**4. Risk factors for mild cognitive impairment and dementia**

Science has gradually shown which risk factors (RF) for MCI and dementia can be currently considered. The knowledge of RF for these pathological processes plays an important role in its prevention. Ideally, prevention strategies should target people who are not even symptomatic [42]. Prevention of dementia is a public health priority [43].

In the health sciences field, a RF is the probability of suffering a certain disease, having a complication or dying [44]. In this paper, we will present some of the most recognized RF, classifying them according to their origin in social, biological, and psychological and by their nature in modifiable and nonmodifiable (see **Table 2**).

#### **4.1. Biological factors**

#### *4.1.1. Vascular disorders*

Dementia is a NCD that usually begins gradually and has a progressive course. It can be variable, and there is often a long period of time between the occurrence of the first signs of cognitive impairment and the moment they meet the criteria for the dementia diagnosis [38]. The American Psychiatric Association (APA) introduced in 2013 the term "Major neurocognitive disorder" replacing the term "dementia," defined as a decline in mental ability severe

**Table 1.** Comparison of the different diagnostic criteria in normal aging, mild cognitive impairment and dementia

**Normal aging** 

Normal objective memory according to age.

Normal cognitive functioning according to age

Preservation of functional independence

(according to DSM-IV and DSM-5).

**Mild cognitive impairment [32]**

Subjective cognitive complaint, raised by the patient or an informant, or observations made by the clinician

Objective cognitive impairment in one or more cognitive domains preferably relative to appropriate normative data for that individual

Preservation of functional independence

No dementia No dementia C. The cognitive deficits do

**Dementia DSM-IV [41] Major neurocognitive** 

The course of deterioration is characterized by a gradual onset and a continuous cognitive impairment.

A2. At least one of the

• Disturbance in executive functioning

not occur exclusively during the course of delirium

B. The cognitive deficits in A1 and A2 each cause significant impairment in social or occupational functioning and represent a significant decline from a previous level of

following: • Aphasia • Apraxia • Agnosia

functioning

A1. Memory impairment A. Evidence of significant

**disorder DSM-5 [34]**

domains:

• Language

cognitive decline from a previous level of performance in one or more cognitive

• Learning and memory

Evidence of decline is based on: Concern of the individual, a knowledgeable informant, or the clinician that there has been a significant decline in cognitive function; and a substantial impairment in cognitive performance, preferably documented by standardized neuropsychological testing or, in its absence, another quantified clinical assessment.

B. The cognitive deficits interfere with independence in everyday activities. At a minimum, assistance should be required with complex instrumental activities of

C. The cognitive deficits do not occur exclusively in the context of a delirium D. The cognitive deficits are not better explained by another mental disorder

daily living

• Executive function • Complex attention • Perceptual-motor • Social cognition

**[31]**

presence or memory complaints

Memory problems are gradual, do not worsen suddenly

Memory Absence or

Other cognitive functions

150 Gerontology

Activities of daily living (ADL)

Associated pathologies Regarding blood pressure (BP), both high and low BP have been linked to cognitive impairment and dementia [45]. The role of cerebral blood vessels in the wide spectrum of pathologies underlying cognitive impairment highlights the importance of vascular structure and function in brain health [46]. The pathophysiology of the relationship between BP and cognition


**Table 2.** Risk factors for MCI and dementia.

is unclear, but hypoperfusion and neurodegeneration have emerged as potential underlying mechanisms [45, 47]. Results from a longitudinal study as part of the Kungsholmen Project [48] showed that low diastolic pressure predicted the risk of dementia among very old people. In the study, blood pressure showed a substantial decrease for approximately 3 years before the dementia syndrome became clinically evident [45].

*4.1.4. Previous brain injuries*

population grows [59].

**4.2. Psychological factors**

*4.2.1. Depression*

**4.3. Social factors**

*4.3.1. Age and sex*

*4.3.2. Education and intellectual commitment*

A new area of interest involves understanding the effect that head trauma has on the behavior and cognitive abilities of brain aging. This issue becomes even more important as the geriatric

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Traumatic brain injury (TBI) is an injury in which effects could be devastating often resulting in lifetime cognitive deficits [60]. More than 70% of people with TBI report memory deficits [61]. Contact sports are a source of recurrent TBI. Athletes whose last concussion was in early adulthood (more than 30 years before examination) were reported to have poorer episodic memory and poorer response inhibition, as well as significantly reduced movement speeds in neuropsychological tests, when compared with same-age athletes without a history of concussion [62]. Regarding the cognitive aging process, the evidence showed that cognition problems exhibited by young adults after severe TBI are similar to many cognitive weaknesses in attention deficit and poor working memory of an elderly population with no neurological history. There is evidence that TBI can result in decreased cognitive reserve that can accelerate the cognitive decline normal process, leading to premature aging, potentially increasing the risk of dementia [63].

Depression can affect cognitive functions and may emulate cognitive impairment. It can be considered comorbidity, a prodromal factor or a consequence of vascular cognitive impairment, more than a factor that specifically alters vascular physiology or neural health, leading to cognitive impairment [64]. Some studies have concluded that depressive symptoms are associated with cognitive impairment; however, the mechanisms underlying the association between these two common conditions need further exploration. It is unclear whether cognitive impairment over time can be explained by depression or it is just a sign of an incipient dementia [65].

Through studies results, the age and sex of the individuals have been considered as risk factors of mild cognitive impairment and dementia. Some studies have reported that the prevalence of dementia increases exponentially with age [66] and doubles every 5 years after the age of 65 years. Several studies showed an increasing prevalence among the older age groups [67, 68]. In higher income countries, prevalence is 5–10% among those over 65 years [68]. Regarding sex, there are results in which dementia is higher in women than in men [68, 69]. One possible explanation for this is that women live longer than men [68]. However, recently, another cohort study reported that both the prevalence and the incidence were higher in men [69, 70].

Dr. James A. Mortimer was one of the first to propose a relationship between years of formal education and risk of dementia. He suggested that education can be a protective factor against

In contrast, cohort studies have found that elevated blood pressure levels in the middle age may increase the risk of dementia in advanced age. As a result, the exposure to four risk factors related to BP: smoking, hypertension, high cholesterol, and diabetes in the middle age increased the risk of dementia in old age compared to only having one of the risk factors [49]. This relationship between blood pressure and the risk of dementia may depend on the age of patients when blood pressure is measured, as well as the time interval between blood pressure and dementia assessments [50, 51].

#### *4.1.2. Metabolic disorders: diabetes mellitus*

Diabetes mellitus (DM) is associated with a dementia risk of 1.5–2.5 times higher among old adults in the community. DM is a significant risk factor not only for vascular dementia but also for Alzheimer's Disease. The mechanisms that support this association are unclear but may be multifactorial in nature, such as cardiovascular risk factors, glucose toxicity, changes in insulin metabolism, and inflammation [52].

Both hyperglycemia and hyperinsulinemia, as part of the metabolic process leading to DM type 2 (DM2), are associated with cognitive dysfunction and dementia due to stroke. This is often accompanied by other mental function disorders, such as depression or anxiety [53]. An epidemiological study showed that the incidence rates of hospitalization for VD in adult aged 70 years and over were twice as high in patients with DM2 as in those who did not presented it [54].

#### *4.1.3. Genetic factors*

Genetics clearly plays a role in AD, both in early and late onset. Early-onset AD or beginning before age 65 years can be caused by one of the more than 200 sequence variants in the genes of the beta amyloid precursor protein, presenilin 1 (PSEN1), or presenilin 2 (PSEN2) [55, 56]. Despite the consistent genetic basis for AD, significant variability in onset age has been observed, suggesting an important role of environmental factors or genetic modifiers in determining the onset age [56]. Late-onset AD is also heavily influenced by genetics, although the Mendelian pattern of inheritance is often unclear. There are several factors that could explain this, even if causal mutations exist [57]. Late-onset AD is complex, and apolipoprotein E is the only genetic risk factor unanimously accepted for its development. Several genes involved in AD have been identified using advanced genetic technologies; however, there are many additional genes that have not been identified [58].

Related to this, a long research that analyzed the Genealogical Index of Familiarity up to 14 generations showed that the pairs of people with family ties who died of AD were significantly related. The relative risk for AD death among the relatives of individuals who died of AD increased significantly for close and distant relatives [57].

#### *4.1.4. Previous brain injuries*

is unclear, but hypoperfusion and neurodegeneration have emerged as potential underlying mechanisms [45, 47]. Results from a longitudinal study as part of the Kungsholmen Project [48] showed that low diastolic pressure predicted the risk of dementia among very old people. In the study, blood pressure showed a substantial decrease for approximately 3 years before

In contrast, cohort studies have found that elevated blood pressure levels in the middle age may increase the risk of dementia in advanced age. As a result, the exposure to four risk factors related to BP: smoking, hypertension, high cholesterol, and diabetes in the middle age increased the risk of dementia in old age compared to only having one of the risk factors [49]. This relationship between blood pressure and the risk of dementia may depend on the age of patients when blood pressure is measured, as well as the time interval between blood pres-

Diabetes mellitus (DM) is associated with a dementia risk of 1.5–2.5 times higher among old adults in the community. DM is a significant risk factor not only for vascular dementia but also for Alzheimer's Disease. The mechanisms that support this association are unclear but may be multifactorial in nature, such as cardiovascular risk factors, glucose toxicity, changes

Both hyperglycemia and hyperinsulinemia, as part of the metabolic process leading to DM type 2 (DM2), are associated with cognitive dysfunction and dementia due to stroke. This is often accompanied by other mental function disorders, such as depression or anxiety [53]. An epidemiological study showed that the incidence rates of hospitalization for VD in adult aged 70 years and over were twice as high in patients with DM2 as in those who did not presented

Genetics clearly plays a role in AD, both in early and late onset. Early-onset AD or beginning before age 65 years can be caused by one of the more than 200 sequence variants in the genes of the beta amyloid precursor protein, presenilin 1 (PSEN1), or presenilin 2 (PSEN2) [55, 56]. Despite the consistent genetic basis for AD, significant variability in onset age has been observed, suggesting an important role of environmental factors or genetic modifiers in determining the onset age [56]. Late-onset AD is also heavily influenced by genetics, although the Mendelian pattern of inheritance is often unclear. There are several factors that could explain this, even if causal mutations exist [57]. Late-onset AD is complex, and apolipoprotein E is the only genetic risk factor unanimously accepted for its development. Several genes involved in AD have been identified using advanced genetic technologies; however, there are many additional genes that

Related to this, a long research that analyzed the Genealogical Index of Familiarity up to 14 generations showed that the pairs of people with family ties who died of AD were significantly related. The relative risk for AD death among the relatives of individuals who died of AD

the dementia syndrome became clinically evident [45].

sure and dementia assessments [50, 51].

*4.1.2. Metabolic disorders: diabetes mellitus*

in insulin metabolism, and inflammation [52].

it [54].

152 Gerontology

*4.1.3. Genetic factors*

have not been identified [58].

increased significantly for close and distant relatives [57].

A new area of interest involves understanding the effect that head trauma has on the behavior and cognitive abilities of brain aging. This issue becomes even more important as the geriatric population grows [59].

Traumatic brain injury (TBI) is an injury in which effects could be devastating often resulting in lifetime cognitive deficits [60]. More than 70% of people with TBI report memory deficits [61]. Contact sports are a source of recurrent TBI. Athletes whose last concussion was in early adulthood (more than 30 years before examination) were reported to have poorer episodic memory and poorer response inhibition, as well as significantly reduced movement speeds in neuropsychological tests, when compared with same-age athletes without a history of concussion [62]. Regarding the cognitive aging process, the evidence showed that cognition problems exhibited by young adults after severe TBI are similar to many cognitive weaknesses in attention deficit and poor working memory of an elderly population with no neurological history. There is evidence that TBI can result in decreased cognitive reserve that can accelerate the cognitive decline normal process, leading to premature aging, potentially increasing the risk of dementia [63].

#### **4.2. Psychological factors**

#### *4.2.1. Depression*

Depression can affect cognitive functions and may emulate cognitive impairment. It can be considered comorbidity, a prodromal factor or a consequence of vascular cognitive impairment, more than a factor that specifically alters vascular physiology or neural health, leading to cognitive impairment [64]. Some studies have concluded that depressive symptoms are associated with cognitive impairment; however, the mechanisms underlying the association between these two common conditions need further exploration. It is unclear whether cognitive impairment over time can be explained by depression or it is just a sign of an incipient dementia [65].

#### **4.3. Social factors**

#### *4.3.1. Age and sex*

Through studies results, the age and sex of the individuals have been considered as risk factors of mild cognitive impairment and dementia. Some studies have reported that the prevalence of dementia increases exponentially with age [66] and doubles every 5 years after the age of 65 years. Several studies showed an increasing prevalence among the older age groups [67, 68]. In higher income countries, prevalence is 5–10% among those over 65 years [68]. Regarding sex, there are results in which dementia is higher in women than in men [68, 69]. One possible explanation for this is that women live longer than men [68]. However, recently, another cohort study reported that both the prevalence and the incidence were higher in men [69, 70].

#### *4.3.2. Education and intellectual commitment*

Dr. James A. Mortimer was one of the first to propose a relationship between years of formal education and risk of dementia. He suggested that education can be a protective factor against dementia, raising the level of "intellectual reserve." Regarding this, a systematic review of the literature on the relationship between education and dementia in the last 25 years concluded that lower education was associated with an increased risk of dementia in many but not all studies.

Finally, the cognitive reserve has been defined as the adaptation of the brain to an injury situation using pre-existing cognitive processing resources or compensation resources through the activation of neural networks [75]. The cognitive reserve allows better tolerance of the effects of the disease associated with dementia, supporting a greater amount of neuropathologies before reaching the symptoms of the disease. The cognitive reserve influences the manifestation of the symptoms of cognitive impairment and, at least partially, in its development toward dementia [76]. People with MCI and low reserves show a steeper decline early in the process of deterioration, compared to the high level of reserve this marked deterioration

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The intervention for the optimization of cognitive functions is based on these concepts to implement nonpharmacological treatments, in order to overcome the challenges of cognitive changes associated with aging, prevent pathologies such as MCI and dementia, and, finally,

According to the British Psychological Society [78], there are a variety of nonpharmacological treatments and interventions which can help people to maintain good mental health, especially after diagnosis of MCI or dementia. Psychosocial interventions can help the diagnosis of dementia, reducing stress and improving mood (such as anxiety or depression), improving and maintaining cognitive functioning, and promoting quality of life in general. Specifically, treatments for improving and maintaining cognitive functioning in aging are Cognitive Training, Cognitive Stimulation Therapy, and Cognitive Rehabilitation that have significant

The Cognitive Training, also called Brain Training, involves specific aspects of memory and other cognitive skills. Since it is not personally tailored, regular pastimes such as crosswords, Sudoku, games, or exercises on a computer would also count as cognitive training. Cognitive training is for anyone who wants to keep his brain active and enjoys brain training games and puzzles, including people living with dementia. Exercises are designed to train specific functions, such as memory of words, logic and reasoning, attention, problem solving, and mathematics. Training could be a regular activity done continuously and can be self-administered [78]. Cognitive Stimulation Therapy (CST) is a group therapy that is used to help strengthen personal communications skills, thinking, and memory. CST groups run for a limited number of sessions (usually 12–14, one or two per week). As a complement, the maintenance cognitive stimulation therapy (MCST) groups continue indefinitely and aim to maintain the benefits that CST groups provide. CST and MCST are suitable for people with diagnosis of mild cognitive impairment or dementia in mild-to-moderate stages. A typical CST session lasts for 1 hour and may involve games, singing, applying reminiscence therapies, sharing stories, discussing current events, practicing arts, and making crafts. CST has shown to be beneficial for cognition and quality of life, and it is also cost-effective. Additionally, if CST is followed by MCST, it offers a significant improvement in cognitive function providing long-term benefits [79].

On the other side, cognitive rehabilitation is an approach to manage the impact that dementiarelated difficulties, such as problems with thinking and memory, can have on everyday life. It is recommended for people who have early-onset dementia. Cognitive rehabilitation is not about curing or reducing dementia-related difficulties with thinking and memory, instead it

would have at the end of the process, due to the protective role of this reserve [77].

differences in terms of their purpose, target population, duration, and management.

if it is necessary, alleviate their effects.

Education associated with the risk of dementia showed different results according to the population, and the years of education did not uniformly reduce the risk of dementia. It seems that a more consistent relationship with dementia occurred when the years of education reflected cognitive ability, suggesting that the effect of education on the risk of dementia can be better assessed in the context of a life development model [71].

In addition to this, occupations performed during lifetime that did not require complex cognitive processes or stimulants seem to be associated with an increased risk of dementia. For example, when studying a group of nuns (average 54 years of age), a strong association was found between low educational and occupational levels with dementia. The risk of dementia increased in those participants with poor education, without professional training and who had never been in charge of a leadership position. These findings support the hypothesis of the benefits of having a cognitive reserve capacity against the consequences of brain diseases [72]. In this sense, it was reported that university preparation represented a lower risk of dementia among five categories, where illiterates showed the highest proportion of individuals with dementia, while the lowest proportion was found in university students [73].
