duce la apariţia leziunilor cerebrale care, la rândul lor, provoacă modificări micro- şi macrovasculare care se pot dezvolta silenţios. Diabetul zaharat reprezintă un fac-tor major de risc pentru declinul cognitiv, mecanismele implicate fiind reprezentate de hiperglicemie, creşterea rezistenţei la insulină şi infl amaţia cronică. Fumatul creşte riscul de demenţă prin dezvoltarea modifi cărilor vasculare aterosclerotice şi având efect de neurotoxicitate directă. Obezitatea prezentă la vârstă medie este un alt factor de risc pentru demenţă, fiind asociat cu atrofie cerebrală şi având influenţă asupra altor factori de risc cardiovascular. Hipercolesterolemia, în spe-cial creşterea LDL colesterolului, ar putea contribui la dezvoltarea demenţei, dar rezultatele studiilor sunt controversate. Exerciţiul fizic are un efect protector asupra proceselor neuro-degenerative, în special combinaţia dintre exerciţiile aerobe şi de rezistenţă, care par să aibă cel mai benefic efect asupra funcţiilor cognitive. Aceşti factori de risc reprezintă obiective importante pentru prevenirea disfuncţiei cognitive, iar screening-ul declinului cognitiv şi al demenţei poate fi util în diagnos-ticarea precoce a acestei boli cu impact social important.
Cuvinte cheie: disfuncţie cognitivă, demenţă, factori de risc modifi cabili, hipertensiune arterială, diabet zaharat tip 2.

INTRODUCTION
Dementia is decribed as continuous decline of cogni-tive function and it is recognized as a major contribu-tor to disability and dependency amongst the elderly. There is an alarmingly rapid increase in the number of people living with dementia across the world. In 2015 dementia affected 47 million people, 63% coming from low-and middle income countries1. By 2050 a near ex-ponential rise is expected reaching a total number of 135 million people, attributable to aging and growth of population1. Although age is undoubtedly the most important risk factor for cognitive decline, dementia is not a normal part of ageing. The most frequently encountered forms of dementia are Alzheimer disease (AD) representing 70% of all cases and vascular de-mentia (VaD) in 15%1. Almost half a century ago re-searchers found a connection between heart disease and altering cognitive function and named it „cardioge-nic dementia”2. Despite this, insight to this matter has been ignored until the early 1990s. Since than, more and more studies focused on understanding the link between cardiovascular risk factors and cognitive de-cline.
Currently there is a considerable amount of scien-tific evidence supporting that cardiovascular diseases and dementia share potentially modifiable risk fac-tors3. Lifestyle related factors like smoking, sedenta-rism, diet and other major cardiovascular risk factors like hypertension, diabetes mellitus, hypercholestero-lemia, obesity are linked to vascular injury as well as neurodegenerative lesions of the brain3-5. These chan-ges lead to worsening cognitive abilities and they can vary from subclinical forms to major neurocognitive disorders called dementia. Subtle modifications in dai-ly functioning or behavior refl ecting subjective cogni-tive failure (SCF) or mild cognitive impairment (MCI) are frequently overlooked, or interpreted in context of the normal aging process. At least half of dementia cases are preceded by mild neurocognitive disorders5.
Dementia was considered an unpreventable affecti-on for a long time. Lately, progresses have been made in this field. Based on a modelling exercise, decreasing level of risk by 10% could lower the overall prevalence of dementia by 8.3%. Furthermore, it is likely to pre-vent more than one third of dementia cases adopting a life-course approach, which takes into account the additive and cummulative effects of modifi able risk fac-tos over the lifespan1. However, only identifying and targeting risk factors in early to midlife seems to have such on impact or at least delay or slow cognitive impairment and dementia. As currently dementia has no cure, evaluating and modifying dementia risk factors is a huge challenge in lowering dementia prevalence.
In this report we summarize the latest findings on six modifiable vascular risk factors connected to cognitive compromise and dementia: arterial hypertension, dia-betes mellitus, smoking, obesity, hypercholesterolemia and physical exercise. Additionally, we synthethise currently available evidence related to interventions on these risk factors proven to be effective in influencing cognitive health.

Hypertension
There is mounting evidence that hypertension is a ma-jor contributor to cognitive decline as well as demen-tia. The association is complex, and variable through the life-span, and still unsettled.
Brain is one of the most vulnerable target organ affected by hypertension. Long term effect of eleva-ted pressures are silent lesions of the brain, ischaemic and haemorrhagic stroke. Mechanisms through which hypertension becomes a risk factor for cognitive de-cline are complex. Microvascular and macrovascular changes are involved, resulting in functional and struc-tural cerebrovascular modifi cations. The deleterious effects of higher pressures result in endothelial dys-function and lesions secondary to mechanical stress, increased vascular resistance and stiffness, reduced vascular lumen caused by vascular smooth muscle hypertrophy. Ultimately, these modifi cations decrea-se cerebral blood flow, alter cerebral autoregulation, predispose to accumulation of beta amyloid, thus com-promising the metabolism and structure of the brain. Vascular changes localized at the resistance vessels are known as cerebral small vesssel disease, and can be si-lent. Markers of cerebral small vessel disease are pre-sent in 35% of hypertensive patients and they can be detected by magnetic resonance imaging (MRI)5. The-se are white matter hyperintensities (WMH), cerebral microbleeds (CMB), lacunar infarcts (LI) and enlarged perivascular spaces (EPS)5. Studies focusing on these lesions concluded that all four markers are related to high blood pressure and cognitive impairment. Addi-tionally results of a recent systematic review showed an association between the stiffening of the large ar-teries, microvascular brain disease and poor cognitive performance6.
Evidence on the association between blood pre-ssure and cognition come mostly from observational studies. We learned from epidemiological cross-sec-tional and longitudinal surveys, that hypertension is one of the most important and most widely explored congitive decline and dementia risk factor, although controversies still exist. On one hand, most of the re-searchers agree that cognitive impairment and demen-tia are more frequent in patients with hypertension5,7, while others found higher prevalence rate connected to hypotension. A U–shaped relationship between hypertension and cognitive abilities has also been de-scribed8. On the other hand, there is strong evidence that high blood pressure starting in mid-life, during the forth and fi fth decade, especially if not treated, favours in later life both vascular dementia and AD. In contrast the promoting role of late-life hypertensi-on on cognitive decline is less clear8. In later life and in very old age both deleterious and beneficial effects of hypertension on cognitive abilities were demons-trated8. Severe atherosclerosis in the very elderly, as well as episodic or sustained hypotension and, possi-bly, excessive treatment of hypertension, may induce cerebral hypoperfusion, ischemia, and hypoxia in this age group5. For example in the Rotterdam Study lower diastolic blood pressure in individuals older than 80 years was linked to higher risk of dementia9. In the Baltimore Longitudinal Study of Aging, both hypertension and hypotension have been shown to be associated with poorer performance on tests of executive functi-on in older individuals10.
However, evidence with respect to the cognitive domains affected by hypertension are consistent, poin-ting specifi cally to executive dsyfunction and slower speed in processing information having an impact on making decisions in daily activities8, regardless of age.
As stated, hypertension is a potentially modifiable risk factor of cognitive decline. Whether blood pre-ssure lowering treatment could also lower the risk of cognitive disruption or at least defer dementia time of onset, have been evaluated in randomized clinical trials (RCTs). They resulted in inconclusive evidence. Several studies, like Progress, SYST-EUR, HOPE found positive association between antihypertensive therapy and cognitive decline as well as dementia5. On the con-trary, no such link was found in other trials like MRC, SHEP, SCOPE, and HYVET-COG5,8,10. A network me-ta-analysis of RCTs which analyzed the effect of di-fferent antihypertensive drugs on cognitive function concluded that antihypertensive agents are beneficial in dementia and cognitive impairment risk reduction8. By contrast, a recent meta-analysis of prospective co-hort studies reported that blood pressure lowering intervention does not influence cognitive impairment, cognitive decline or Alzheimer’s disease, although it significantly reduces the risk of dementia11.

Diabetes mellitus
Hyperglycaemia is one of the modifiable cardiovas-cular risk factors. Dysglycaemia and type 2 diabetes (T2DM) were demonstrated to be linked to cognitive decline in large epidemiological studies12-14. This rela-tion is stronger with age progression, but was found to be present at any stage of life, not only in older patients, as it was shown in the meta-analyses of Pe-limanni and Jehkonen15, and even present among type 1 or type 2 diabetes children and adolescents. Recent studies concluded that diabetes related complications (like albuminuria in nephropathy, visual impairment in retinopathy or hear loss) are also associated with in-creased risk of dementia16,17. The causes of cognitive impairment in diabetes are diverse. Most of the pa-tients have a variety of reasons to have neurological impairment. High blood glucose levels are related to a greater cognitive decay, as it is expected18.
However, hypoglycaemia, in insulin or sulphonylu-rea treated patients, is also associated with alteration of cognitive function. The effect of low blood sugar will depend on its degree, duration and recurrence. In acute hypoglycaemia attention-concentration, pro-cessing speed are altered. Recurrent episodes of low blood sugar will cause memory decline and impaired problem solving19. In a cohort of the Nurse Health Study higher level of C peptide predicted a worse cog-nitive decline after 10 years of follow up20.
Brain insulin resistance is parallel with systemic in-sulin resistance. The diminished intracellular insulin effect will result in weakened memory function, cell proliferation and enhanced cell apoptosis. There are studies suggesting that insulin resistance, and sub-sequent hyperinsulinaemia are involved in the increa-sed concentration of amyloid- in the brain21.
The occurrence of one or more APOE epsilon4 alle-les, frequently present in metabolic syndrome, is asso-ciated with a lower cognitive performance in patients with diabetes, even if adjusted for age, education, sex, race/ethnicity and APOE genotype22.
Diabetes related accelerated atherosclerosis and microangiopathy promote vascular brain damage, not only through hypoxic neuronal damage, but also via neurovascular uncoupling. Hyperglycaemia causes endothelial dysfunction, accumulation of AGE molecules, and increases the production of reactive oxygen speci-es which will finally result in reduced local blood flow.
The chronic inflammation present in T2DM, accom-panying insulin resistance is linked to beta-amyloid deposition in the brain, the cornerstone pathological change in AD. Epidemiological studies have long de-monstrated that AD is more frequent in T2DM, due to the common cause of insulin resistance23. Howe-ver in patients with diabetes clinical dementia is not equal with AD diagnoses, because cerebral autopsy demonstrated in these patients a frequent association of cerebral infarcts with Alzheimer type neuropatho-logical changes23,24.
The best brain imaging techniques in diabetes, whi-ch might help in identifying the cause of cognitive de-cline, are amyloid PET scan, SPECT, angioMRI, diffusi-on tensor imaging (DTI)25.
Regarding the type of cognitive functions affected, the largest differences in performance between pati-ents with diabetes and control subjects are found in information processing speed, attention-concentrati-on, executive functions and working memory. How-ever, there are differences between cognitive impair-ment in type 1 and type 2 diabetes. In the first slowing of information processing, impaired problem solving and lower psychomotor effi ciency were largely obser-ved, while in the latter impaired memory, executive function defi cit, and depression were more evident26. Because of the metabolic memory of cells, caused by epigenetic modifications at mitochondrial level due to hyperglycaemia, improving glycaemic control will not necessarily improve cognitive outcomes. Early inter-vention on blood sugar may prevent or slower intel-lectual decline. Knowing the role of insulin resistance in the increased risk for dementia, early weight con-trol and healthy diet are an effective tool in preserving the intellectual capacity of the individual. Regular con-sumption of fruits and vegetables is also diminishing the risk of dementia27. It is also demonstrated, that higher fish consumption may be capable of preserving memory28.
Prevention of hypoglycaemia in type 1 and type 2 di-abetes is crucial for preserving the cognitive functions. In the former, frequent blood glucose monitoring, and using continuous glucose monitoring systems might be helpful. In T2DM newer glucose lowering drug classes and avoiding sulphonyureas may diminish the possibi-lity of low blood sugar level.
There is emerging evidence that incretin effect ba-sed glucose-lowering therapies (DPP4 inhibitors and GLP1 analogues) might slower the cognitive decline in patients with diabetes, and may improve cognitive recovery after stroke29.
Hyperglycaemia and hypoglycaemia will contribute to cognitive impairment at any age, both in type 1 and type 2 diabetes. Only early and aggressive interventi-ons on hyperglycaemia will have benefi cial effect on cognitive decline and dementia prevention. The risk of hypoglycaemia must be addressed in the treatment of diabetes. Using the incretin based therapies in diabe-tes might bring an additional beneficial effect regarding the cognitive decline29.

Smoking
The role of smoking in the development of cogniti-ve impairment and dementia is now clear. A meta-analysis of 17 longitudinal studies assessing the effect of current smoking on the development of demen-tia involving 937.392 subjects for all-cause dementia, 907.077 subjects for AD respectively 882.548 subjects for vascular dementia found that current smokers had signifi cantly increased risk of all-cause dementia (RR 1.30, 95% CI 1.18–1.45), AD (RR 1.40, 95% CI 1.13–1.73) and vascular dementia (RR 1.38, 95% CI 1.15–1.66) compared to never smokers30. There is a li-near dose-response relationship between the amount of cigarettes smoked per day and the relative risk of dementia30. The most likely mechanism underlying the association between smoking and AD is vascular di-sease. Smoking contributes to a variety of subclinical and clinical vascular disorders including atherosclero-sis and stroke (symptomatic or asymptomatic), which, in turn, could lead to increased risk of dementia. To-bacco smoke also contains hundreds of neurotoxins which could contribute to cognitive decline through oxidative stress, inflammatory processes, or direct to-xicity mechanisms31. Second hand smoking is also con-sidered as a risk factor for cognitive decline, the higher the exposure, the higher the risk of cognitive decline32.
Quitting smoking is beneficial for the purpose of preventing the development of cognitive decline and dementia. The Whitehall II Cohort study found that in ex-smokers, with at least a 10-year cessation, there were no adverse effects of their past smoking on cog-nitive decline33. Other long-term cohort studies also suggest that the risk for dementia in former smokers (after several years of not smoking) approaches that of never smokers30.
Prevention of dementia is a good argument for smo-king cessation, because more patients are concerned about the risk of cognitive decline than other smoking related complications.

Obesity
Epidemiological studies addressing the risk of obesity and dementia have reported equivocal results. Incon-sistencies mainly appear with regard to the age at whi-ch the presence of obesity was assessed34.
Most of the studies agree that midlife obesity is a risk factor for dementia35. Results from the Whitehall study of more than 10.000 patients with repeated BMI assessments for more than 28 years show that obesity (BMI ≥30 kg/m2) at 50 years is a risk factor for dementia36. This association was greatly attenua-ted when BMI was assessed at ages 60 and 70 years36. This study demonstrated that the association betwe-en obesity and dementia is modified by age at obesity measurement, such that midlife obesity is a risk factor for dementia but BMI begins to decline in those with dementia in the years before diagnosis36. The study suggests that patients who develop dementia have different BMI trajectories than patients who will not develop dementia36.
The exact mechanisms explaining the increased risk of dementia associated with obesity are not ful-ly understood. Obesity in midlife and at older ages is associated with brain atrophy37. There is also evidence suggesting that a variant of the fat mass and obesity-associated gene affects brain structure, causing deficits in the frontal and occipital lobes38. Obesity is also li-kely to influence cognition through its impact on other cardiovascular risk factors, and the role of adipocyte hormones and cytokines is under investigation. Geno-me-wide association studies, showed genetic risk va-riants that could influence vascular and inflammatory pathways to be associated with dementia39.
It is not clearly demonstrated that weight loss in midlife could prevent cognitive decline or dementia, but several studies suggest that the better the cardi-ovascular risk profile, the lower the risk of cognitive decline40,41.

Hypercholesterolemia
Association between cholesterolemia and cognitive decline has been investigated by several studies and the outcome is controversial. There are large popula-tion-based prospective studies such as the NEDICES study performed in Spain showing that elderly subjects with hypercholesterolemia presented significantly slower cognitive decline compared to those with nor-mal cholesterol levels during a 3-year follow-up, MMSE test being used for assessment of cognitive functions42. Researchers investigating the hippocampus found in a study performed in China that type 2 diabetic patients with poorly controlled cholesterolemia showed impairment in attention and executive function, and decreasing the LDL-cholesterol/HDL-cholesterol ratio can be protective against cognitive decline43. Another community-based study on elderly Chinese population showed that higher serum total and LDL-cholesterol were signifi cantly associated with greater cognitive impairment based on the MMSE test score44. The REGARDS study conducted in the USA showed no association between lower LDL-cholesterol levels and cognitive dysfunction in the studied population45.
Other studies investigated the effect of cholesterol lowering medication on cognitive functions. Resear-chers in the USA found that statins have a benefi cial effect on cognitive functions, subjects under this kind of treatment showing less impairment in their cogni-tive functions46.
In a study performed on Irish population Montre-al Cognitive Assessment test was used to evaluate cognitive performance and no relationship was found between use of cardiovascular medication (antihyper-tensive, antithrombotic, lipid-modifying drugs) and cognitive function47. The controversial outcome of di-fferent studies suggests that statins may have double effect through independent mechanisms. Statins might have a contribution to reversible cognitive dysfunc-tion, and in the same time they are drugs useful in prevention of dementia. The negative impact of statins on cognitive function might be due to lowering choles-terol level in the brain, especially in case of high doses and genetic vulnerability. On the other hand, statins have protective effect against dementia by prevention of stroke and lowering the incidence of microvascu-lar infarction in the brain, and by reducing neuroin-flammation48.
In spite of all the controversies, there is consistent evidence supporting the role of atherosclerosis in the development of dementia and cognitive impairment49, so minimalizing cardiovascular risk factors and redu-cing the development of atheromas is essential for ma-intaining proper brain function of the patients.

Physical exercise
Sedentary lifestyle is a negative attribute of modern lifestyle and a well-known cardiovascular risk factor. There is many convincing data supporting that phy-sical exercise (PE) as a healthy behavior has positive effects not only on general and cardiovascular health, but also on brain structure and function. Opposite to this sedentary behavior may lead to worsening of both cardiovascular health and cognitive abilities. Accordingly, a recent work of Siddarth et al. showed that se-dentary lifestyle was connected to less temporal lobe thickness which might have an influence on long-term memory loss50. An analysis of population-based data made by Norton and collaborators concluded that the population-attributable risk of low PE for dementia is 20.3% in Europe (95% CI 5.6-35.6)51.
Physical exercise has been proven to have protective effects on neuro-degenerative processes through se-veral mechanisms. These include morphological chan-ges like increasing of grey matter volume in the frontal and hippocampal regions, and functional modifi cations like increase in neutrophic factors, growth factors, testosterone, level of serotonin, beta-endorphins, ce-rebral blood flow and decreased insulin resistance52. Recently, epigenetic mechanisms, increased gene ex-pression mediated by PE have also been evoked52. All these changes reduce beta amyloid accumulation in the brain, enhance neurogenesis in the hippocampal area, neuroplasticity and decrease neurodegeneration52. In addition, PE is also related to higher cognitive re-serve through promoting more effective connections between existing neurons52. Finally, combined with the positive psychological effects of PE, like increased self-confidence, decreased depression and anxiety, cog-nitive performances are improved52. Furthermore, a wealth of evidence points out that PE improves quality of life, prevents age-related cognitive worsening and lowers the risk of dementia. Indeed, longitudinal and cross sectional studies have consistently demonstra-ted that individuals with regular physical activity have higher cognitive function and less likely to develop any form of dementia including Alzheimer disease52. In addition, randomized intervention trials demonstra-ted a positive infl uence when investigating the impact of aerobic PE on cognitive abilities and/or cognitive decline53. Beneficial effects of PE on cognitive perfor-mance appear regardless of age. However, type and duration of exercise may interfere with the impact on brain health. Moderately intense chronic aerobic exer-cise has important infl uence on memory and executive functions while high intensity PE has positive effect on processing speed. Effects of acute aerobic exercise on cognitive improvement have been also demonstrated, although these effects are less small54. According to a meta-analysis combination of aerobic and resistance exercise might have the greatest results on improving cognitive abilities55. With respect to PE duration sci-entists agree that weekly 150 minutes of moderate to intense exercise should be completed to reach beneficial effects on cognition. It has also been stated, that people need to commit to regular PE lifelong56.

Conclusions
This report explored current knowledge regarding the effect of modifiable cardiovascular risk factors on cognitive function. In light of the presented infor-mation we conclude there is an overlapping betwe-en known vascular risk factors and risk factors for dementia. Association of risk factors with cognitive decline is not yet fully clarifyed, yet it is stated that potentially modifiable risk factors are responsible for one third of AD51. We believe, there is enough evi-dence to support the fact that mid-life cardiovascular risk factors can promote cognitive impairment and/or dementia later in life. Hypertension, diabetes mellitus, obesity, hypercholesterolemia, smoking and sedenta-rism are promising intervention targets for preventing or delaying dementia. They should be monitored and treated aggressively as soon as possible. Finally, we consider that in the presence of vascular risk factors routine cognitive screening and follow-up of cognitive worsening are recommended.
Conflict of interest: none declared.

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