Introduction

Ageing is a natural process occurring in all living organisms and impacting all human organs, including the brain. A decline in memory and thinking is expected as we age but it typically does not interfere with daily tasks. Mild cognitive impairment (MCI) is a condition described as the intermediate stage between normal age-related cognitive decline and dementia.

People with MCI experience more noticeable cognitive decline compared to their peers, but the symptoms are less severe than those seen in dementia and Alzheimer’s disease (AD).¹ Memory problems, cognitive deficits, such as language, attention, and reasoning difficulties, and visuospatial impairment are some of the common symptoms linked to MCI.

People with MCI are aware of their cognitive changes, which may also be noticeable to other people close to them. However, these differences are not severe enough to impede daily activities or independence and thus do not indicate a diagnosis of dementia.²

MCI is one of the most common conditions among the elderly, with an overall prevalence of 15% in individuals above the age of 50, a rate that significantly increases with age.³ Additionally, MCI is associated with an increased risk of developing dementia, with approximately 6-15% of MCI patients developing AD per year.¹ MCI is a multifactorial condition with various aspects influencing its development. Let us analyse in more detail the risk factors and causes associated with this condition.

Risk factors associated with MCI

Non-modifiable risk factors

Age

The principal risk factor for MCI is ageing. According to multiple studies, older populations have an increased prevalence of MCI. The cognitive decline observed with increasing age is inevitable, and therefore, the risk of developing MCI is heightened with age. This impairment is predominantly impacted by age-related vascular and brain structure changes. The age of onset of MCI also seems to influence cognitive performance, with individuals experiencing early onset of MCI showing less severe decline and pathology in comparison to those with mid or late onset of the same condition.^2,4

Genetics

Family history and the presence of specific genes play a significant role in the development of MCI as well as AD. Specifically, the presence of one or two copies of the allele ε4 of a specific gene named apolipoprotein E (APOE) is a well-documented risk factor of AD, which can increase the risk of the disease up to 15 times. These copies may also predict the likelihood of MCI progressing into AD. The biological mechanism behind this connection involves the APOE ε4 allele’s association with an increased amyloid-β deposition and formation of neurofibrillary tangles in the brain, which may eventually lead to the destruction of brain cells and dementia.⁵

Additional AD-related genes have also been identified as modulating factors for MCI. Further studies on genes beyond APOE, such as PICALM, CLU, and CR1, as well as their relationship with environmental factors, along with polygenic risk scores, can significantly contribute to understanding the associated risk for MCI. A thorough research into the genetic predisposition of individuals can be helpful in providing personalised preventive and therapeutic strategies, particularly targeting the potential progression of MCI to AD.⁶

Modifiable risk factors

Cardiometabolic health

Cardiovascular conditions are among the most important reversible risk factors for cognitive dysfunction. Numerous epidemiologic studies have demonstrated an association between high blood pressure (hypertension) and poor cognitive behaviour, MCI, and dementia. Hypertension, in particular, has been linked to an increased risk of MCI and worse outcomes, observed as a gradual deterioration in cognitive performance, affecting memory, thinking, attention, and executive functions, without necessarily impacting daily tasks to the extent seen in dementia.

Furthermore, individuals already diagnosed with MCI who also have high blood pressure are at higher risk of progressing to more severe cognitive decline and dementia. The time in life of hypertension onset also seems to play a key role in the cognitive health of individuals.

Those who develop hypertension in midlife (40-65 years old) seem to have a higher risk of developing MCI and dementia compared to those who develop hypertension later in life (ages 65 or older). Thus, managing hypertension in its early stages and sustaining blood pressure control can help mitigate the risk of MCI and other cognitive dysfunctions.⁷

Apart from high blood pressure, obesity and diabetes have also been linked to cognitive decline. Obesity, in particular, is associated with worse memory function, and although further investigation is needed to identify it as a clear risk factor for MCI, certain studies have found a higher prevalence of MCI in obese populations at specific age groups. The combined effect of obesity and other parameters including age, and other comorbidities on the brain should be taken into consideration when assessing the risk of MCI.⁸

Moreover, according to specific studies, diabetes, high cholesterol, and high blood sugar (hyperglycaemia) may have detrimental effects on the brain, increasing the risk of MCI and the progression of MCI to dementia, though further research is needed to confirm this relationship.⁹

Lifestyle factors

The lifestyle habits of individuals can impact their health in various ways, including their cognitive function. It has been found that unhealthy diets, physical inactivity, alcohol consumption, and smoking have all been linked to a higher risk of developing MCI. These factors may not impact MCI directly but usually aggravate the overall health status of individuals. Adhering to healthier lifestyles could significantly prevent and minimise the risk of MCI along with a plethora of other conditions.¹⁰

Education and mental health

Socioeconomic factors and illiteracy are strongly associated with an increased risk of MCI, as they directly influence cognitive reserve. Early-life education helps train the brain and develop cognitive skills that can be maintained even while ageing, thereby decreasing the risk of MCI. Simultaneously, education is related to a higher socioeconomic profile, which allows healthier lifestyle choices, further reducing the risk of MCI indirectly. Moreover, a connection between education and gut microbiome diversity has been suggested to play a role in MCI risk.¹¹

Depression and anxiety can significantly impact cognitive health of individuals, increasing the risk of developing MCI as well as dementia. According to a specific study, recently diagnosed depression was associated with cognitive decline, and was stated as a significant risk factor for MCI appearance and progression to AD. The underlying mechanisms of this connection may involve pathophysiological alterations such as inflammation, sleep pattern changes, and disruptions in brain circuits that can cause cognitive decline.

Resolving depressive symptoms could be an effective method for minimising the risk or slowing MCI deterioration, although some individuals are predisposed to having worse outcomes regardless of a potential treatment with antidepressants.¹² Similarly, anxiety, often reported by older patients, increases the risk of MCI and dementia, with higher severity of anxiety correlated with greater cognitive decline.¹³

Causes of MCI

There is no distinct aetiology for MCI, highlighting the importance of recognising the aforementioned risk factors and underlying conditions associated with this condition. In other words, MCI can be due to heterogeneous factors and overlapping underlying conditions, which all give rise to complex interactions that impact cognitive health. Other factors potentially contributing to MCI may include:^14-16

• Neurodegenerative diseases: AD is the most common cause of MCI in individuals older than 65 years, leading to progressive cognitive decline. Parkinson’s disease with cognitive impairment is also observed in older populations, potentially resulting in MCI. These diseases are progressive and usually have poor outcomes for individuals with MCI. Additionally, other conditions, such as Lewy body dementia and traumatic brain injury, may present with cognitive impairment in later stages.
  
• Cerebrovascular diseases: Atherosclerosis, coronary artery disease, stroke, chronic obstructive pulmonary disease, and other cardiovascular risk factors are significant contributors to cognitive decline in the ageing brain. Multimorbidity, in combination with other risk factors, may be strongly involved in cognitive decline, leading to MCI.
  
• Polypharmacy: The use of multiple medications and their interactions can sometimes impair memory, leading to cognitive loss. Fortunately, early recognition of such signs and tailored pharmacological treatment can often reverse these problems.
  
• Metabolic diseases: Vitamin B12 deficiency, hypothyroidism, dehydration, and other reversible metabolic conditions may also drive cognitive impairment but are easily treated.
  
• Sleep disorders: Obstructive sleep apnoea can have devastating effects on cognitive function, but can be improved the appropriate treatment.

Summary

MCI is a complex neurocognitive disorder, representing the intermediate state between the normal cognitive decline associated with ageing and dementia. Individuals with MCI are subjectively aware of their cognitive deficits, which are also observable by others, yet these deficits are not as severe as those experienced by people with dementia. Nevertheless, MCI can serve as an early indicator for dementia and may lead to AD, underscoring the importance of analysing potential risks and taking measures to prevent or delay such deterioration.

Multiple risk factors and causes have been linked to MCI, some of which are non-modifiable, including the presence of specific genes, placing certain individuals at higher risk of developing MCI, and age, which inevitably alters the cognitive abilities of all people. On the contrary, modifiable risk factors associated with MCI include hypertension, obesity, mental health problems, educational level, and lifestyle habits.

This implies that while some of the causes of MCI are unavoidable, others can be well-addressed, particularly when identified early. Recognising and managing underlying comorbidities, and getting medical help for conditions affecting sleep patterns and mental health, are methods that can significantly reduce the risk of cognitive decline and prevent or delay conditions such as MCI and dementia.