Epidemiology of mild cognitive impairment

Summary

Background:
Mild cognitive impairment (MCI) is a transitional phase between cognitive changes in physiological aging and early dementia. The amnestic form of MCI is considered a precursor to Alzheimer’s disease. The increasing number of elderly persons in the population is associated with an increase in the prevalence of chronic diseases including cognitive impairment and subsequent dementia.

Aim:
The aim of this work is to describe factors influencing the decrease of cognitive functions and development of MCI and subsequent dementia. Hypertension, hypercholesterolemia, diabetes mellitus and obesity are more frequent during middle age and contribute to the risk of dementia in older age through various cerebrovascular diseases and inflammatory/neurodegenerative mechanisms. At the same time, impaired cognitive functioning is associated with behavioral and psychosocial factors. The article provides an overview of potential vascular, behavioral and psychosocial risk factors for MCI and dementia.

Conclusion:
Knowledge of the risk factors for MCI and dementia will allow early prevention and effective therapy of these serious diseases.

Key words:
mild cognitive impairment – dementia – epidemiology – risk factors

Background

Mild cognitive impairment (MCI) is a transitional phase between cognitive changes in physiological aging and early dementia [1,2]. In 1994, Levy introduced the term aging-associated cognitive decline. It was defined by a standardized cognitive test that was at least one standard deviation below age-adjusted norms in at least one of the cognitive domains memory and learning, attention and cognitive speed, language or visuoconstructional abilities. At the same time, no other disorders that could cause cognitive impairment, including dementia, are present. Normal activities of daily living are preserved in MCI [3].

The term mild cognitive impairment was introduced by Reisberg in 1982 [4]. In 2004, Petersen used the term to describe a period of neurodegenerative disease where cognition is no longer normal relative to age but daily function is not sufficiently disrupted to correlate with the diagnosis of dementia [5].

In 2005, Petersen and Morris distinguished two forms of MCI: 1. amnestic; 2. non-amnestic [5,6].

The new clinical criteria of MCI published in 2011 have the following characteristics:

• changes in cognition confirmed by an informant or clinician;
• not being demented;
• impairment of episodic memory with is common in patients with MCI subsequently prograding to Alzheimer´s dementia (AD);
• impairment in one or more cognitive domains greater than expected for age and education, and preservation of independence [7,8].

The amnestic form of MCI is considered a precursor to AD. Conversion of amnestic MCI to AD is estimated at 10–15% a year [9].

In amnestic form of MCI, memory is objectively impaired; the affected individual also complains of memory problems. The other cognitive functions are normal; activities of daily living are preserved; there are no signs of dementia [10,11].

If we accept the fact that MCI may be a precursor to AD, it is useful to study potential risk factors, including genetic markers, before dementia develops, that is, already in MCI patients. Knowing these factors will enable early prevention and effective treatment of dementia.

Prevalence and incidence

At the present time, nearly 900 million people worldwide are older than 60 years of age. Between 2015 and 2050, the number of elderly people is expected to rise considerably, by 56% in high income countries as compared with 239% in low income countries (138% and 185% in upper and lower middle income countries, respectively). Rising life expectancy contributes to rapid increases in numbers of elderly people, leading to increased prevalence of chronic diseases including cognitive decline and subsequent dementia [12]. The prevalence of MCI in adults aged 65 or more ranges between 10% and 20%. The risk increases with age [1,13]. Other authors reported prevalence rates between 5.5% and 7.7% in those aged 60 or more. Overall, the incidence of MCI ranges from 8.5 to 76.8 per 1,000 person-years. The incidence of amnestic MCI is between 9.9 and 40.6 per 1,000 person-years [14]. Population studies suggest that patients with MCI are at a higher risk of developing dementia (a conversion rate of 5–20% per year) [1,13].

Risk factors

There are significant interindividual differences in the level of cognition in older age. These may be explained by varied exposure to numerous risk or protective factors throughout life.

A life course approach supports the hypothesis that some risk factors may operate with varying strength at critical periods. Brain and cognitive reserve, developed early in life and consolidated in midlife, may slow the onset of dementia symptoms [15,16]. The process may be contributed to by early life growth and development, higher educational achievement, mentally stimulating activity, social engagement and, last but not least, physical activity that has recently been widely discussed. These activities help to ward off the development of clinical manifestations of dementia in later life [17].

Vascular risk factors such as arterial hypertension (AH), hypercholesterolemia, diabetes mellitus (DM) and obesity may contribute to the risk of dementia in older age through various cerebrovascular diseases and inflammatory and neurodegenerative mechanisms. In stroke, for example, there are several mechanisms potentially causing cognitive impairment or AD. Stroke may directly damage certain areas in the brain that are related to memory such as the thalamus. Additionally, inflammatory mechanisms may be induced, leading to impaired cognitive functioning. Finally, brain hypoperfusion may result in increased expression of cyclin-dependent kinase 5 which is important for synapse formation and plasticity and thus for learning and memory [18].

The relationship between behavioral and social factors and cognitive functioning significantly fluctuates with age. Some studies concluded that maintenance of cognitive health in older age depends, among others, on the development and optimal achievement of a level of cognitive functioning throughout life, which may contribute to higher structural and cognitive reserve in older age [19,20]. A known risk factor for dementia is older age. In german general practitioners study was frequency of MCI in persons 75 years and older 56,5 per 1,000 person-years [21].

Data on gender as a risk factor are inconsistent. While some authors claim that males are at a higher risk for developing MCI, others report that the risk is more pronounced in females. Yet other studies report no gender differences [2,13,21–23].

Vascular risk factors

Diabetes mellitus

DM is one of the main health problems in older age. In developed countries, type 2 DM is considered an epidemic. Due to its high prevalence, it is one of important risk factors for both MCI and Alzheimer´s dementia. In large and fine epidemiological and clinical studies was demonstrated, that persons with amnestic MCI and diabetes prograde to AD more often than persons without diabetes [24,25,26]. The incidence of MCI is reported to be higher in individuals with type 2 DM [27]. Poor control of diabetes, measured by glycohaemoglobin, is also connected with cognitive decline [28].

Diabetic complications such as diabetic retinopathy, diabetic foot syndrome, cerebrovascular and cardiovascular diseases (CVDs) are associated with poor diabetes control and may contribute to a higher risk of cognitive loss [28–30]. Therefore, good diabetes control and adequate insulin therapy may reduce the incidence of cognitive decline [31,32].

British researchers found that through glycation, high glucose levels modify macrophage migration inhibitory factor (MIF enzyme) that is involved in brain cell response to accumulation of pathological proteins in the brain [33].

Insulin resistance, an increasingly common condition in developed countries, is significantly associated with reduced glucose metabolism in the brain. Middle age is often reported as a critical period for starting insulin resistance treatment to maintain neuronal metabolism and cognitive functioning [34].

Insulin resistance in brain tissue is probably key phenomenon in AD causing neuronal dysfunction and cognitive impairment. In brain tissue abnormal aggregation  of peptide amyloid-β and polypeptide amyloid are occurring and contributing to sell death and pathogenesis of dementia development. This amyloid is also present in pancreas supporting hypothese of its part on development of insulin resistance [35,36].

Arterial hypertension

High blood pressure, especially AH in middle age, is associated with an increased risk for the development of cognitive impairment and dementia [37]. Hypertension is also the most important risk factor for the development of stroke. Additionally, it contributes to the pathogenesis of AD and vascular dementia [38].

One of the first studies on the relationship between high blood pressure and cognitive decline was the Framingham Study. It concluded that AH was associated with MCI. Later studies (e.g. the Rotterdam Study, Kungsholmen Project, Honolulu-Asia Aging Study or Epidemiology of Vascular Aging Study) confirmed the Framingham Study results. This issue is characterized by vascular pathology leading to cerebral amyloid angiopathy and subsequent blood-brain barrier dysfunction. Evidence from epidemiological, clinical, pathological and imaging studies considers neurovascular dysfunction an integral part of AD, leading to the vascular hypothesis of AD [39].

Clinical studies have shown that reduction of both systolic and diastolic blood pressure by 10 mmHg significantly decreases the risk of conversion of MCI to dementia. A study by Ravaglia et al followed 165 patients with MCI for 3 years; of those, 48 converted to dementia (29%) [40].

The mechanism of hypertension-related cognitive changes is complex and not yet fully understood. Both hypertension and, especially in older age, hypotension are thought to be related to impaired cognitive function and subsequent dementia. Therefore, early and adequate antihypertensive therapy is crucial to prevent cognitive decline [41,42].

Hypercholesterolemia

Lipids, an essential structural component of the nerve cell membrane, play a key role in the development and maintenance of neuronal plasticity and function. The brain is an organ rich in cholesterol, containing about 30% of the total body cholesterol. As shown by numerous studies, high levels of total serum cholesterol in middle age is a risk factor for the development of dementia including AD and cognitive impairment in older age [43,44]. High serum levels of non-HDL cholesterol is thought to be associated with the risk of cognitive impairment in patients after stroke [48].

Recently accumulated evidence, however, does not support the hypothesis that prevention or treatment of dyslipidemia aid in preventing cognitive decline, AD or other forms of dementia [46–49]. A Cochrane review processed data from the special Cochrane Dementia and Cognitive Improvement Group registry and other databases such as the Cochrane Library or MEDLINE. Relevant cognitive tests failed to show positive effects of statin therapy (p = 0.44) [46].

An important role in the pathophysiology of psychiatric and neurodegenerative diseases is also played by adiponectin, a protein produced by white adipose tissue. It is a member of adipocytokines, along with leptin, tumor necrosis factor a, resistin and free fatty acids. According to some studies, low adiponectin levels are associated with cognitive impairment [50].

Lifestyle factors

Smoking

Cortical atrophy predicts cognitive decline and the onset of dementia. Recent MRI studies have shown that smokers have reduced gray matter volume. Cerebrovascular diseases are often defined by the presence of lacunar infarcts associated with cognitive impairment and dementia. These phenomena are linked to chronic smoking [51].

The World Alzheimer Report 2014 showed pooled statistical significant effects in current smokers vs never smokers (RR 1.52; 95% CI 1.18–1.86) and in ever smokers vs never smokers (RR 1.55; 95% CI 1.15–1.95), both on incident AD [17]. Long-term cigarette smoking may contribute to exacerbation of certain pathological processes such as reduced oxygen supply to the brain or decreased blood flow, probably allowing the development of dementia in smokers [52].

Since smoking greatly reduces life expectancy, smoking-related deaths may conceal the actual impact of smoking on the development of MCI and dementia.

Alcohol

Similar to smoking, alcohol abuse is a serious global public health problem. Alcohol is the fifth most important risk factor for death and disability, being reported as a causal factor for over 200 conditions and injuries such as cirrhosis of the liver, certain tumors and CVDs [53,54]. The detrimental effect of alcohol on the brain is mainly characterized by white matter volume loss, being related to memory and visual and spatial functions. Higher amount of alcohol is toxic for brain cells, particularly Purkyne cells of cerebellum (but in small amount has stimulated effect) [55].

J- or U-shaped curves representing the relationship between alcohol consumption and CVDs suggest that light drinkers have a lower risk than abstainers or heavy drinkers. Although the association between alcohol consumption and cognitive impairment and dementia is more controversial, the J-curve relationship was confirmed, with light drinkers having a lower risk of developing dementia than abstainers and heavy drinkers [56,57]. There is evidence that in older age, small amounts of alcohol have protective effects. However, more relevant studies are needed on the potential protective effect of alcohol on cognitive functioning [58].

Diet

The Mediterranean diet, comprising a high intake of cereals, fruit, vegetables, fish, nuts and olive oil, is associated with a reduced risk of numerous conditions such as CVDs, DM or certain tumors [59,60]. Moreover, results of some epidemiological studies suggest that people eating the Mediterranean diet have a lower risk of MCI and dementia and are less likely to convert from MCI to AD [61–63].

Physical activity

Decreased blood pressure, better glucose tolerance, reduced insulin resistance, improved lipid profile, adequate body weight, increased brain blood flow as well as improved brain structure and function and reduced hippocampal neuronal loss are all mechanisms through which physical activity contributes to better physical and mental health [64].

Physical activity, sometimes even mild exercise such as walking, is associated with a lower risk of MCI through improved cognitive functioning. Results of randomized studies in the Cochrane database suggest that inactive but otherwise healthy elderly people who started to exercise significantly improved their cognitive functioning [59]. The Canadian Study of Health and Aging, a prospective cohort study of the impact of physical activity on cognitive functioning, confirmed an association between exercise and a lower risk for cognitive decline. After adjusting for age, gender and education, the OR was 0.58 (95% CI 0.41–0.83) for MCI and 0.,5 (95% CI 0.28–0.90) [65].              

Stroke

Stroke is connected with temporary deteriorated cognitive functions. In part of patients decrease of cognitive functions persists and leads to MCI to dementia. Infarcts in certain parts of brain (thalamus, basal ganglia) are connected with higher risk of MCI and dementia. Higher risk od MCI and dementia is also in patients with brain microinfacrts, witch are usually clinically silent [66].

Several studies describe development of cognitive decline as a consequence of stroke. Observational study of 4,212 patients after stroke discovered cognitive decline in 22% patients in interval 3 months afret stroke, 22% in interval 5 years after stroke and in 21 % after 14 years of follow up [67]. Frequent consequence of stroke is impairment of speech and depression with after that influence cognitive functions. Higher risk of cognitive deficit is also connected with not only ischemic but haemorrhagic stroke as well [68,69].

Psychological and psychosocial factors

Mental distress is associated with impaired cognitive functioning and increased incidence of MCI in older age [70,71]. Cognitive impairment is often accompanied by depression but the mechanism behind this association has not yet been fully explained [72].

The World Alzheimer Report 2014 identified three possible explanations for the relationship between depression and cognitive impairment:

1. Depression results from early cognitive decline. Depressive symptoms may stem from increasing awareness of diminishing cognitive functioning or in response to a diagnosis of dementia. The relationship may also arise from biological mechanisms (limbic and cortical atrophy, white matter lesions) common in both dementia and late onset depression.
2. Depression is a prodromal syndrome of dementia. The onset of depression may be driven by changes in brain structure and function that are part of the neuropathological course of dementia. In this case, symptoms of depression should appear just before or early in the onset of dementia.
3. Depression is an independent risk factor for dementia. Depression preceding dementia may be a causal risk factor. The following biological mechanisms are presumed: depression-related predisposition to vascular diseases, release of pro-inflammatory cytokines and chemokines, increased glucocorticoid production, amyloid deposition and neurofibrillary formation. All of the above may lead to hippocampal injury.

Recent studies seem to be consistent with earlier ones, strengthening the evidence that depression may increase the risk of dementia (pooled effect size 1.97; 95% CI 1.67–2.23) [17].

People with greater cognitive stimulation throughout their lives are at a lower risk of cognitive decline and dementia in older age. This may be explained by greater cognitive reserve through cognitive training and work or leisure time activities. Cognitive training seems to be an effective instrument for preventing the development of dementia in the elderly population [73].

Important psychosocial factors include education and socioeconomic status. Education and employment are closely linked. As early as in the 1980s, Mortimer found that years of formal education may raise the level of the so-called intellectual reserve and thus enhance the protective effect against the development of cognitive decline and subsequent dementia [74].

The data so far suggest that lower education levels are consistently linked with an increased incidence of MCI and dementia. Most epidemiological studies found a protective effect of higher education levels even after adjusting for significant confounders such as age [59]. Education and employment may be expected to be highly correlated with each other and associated with other factors such as innate intelligence and lifelong healthy behavior.

An active and socially integrated lifestyle may be impaired in older age. Longitudinal observational studies suggested that a poor social network or a lack of social involvement are associated with cognitive decline and dementia [75,76]. Lower social integration may be contributed to by various age-related life events such as retirement, reduced ability or inability to drive a motor vehicle, death of a spouse and the associated loneliness, loss of close friends from the group of same-age peers or dissatisfaction with life. Disruption of these bonds is an important risk factor influencing the development of cognitive impairment [77,78].

Conclusion

MCI is a transitional phase between cognitive changes in physiological aging and early dementia. The term describes a period of neurodegenerative disease where cognition is no longer normal relative to age but daily function is not sufficiently disrupted to correlate with the diagnosis of dementia. Conversion of amnestic MCI to AD is reported at 5–20% a year.

Vascular, behavioral and psychosocial risk factors are presented as the main groups of risk factors for MCI.

MCI has become a major challenge in both research and clinical practice. Knowledge of the risk factors and early diagnosis of the condition might be beneficial for both preventing the development of MCI and early treatment of AD.

The authors of this article are responsible for the quality of the English translation and the accuracy of used terminology.

doc. MUDr. Jana Janoutová, Ph.D.

Ústav epidemiologie a ochrany veřejného zdraví

Lékařská fakulta Ostravská univerzita

Syllabova 19 703 00 Ostrava 3

e-mail: jana.janoutova@osu.cz