**2. Occurrence of Alzheimer's disease**

The occurrence of a disease can be measured as proportion of people affected by the disease in a defined population at a specific time point (prevalence), or as number of new cases that occur during a specific time period in a population at risk for developing that disease (inci‐ dence). The prevalence reflects the public health burden of the disease, whereas the inci‐ dence indicates the risk of developing that disease. The prevalence is determined by both incidence and duration of the disease, and in certain circumstances, the prevalence may be estimated as incidence × average disease duration.

#### **2.1. Prevalence**

**1.2. Dementia and Alzheimer's disease**

330 Understanding Alzheimer's Disease

common type of dementia [10].

Dementia is defined as a clinical syndrome, and characterized by the development of multi‐ ple cognitive deficits that are severe enough to interfere with daily functioning, including social and professional functioning. The cognitive deficits include memory impairment and at least one of the other cognitive domains, such as aphasia, apraxia, agnosia or disturbances in executive functioning [5, 6]. Alzheimer's disease is the most common cause of dementia in the elderly, accounting for 60-70% of all demented cases [7]. Alzheimer's disease is strictly a neuropathological diagnosis determined by the presence of neurofibrillary tangles and se‐ nile plaques in the brain of patients with dementia. The disease frequently starts with mem‐ ory impairment, but is invariably followed by a progressive global cognitive impairment [8]. Vascular dementia is the second most common cause of dementia in the elderly after Alz‐ heimer's disease. Vascular dementia is defined as loss of cognitive function resulting from ischemic, hypoperfusive, or haemorrhagic brain lesions due to cerebrovascular disease or cardiovascular pathology. Diagnosis of vascular dementia requires cognitive impairment; vascular brain lesions, often predominantly subcortical, as demonstrated by brain imaging; a temporal link between stroke and dementia; and exclusion of other causes of dementia [9]. The combination of Alzheimer's disease and vascular dementia pathological changes in the brains of older people are extremely common, making mixed dementia probably the most

Alzheimer's disease was first identified more than 100 years ago, but research into its symp‐ toms, causes, risk factors and treatment has gained momentum only in the last 30 years. Al‐ though research has revealed a great deal about Alzheimer's, the precise physiologic changes that trigger the development of Alzheimer's disease largely remain unknown. The only exceptions are certain rare, inherited forms of the disease caused by known genetic mu‐ tations. Alzheimer's disease affects people in different ways, but the most common symp‐ tom pattern begins with gradually worsening ability to remember new information. This occurs because disruption of brain cell function usually begins in brain regions involved in forming new memories. As damage spreads, individuals experience other difficulties. The following are warning signs of Alzheimer's disease: memory loss that disrupts daily life; challenges in planning or solving problems; difficulty completing familiar tasks at home, at work or at leisure; confusion with time or place; trouble understanding visual images and spatial relationships; new problems with words in speaking or writing; misplacing things and losing the ability to retrace steps; decreased or poor judgment; withdrawal from work or social activities; and changes in mood and personality. As the disease progresses, the in‐ dividual's cognitive and functional abilities decline. In advanced Alzheimer's disease, peo‐ ple need help with basic activities of daily living, such as bathing, dressing, eating and using the bathroom. Those in the final stages of the disease lose their ability to communicate, fail to recognize loved ones and become bed-bound and reliant on around-the-clock care. When an individual has difficulty moving because of Alzheimer's disease, they are more vulnera‐

ble to infections, including pneumonia (infection of the lungs).

Based on the available epidemiological data, a group of experts estimated that 24.3 million people have dementia today, with 4.6 million new cases of dementia every year (one new case every 7 seconds). The number of people affected will double every 20 years to 81.1 mil‐ lion by 2040 [11]. Similar estimates have been reported previously [12]. Most people with dementia live in developing countries. China and its western Pacific neighbours have the highest number of people with dementia (6 million), followed by the European Union (5.0 million), USA (2.9 million), and India (1.5 million). The rates of increase in the number of dementia cases are not uniform across the world; numbers in developed countries are fore‐ casted to increase by 100% between 2001 and 2040, but to increase by more than 300% in In‐ dia, China, and other south Asian and western Pacific countries [11]. About 70% of these cases were attributed to Alzheimer's disease [11, 13]. The pooled data of population-based studies in Europe suggests that the age-standardized prevalence in people 65+ years old was 6.4 % for dementia and 4.4 % for Alzheimer's disease [14]. In the US, a study of a national representative sample of people aged >70 years yielded a prevalence for Alzheimer's disease of 9.7 % [15].

Worldwide, the global prevalence of dementia was estimated to be 3.9 % in people aged 60+ years, with the regional prevalence being 1.6 % in Africa, 4.0 % in China and Western Pacific regions, 4.6 % in Latin America, 5.4 % in Western Europe, and 6.4 % in North America [11]. A meta-analysis including 18 studies from China during 1990-2010 showed prevalence of Alzheimer's disease of 1.9% [16]. More than 25 million people in the world are currently af‐ fected by dementia, most suffering from Alzheimer's disease, with around 5 million new cases occurring every year [11]. The number of people with dementia is anticipated to dou‐ ble every 20 years. Despite different inclusion criteria, several meta-analyses and nationwide surveys have yielded roughly similar age-specific prevalence of AD across regions (Figure 1) [17]. The age-specific prevalence of Alzheimer's disease almost doubles every 5 years af‐ ter aged 65. Among developed nations, approximately 1 in 10 older people aged ≥ 65 is af‐ fected by some degree of dementia, whereas more than one third of very old people aged ≥85 years may have dementia-related symptoms and signs [18, 19]. There is a similar pattern of dementia subtypes across the world, with Alzheimer's disease and vascular dementia, the two most common forms of dementia, accounting for 50 % to 70 % and 15 % to 25 %, respec‐ tively, of all dementia cases.

years in the US Seattle and Baltimore areas yielded an incidence rate for Alzheimer's disease of 15.0 (male, 13.0; female, 16.9) per 1000 person-year [27, 28]. The incidence rate of Alzheim‐ er's disease increases almost exponentially with increasing age until 85 years of age (Figure 2) [17]. A consistently exponential increase, with advancing age in Alzheimer incidence sug‐ gests that Alzheimer's disease is an inevitable consequence of aging, whereas a convergence to or a decline at certain age may suggest that very old people may have reduced vulnerabil‐ ity, owing perhaps to genetic or environmental factors. The Cache County Study further found that the incidence of AD increased with age, peaked, and then started to decline at extreme old ages for both men and women [29]. However, some meta-analyses and largescale studies in Europe provided no evidence for the potential decline in the incidence of de‐ mentia and Alzheimer's disease among the oldest-old age groups [26, 30, 31]. The apparent decline suggested in some studies may be an artifact of poor response rate and survival ef‐ fect in these very old age groups. Several studies from Europe observed a higher incidence rate of Alzheimer's disease among women than men, especially among the oldest-old age groups, whereas studies in North America found no significant gender difference [17].

Epidemiology of Alzheimer's Disease http://dx.doi.org/10.5772/54398 333

**Figure 2.** Age-specific incidence of Alzheimer's disease (per 1 000 person years) across continents and countries. \*inci‐

There appears to be some geographic variations in the incidence of Alzheimer's disease. The pooled data of eight European studies suggested a geographical dissociation across Europe, with higher incidence rates being found among the oldest-old people of north-western countries than among southern countries [26]. The incidence rates of Alzheimer's disease were reported to be slightly lower in North America than in Europe. Differences in method‐ ology (e.g., differences in study design and procedure of case ascertainment), rather than re‐ al different regional distributions of the disease, may be partly responsible for the

dence of all types of dementia [17].

**Figure 1.** Age-specific prevalence of Alzheimer's disease (per 100 population) across continents and countries. \*preva‐ lence of all types of dementia [17].

Epidemiological research of dementia and AD in low- and middle-income countries has drawn much attention in recent years. A systematic review estimated that the overall preva‐ lence of Alzheimer's disease in developing countries was 3.4 % (95 % CI,1.6 % - 5.0 %) [20]. The prevalence of dementia (DSM-IV criteria) in people aged 65+ years in seven developing nations varied widely from less than 0.5 % to more than 6 %, which is substantially lower than in developed countries [21]. Indeed, the prevalence rates of dementia in India and rural Latin America were approximately a quarter of the rates in European countries. However, the prevalence of AD in persons 65+ years in urban areas of China was 3.5 %, and even high‐ er (4.8 %) after post-hoc correction for negative screening errors [22], which is generally comparable with those from Western nations. Similar prevalence rates of dementia were al‐ so reported from the urban populations of Latin American nations such as Havana in Cuba (6.4 %) and São Paulo in Brazil (5.1 %) [20, 23, 24].

#### **2.2. Incidence**

The global annual incidence of dementia is around 7.5 per 1,000 persons [11]. The incidence rate of dementia increases exponentially with age, from approximately one per 1,000 personyear in people aged 60-64 years to more than 70 per 1,000 person-year in 90+ year-olds. The incidence rates of dementia across regions are quite similar in the younger-old (<75 years), but greater variations are seen among the older ages [25]. Slightly lower rates have been de‐ tected in the USA in comparison with Europe and Asia, and this is possibly due to differen‐ ces in the study designs and the case ascertainment procedures. The pooled incidence rate of Alzheimer's disease among people 65+ years of age in Europe was 19.4 per 1000 person-year [26]. The pooled data from two large-scale community-based studies of people aged ≥65 years in the US Seattle and Baltimore areas yielded an incidence rate for Alzheimer's disease of 15.0 (male, 13.0; female, 16.9) per 1000 person-year [27, 28]. The incidence rate of Alzheim‐ er's disease increases almost exponentially with increasing age until 85 years of age (Figure 2) [17]. A consistently exponential increase, with advancing age in Alzheimer incidence sug‐ gests that Alzheimer's disease is an inevitable consequence of aging, whereas a convergence to or a decline at certain age may suggest that very old people may have reduced vulnerabil‐ ity, owing perhaps to genetic or environmental factors. The Cache County Study further found that the incidence of AD increased with age, peaked, and then started to decline at extreme old ages for both men and women [29]. However, some meta-analyses and largescale studies in Europe provided no evidence for the potential decline in the incidence of de‐ mentia and Alzheimer's disease among the oldest-old age groups [26, 30, 31]. The apparent decline suggested in some studies may be an artifact of poor response rate and survival ef‐ fect in these very old age groups. Several studies from Europe observed a higher incidence rate of Alzheimer's disease among women than men, especially among the oldest-old age groups, whereas studies in North America found no significant gender difference [17].

**Figure 1.** Age-specific prevalence of Alzheimer's disease (per 100 population) across continents and countries. \*preva‐

Epidemiological research of dementia and AD in low- and middle-income countries has drawn much attention in recent years. A systematic review estimated that the overall preva‐ lence of Alzheimer's disease in developing countries was 3.4 % (95 % CI,1.6 % - 5.0 %) [20]. The prevalence of dementia (DSM-IV criteria) in people aged 65+ years in seven developing nations varied widely from less than 0.5 % to more than 6 %, which is substantially lower than in developed countries [21]. Indeed, the prevalence rates of dementia in India and rural Latin America were approximately a quarter of the rates in European countries. However, the prevalence of AD in persons 65+ years in urban areas of China was 3.5 %, and even high‐ er (4.8 %) after post-hoc correction for negative screening errors [22], which is generally comparable with those from Western nations. Similar prevalence rates of dementia were al‐ so reported from the urban populations of Latin American nations such as Havana in Cuba

The global annual incidence of dementia is around 7.5 per 1,000 persons [11]. The incidence rate of dementia increases exponentially with age, from approximately one per 1,000 personyear in people aged 60-64 years to more than 70 per 1,000 person-year in 90+ year-olds. The incidence rates of dementia across regions are quite similar in the younger-old (<75 years), but greater variations are seen among the older ages [25]. Slightly lower rates have been de‐ tected in the USA in comparison with Europe and Asia, and this is possibly due to differen‐ ces in the study designs and the case ascertainment procedures. The pooled incidence rate of Alzheimer's disease among people 65+ years of age in Europe was 19.4 per 1000 person-year [26]. The pooled data from two large-scale community-based studies of people aged ≥65

lence of all types of dementia [17].

332 Understanding Alzheimer's Disease

**2.2. Incidence**

(6.4 %) and São Paulo in Brazil (5.1 %) [20, 23, 24].

**Figure 2.** Age-specific incidence of Alzheimer's disease (per 1 000 person years) across continents and countries. \*inci‐ dence of all types of dementia [17].

There appears to be some geographic variations in the incidence of Alzheimer's disease. The pooled data of eight European studies suggested a geographical dissociation across Europe, with higher incidence rates being found among the oldest-old people of north-western countries than among southern countries [26]. The incidence rates of Alzheimer's disease were reported to be slightly lower in North America than in Europe. Differences in method‐ ology (e.g., differences in study design and procedure of case ascertainment), rather than re‐ al different regional distributions of the disease, may be partly responsible for the geographic variations. The study using identical methods in UK found no evidence of varia‐ tion in dementia incidence among five areas in England and Wales [30]. Studies have con‐ firmed that AD incidence in developing countries is generally lower than in North America and Europe. For example, the incidence rate of AD among people aged 65+ years was 7.7 per 1 000 person-year in Brazil and 3.2 per 1 000 person-year in India [20, 32].

creasing age may partially reflect the cumulative effect of different risk and protective factors over the lifespan, including the effect of complex interactions of genetic susceptibili‐ ty, psychosocial factors, biological factors, and environmental exposures experienced over the lifespan. Evidence from epidemiological, neuroimaging, and neuropathological research, supports the role of genetic, vascular, and psychosocial factors in the development of Alz‐ heimer's disease, whereas evidence for the etiologic role of dietary or nutritional factors, oc‐

Epidemiology of Alzheimer's Disease http://dx.doi.org/10.5772/54398 335

Mutations in amyloid precursor protein, presenilin-1, and presenilin-2 genes can cause ear‐ ly-onset familial Alzheimer's disease that account for no more than 5% of all cases. The ma‐ jority of AD cases are sporadic, with considerable heterogeneity in their risk profiles and

The *APOE* ε4 allele is the only established susceptibility gene for both early- and late-on‐ set Alzheimer's disease, and is a susceptibility gene, being neither necessary nor suffi‐ cient for the development of Alzheimer's disease. *APOE* ε4 is one of three common forms (ε2, ε3 and ε4) of the *APOE* gene, which provides the blue print for a protein that carries cholesterol in the bloodstream. Everyone inherits one form of the *APOE* gene from each parent. Those who inherit one *APOE* ε4 gene have increased risk of develop‐ ing Alzheimer's disease and of developing it at an earlier age than those who inherit the ε2 or ε3 forms of the *APOE* gene [40]. Those who inherit two *APOE*-ε4 genes have an even higher risk. Unlike inheriting a known genetic mutation for Alzheimer's disease, in‐ heriting one or two copies of this form of the *APOE* gene does not guarantee that an in‐ dividual will develop Alzheimer's disease. The risk effect of the *APOE* ε4 allele decreases with increasing age, and after age 75, 15–20% of Alzheimer's cases are attribut‐ able to *APOE* genotype [41]. Several other genes have been examined as possible candi‐

However, not all (4-carriers develop dementia. Studies have demonstrated that high educa‐ tion, active leisure activities, or maintaining vascular health seems to reduce the risk of de‐ mentia related to APOE ε4 [40, 41]. The ε4-carriers with these characteristics appear to have similar dementia-free survival time to non ε4-carriers. Further, the obese related FTO gene

Individuals who have a parent, brother or sister with Alzheimer's are more likely to develop the disease than those who do not have a first-degree relative with Alzheimer's [45-47]. Those who have more than one first-degree relative with Alzheimer's disease are at even higher risk of developing the disease [48]. When diseases run in families, heredity (genetics),

dates, but the reports are sporadic, and the results are inconsistent [42].

may interact with *APOE* ε4 to increase the risk of Alzheimer's disease [44].

shared environmental and /or lifestyle factors or both may play a role.

cupational exposures, and inflammation is less clear [39].

**4.1. Genetic factors**

*4.1.2. Family history*

neuropathological features.

*4.1.1. Apolipoprotein E ε4 (APOE ε4)*
