**3. Prognosis and impact**

Dementia is one of the leading causes of death in older people. However, death certificates grossly underreport its cause, even when multiple underlying causes of death are taken into account. The community-based follow-up studies could provide reliable data on mortality. In the Swedish Kungsholmen Project of people aged 75 years or over, the mortality rate of dementia was 2.4 per 100 person-year; 70% of incident dementia cases died within five years following the diagnosis. In three years, more than 50% of the dementia cases reached the se‐ vere stage. In the Kungsholmen Project, the proportion of severe dementia among prevalent cases increased from 19% at baseline to 48% after three years, and to 78% after seven years. This progression is due to both cognitive and functional decline [33]. Dementia is strongly associated with disability as it has been found to be the major determinant of developing dependence and functional decline over three years. Approximately half of the persons who developed functional dependence in a three year period can attribute to dementia [34]. In industrialised countries, mental disease and cognitive impairment are the most prevalent disorders among older adults living in nursing homes or other institutions. However, insti‐ tutionalisation of demented patients varies depending on age structure, urban or rural resi‐ dence, and other cultural aspects. In a 75+ year old population, 70% of incident dementia cases died in the five years following the diagnosis, accounting for a mortality rate specific for dementia of 2.4 per 100 person-years. Dementia triples the risk of death [35]. The de‐ mands of healthcare and social service of the huge and rapidly growing numbers of demen‐ tia patients have a major economic impact at the societal level [36]. The worldwide direct costs for dementia in 2003 were estimated at 156 billion USD in the main scenario of a worldwide prevalence of 27.7 million demented persons. It is obvious that due to these costs and the expected increase in the number of elderly people in developing countries, the de‐ menting conditions will present a great challenge [37,38].

## **4. Risk and protective factors**

Alzheimer's disease is multifactorial disorder that is determined by genetic and environ‐ mental factors as well as their interactions. Population-based prospective study is the major epidemiological approach to identifying influential factors for chronic multifactorial diseas‐ es such as dementia, in which the life-course approach should be taken into consideration. Age is the most powerful determinant of Alzheimer's disease, and gene mutations contrib‐ ute to a small proportion of all cases. The strong association of Alzheimer's disease with in‐ 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‐ cupational exposures, and inflammation is less clear [39].

#### **4.1. Genetic factors**

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

Dementia is one of the leading causes of death in older people. However, death certificates grossly underreport its cause, even when multiple underlying causes of death are taken into account. The community-based follow-up studies could provide reliable data on mortality. In the Swedish Kungsholmen Project of people aged 75 years or over, the mortality rate of dementia was 2.4 per 100 person-year; 70% of incident dementia cases died within five years following the diagnosis. In three years, more than 50% of the dementia cases reached the se‐ vere stage. In the Kungsholmen Project, the proportion of severe dementia among prevalent cases increased from 19% at baseline to 48% after three years, and to 78% after seven years. This progression is due to both cognitive and functional decline [33]. Dementia is strongly associated with disability as it has been found to be the major determinant of developing dependence and functional decline over three years. Approximately half of the persons who developed functional dependence in a three year period can attribute to dementia [34]. In industrialised countries, mental disease and cognitive impairment are the most prevalent disorders among older adults living in nursing homes or other institutions. However, insti‐ tutionalisation of demented patients varies depending on age structure, urban or rural resi‐ dence, and other cultural aspects. In a 75+ year old population, 70% of incident dementia cases died in the five years following the diagnosis, accounting for a mortality rate specific for dementia of 2.4 per 100 person-years. Dementia triples the risk of death [35]. The de‐ mands of healthcare and social service of the huge and rapidly growing numbers of demen‐ tia patients have a major economic impact at the societal level [36]. The worldwide direct costs for dementia in 2003 were estimated at 156 billion USD in the main scenario of a worldwide prevalence of 27.7 million demented persons. It is obvious that due to these costs and the expected increase in the number of elderly people in developing countries, the de‐

Alzheimer's disease is multifactorial disorder that is determined by genetic and environ‐ mental factors as well as their interactions. Population-based prospective study is the major epidemiological approach to identifying influential factors for chronic multifactorial diseas‐ es such as dementia, in which the life-course approach should be taken into consideration. Age is the most powerful determinant of Alzheimer's disease, and gene mutations contrib‐ ute to a small proportion of all cases. The strong association of Alzheimer's disease with in‐

1 000 person-year in Brazil and 3.2 per 1 000 person-year in India [20, 32].

menting conditions will present a great challenge [37,38].

**4. Risk and protective factors**

**3. Prognosis and impact**

334 Understanding Alzheimer's Disease

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 neuropathological features.

#### *4.1.1. Apolipoprotein E ε4 (APOE ε4)*

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

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

#### *4.1.2. Family history*

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

#### **4.2. Biological risk factors**

Increasing age is a well-established risk factor for Alzheimer's disease. The incidence of Alz‐ heimer's disease almost doubles with every 5 years of age [49, 50]. Female sex is often asso‐ ciated with an increased risk of AD, especially at the oldest-old age [25]. Men seem to be at greater risk for vascular dementia than women [51].

with peripheral arterial disease [58], suggesting that extensive peripheral atherosclerosis is a risk factor for Alzheimer's disease. Other cardiovascular diseases, such as heart failure and atrial fibrillation, have been independently related to increased risk of dementia. In the Kungsholmen Project, heart failure was associated with a more than 80% increased risk of

Epidemiology of Alzheimer's Disease http://dx.doi.org/10.5772/54398 337

Cerebrovascular changes such as haemorrhagic infarcts, small and large ischemic cortical in‐ farcts, vasculo-pathie, and white matter changes all increase the risk of dementia [13]. Sys‐ tematic reviews of population-based studies reveal an approximately two- to four-fold increased risk of incident dementia associated with clinical stroke (post-stroke dementia). Multiple cerebral infarcts, recurrent and strategic strokes are main risk factors for poststroke dementia. Silent stroke and white matter lesions detected on neuroimaging are asso‐ ciated with increased risk of dementia and cognitive decline. Spontaneous cerebral emboli were related to both AD and VaD. Some studies reported an association of stroke with Alz‐ heimer's disease and cognitive decline [60]. Cerebral vascular lesions may interact with neu‐ rodegenerative lesions to produce a dementia syndrome in individuals not having sufficient neurodegenerative damages to express dementia [25]. Neuropathological studies suggested that cerebrovascular lesions, atherosclerosis, and neurodegenerative changes in the brain of‐ ten coexist, and may be coincident processes converging to cause additive damage to the ag‐

A potential link between diabetes and cognitive impairment was first reported more than 80 years ago. The association of diabetes with these cognitive changes is now well established [62]. There is substantial evidence suggesting that type 2 diabetes is associated with cogni‐ tive impairment involving both memory and executive function [63-65]. Several large longi‐ tudinal population-based studies have also shown that the rate of cognitive decline is accelerated in elderly people with type 2 diabetes [66]. An increased risk of not only vascu‐ lar dementia but also neurodegenerative type dementia among persons with diabetes has been reported in several longitudinal studies [67-70], and the risk effect was confirmed by a systematic review [71]. Midlife diabetes or a longer duration of diabetes may play a crucial role in dementia and Alzheimer's disease [68, 72]. Overall, diabetes leads to a 20-70% greater decline in cognitive performance, and a 60% higher risk of dementia [73]. In addition, bor‐ derline or prediabetes or impaired glucose tolerance, is also linked to an increased risk of

Similar to hypertension, recent studies suggested a lifespan-dependent relation of obesity with dementia [75, 76]. A higher body mass index (BMI) at middle age was related to an in‐ creased risk of dementia in late life [77, 78]. A greater decline in BMI approximately 10 years prior to dementia onset was detected, which is in line with the other studies suggesting an

ing brain and to promote clinical expression of the dementia syndrome [61].

dementia and Alzheimer's disease in very old people [74].

dementia and Alzheimer's disease [59].

*4.3.3. Cerebrovascular disease*

*4.3.4. Diabetes mellitus*

*4.3.5. Overweight and obesity*

#### **4.3. Vascular disorders and risk factors**

A number of vascular risk factors and disorders have been linked to Alzheimer's disease, but some factors may have a differential association with the risk of Alzheimer's disease de‐ pending on the age when the exposure is assessed.

#### *4.3.1. Blood pressure*

Several studies have consistently reported an association between midlife high blood pres‐ sure and increased risk of dementia and Alzheimer's disease [52, 53]. Hypertension has been linked to neurodegenerative markers in the brain, suggesting that long-term high blood pressure may play a causal role in the neurodegenerative process itself or by causing brain atrophy. In very old people, the deleterious effect of high blood pressure is less evident, whereas low blood pressure seems to be predictive of dementia and Alzheimer's disease. As dementia has a long latent period, low blood pressure may be a sign of impending illness [54], which was confirmed by the longitudinal data from the Kungsholmen Project, suggest‐ ing the involvement of late life low blood pressure and cerebral hypo-perfusion in the devel‐ opment of dementia and Alzheimer's disease [55]. All these findings suggest that the relation of blood pressure to dementia may be age-dependent [25].

Recent follow-up studies have suggested that the protective effect of antihypertensive thera‐ py on dementia and AD may depend on the duration of treatment and the age when people take the medications; the more evident efficacy was seen among young-old people (i.e., <75 years) and those with long-term treatment [56, 57]. Evidence from clinical trials of antihy‐ pertensive therapy and dementia is summarized in the section on intervention trials to‐ wards primary prevention. Antihypertensive treatment may protect against dementia and AD by postponing atherosclerotic process, reducing the number of cerebrovascular lesions, and improving cerebral perfusion [52]. It has also been suggested that some antihyperten‐ sive agents (e.g., calcium-channel antagonists) may have neuroprotective effects. The recent neuropathological study found substantially less Alzheimer neuropathological changes (i.e., neuritic plaque and neurofibrillary tangle densities) in the medicated hypertension group than non-hypertensive group, which may reflect a salutary effect of antihypertensive thera‐ py against Alzheimer's disease-associated neuropathology [57].

#### *4.3.2. Cardiovascular disease*

A healthy heart helps ensure that enough blood is pumped through blood vessels to the brain. The follow-up data of the Cardiovascular Health Study showed that cardiovascular disease was associated with an increased risk of Alzheimer's disease, especially in people with peripheral arterial disease [58], suggesting that extensive peripheral atherosclerosis is a risk factor for Alzheimer's disease. Other cardiovascular diseases, such as heart failure and atrial fibrillation, have been independently related to increased risk of dementia. In the Kungsholmen Project, heart failure was associated with a more than 80% increased risk of dementia and Alzheimer's disease [59].

#### *4.3.3. Cerebrovascular disease*

**4.2. Biological risk factors**

336 Understanding Alzheimer's Disease

*4.3.1. Blood pressure*

greater risk for vascular dementia than women [51].

pending on the age when the exposure is assessed.

relation of blood pressure to dementia may be age-dependent [25].

py against Alzheimer's disease-associated neuropathology [57].

*4.3.2. Cardiovascular disease*

**4.3. Vascular disorders and risk factors**

Increasing age is a well-established risk factor for Alzheimer's disease. The incidence of Alz‐ heimer's disease almost doubles with every 5 years of age [49, 50]. Female sex is often asso‐ ciated with an increased risk of AD, especially at the oldest-old age [25]. Men seem to be at

A number of vascular risk factors and disorders have been linked to Alzheimer's disease, but some factors may have a differential association with the risk of Alzheimer's disease de‐

Several studies have consistently reported an association between midlife high blood pres‐ sure and increased risk of dementia and Alzheimer's disease [52, 53]. Hypertension has been linked to neurodegenerative markers in the brain, suggesting that long-term high blood pressure may play a causal role in the neurodegenerative process itself or by causing brain atrophy. In very old people, the deleterious effect of high blood pressure is less evident, whereas low blood pressure seems to be predictive of dementia and Alzheimer's disease. As dementia has a long latent period, low blood pressure may be a sign of impending illness [54], which was confirmed by the longitudinal data from the Kungsholmen Project, suggest‐ ing the involvement of late life low blood pressure and cerebral hypo-perfusion in the devel‐ opment of dementia and Alzheimer's disease [55]. All these findings suggest that the

Recent follow-up studies have suggested that the protective effect of antihypertensive thera‐ py on dementia and AD may depend on the duration of treatment and the age when people take the medications; the more evident efficacy was seen among young-old people (i.e., <75 years) and those with long-term treatment [56, 57]. Evidence from clinical trials of antihy‐ pertensive therapy and dementia is summarized in the section on intervention trials to‐ wards primary prevention. Antihypertensive treatment may protect against dementia and AD by postponing atherosclerotic process, reducing the number of cerebrovascular lesions, and improving cerebral perfusion [52]. It has also been suggested that some antihyperten‐ sive agents (e.g., calcium-channel antagonists) may have neuroprotective effects. The recent neuropathological study found substantially less Alzheimer neuropathological changes (i.e., neuritic plaque and neurofibrillary tangle densities) in the medicated hypertension group than non-hypertensive group, which may reflect a salutary effect of antihypertensive thera‐

A healthy heart helps ensure that enough blood is pumped through blood vessels to the brain. The follow-up data of the Cardiovascular Health Study showed that cardiovascular disease was associated with an increased risk of Alzheimer's disease, especially in people Cerebrovascular changes such as haemorrhagic infarcts, small and large ischemic cortical in‐ farcts, vasculo-pathie, and white matter changes all increase the risk of dementia [13]. Sys‐ tematic reviews of population-based studies reveal an approximately two- to four-fold increased risk of incident dementia associated with clinical stroke (post-stroke dementia). Multiple cerebral infarcts, recurrent and strategic strokes are main risk factors for poststroke dementia. Silent stroke and white matter lesions detected on neuroimaging are asso‐ ciated with increased risk of dementia and cognitive decline. Spontaneous cerebral emboli were related to both AD and VaD. Some studies reported an association of stroke with Alz‐ heimer's disease and cognitive decline [60]. Cerebral vascular lesions may interact with neu‐ rodegenerative lesions to produce a dementia syndrome in individuals not having sufficient neurodegenerative damages to express dementia [25]. Neuropathological studies suggested that cerebrovascular lesions, atherosclerosis, and neurodegenerative changes in the brain of‐ ten coexist, and may be coincident processes converging to cause additive damage to the ag‐ ing brain and to promote clinical expression of the dementia syndrome [61].

#### *4.3.4. Diabetes mellitus*

A potential link between diabetes and cognitive impairment was first reported more than 80 years ago. The association of diabetes with these cognitive changes is now well established [62]. There is substantial evidence suggesting that type 2 diabetes is associated with cogni‐ tive impairment involving both memory and executive function [63-65]. Several large longi‐ tudinal population-based studies have also shown that the rate of cognitive decline is accelerated in elderly people with type 2 diabetes [66]. An increased risk of not only vascu‐ lar dementia but also neurodegenerative type dementia among persons with diabetes has been reported in several longitudinal studies [67-70], and the risk effect was confirmed by a systematic review [71]. Midlife diabetes or a longer duration of diabetes may play a crucial role in dementia and Alzheimer's disease [68, 72]. Overall, diabetes leads to a 20-70% greater decline in cognitive performance, and a 60% higher risk of dementia [73]. In addition, bor‐ derline or prediabetes or impaired glucose tolerance, is also linked to an increased risk of dementia and Alzheimer's disease in very old people [74].

#### *4.3.5. Overweight and obesity*

Similar to hypertension, recent studies suggested a lifespan-dependent relation of obesity with dementia [75, 76]. A higher body mass index (BMI) at middle age was related to an in‐ creased risk of dementia in late life [77, 78]. A greater decline in BMI approximately 10 years prior to dementia onset was detected, which is in line with the other studies suggesting an association of accelerated BMI decline with Alzheimer's disease [79, 80]. Low BMI in late life and weight loss may be related to high risk of dementia and Alzheimer's disease [81], but low BMI and weight loss can be interpreted as markers of preclinical Alzheimer's disease, especially when measured less than 10 years prior to clinical diagnosis [25]. In line with these findings, several follow-up studies of older people suggested that accelerated decline in BMI was associated with future development of Alzheimer's disease [79, 82, 83]. Low BMI in late life was related to a higher risk for Alzheimer's disease over a subsequent 5- to 6 year period [81]. Thus, late-life low BMI and weight loss can be interpreted as markers for preclinical Alzheimer's disease, particularly when measured just a few years prior to clinical diagnosis of the disease [17].

cause the inverse association may be due to information bias, the confounding of healthy lifestyles and high socioeconomic status, different approaches in assessments of alcohol con‐

Epidemiology of Alzheimer's Disease http://dx.doi.org/10.5772/54398 339

The relationship between smoking and cognitive decline remains uncertain. Case-control studies have largely suggested that smoking lowers the risk of Alzheimer's disease [13]. Some prospective studies have found an increased risk of Alzheimer's disease associated with smoking [94]. A meta-analysis that examined the association between smoking and Alzheimer's disease while accounting for tobacco-industry affiliation found that the com‐ bined results of 18 cross-sectional studies without industry affiliations yielded no associa‐ tion [95]. Analysis of 14 cohort studies without tobacco-industry affiliations yielded a significant increase in the risk of Alzheimer's disease [13]. In the Kungsholmen Project, smoking affected survival in Alzheimer's disease cases more than in non-demented subjects, and the protective effect of smoking on the Alzheimer's disease was no longer present when incident Alzheimer's cases were studied [7] suggesting that previously reported association of cigarette smoking with low prevalence of dementia was probably due to survival bias.

Diets high in fish, fruits and vegetables are high in anti-oxidants and polyunsaturated fatty acids (PUFAs). In some observational studies, high or supplementary intake of vitamins C, E, B6, B12, and folate has been related to a decreased risk of Alzheimer's disease [96, 97]. Indeed, low levels of B12 and folate were found to be related to an increased risk of Alz‐ heimer's disease in a study from the Kungsholmen Project [98]. Investigations on the effect of dietary PUFAs on the risk of cognitive dysfunction proved inconclusive. Several studies showed that the consumption of PUFAs led to reduction in the risk of Alzheimer's disease and dementia, mild cognitive impairment [99]. Population-based studies suggested that moderate to high intake of unsaturated fats at midlife is protective, whereas a moderate in‐ take of saturated fats may increase the risk of dementia and Alzheimer's disease [100, 101], especially among *APOE* ε4 carriers [102, 103]. Fatty acids may affect dementia through vari‐ ous mechanisms such as atherosclerosis and inflammation. Adherence to 'Mediterranean di‐ et' (higher intake of fish, fruits, and vegetables rich in antioxidants) was associated with a

reduced risk of Alzheimer's disease independent of vascular pathways [104].

the onset of dementia, possibly by enhancing cognitive reserve.

Psychological factors include social economic status, education attainment in early life, and work complexity in adult-life and leisure activities. Evidence from epidemiological research has been accumulating that some psychosocial factors and healthy lifestyle may postpone

sumption, or outcome misclassification.

*4.3.9. Cigarette smoking*

*4.3.10. Diet and nutrients*

**4.4. Psychosocial factors**

#### *4.3.6. Hyperlipidaemia*

An association of elevated cholesterol at middle life with increased risk of late-life Alzheim‐ er's disease was reported in some studies [53]. Controversial findings have also been report‐ ed on the relation of cholesterol in late life to dementia risk. Some cohort studies found no association or even an inverse association of total cholesterol with dementia risk [84]. A study showed a decline in total cholesterol at least 15 years before dementia onset [85]. Re‐ cently, a bidirectional cholesterol-cognition relationship has been reported. High midlife cholesterol was associated with poorer late-life cognition, but decreasing cholesterol after midlife may reflect poorer cognitive status [86].

#### *4.3.7. The metabolic syndrome*

Instead of exploring the effect of its subcomponents, several studies have assessed the rela‐ tionship between metabolic syndrome as a whole and the risk of Alzheimer's disease or cog‐ nitive decline. A clustering of interrelated metabolic risk factors such as diabetes, obesity, hypertension and dyslipidaemia has received increasing attention in the past few years. Sev‐ eral components of the metabolic syndrome have been individually related to cognitive out‐ comes. A prospective study found that the metabolic syndrome contributed to cognitive decline [87]. But this finding was not confirmed in a population of the oldest old. The con‐ cept of the metabolic syndrome may be less valid in this age group [88]. Finally, two studies showed that metabolic syndrome was associated with an increased risk of Alzheimer's dis‐ ease [89, 90].

#### *4.3.8. Alcohol consumption*

Excessive alcohol intake can cause alcoholic dementia and may increase the risk of vascular dementia. Heavier alcohol intake at middle age was associated with increased risk of latelife dementia [91]. By contrast, increasing evidence suggests that light to moderate alcohol consumption may be associated with a reduced risk of dementia and cognitive decline [92], a similar effect as observed for cardiovascular disease [25]. In a meta-analysis of 15 prospec‐ tive studies on the effect of alcohol on dementia risk, light to moderate alcohol consumption was associated with a reduction in the risk of Alzheimer's disease and dementia [93]. How‐ ever, the role of moderate alcohol consumption in dementia still remains controversial be‐ cause the inverse association may be due to information bias, the confounding of healthy lifestyles and high socioeconomic status, different approaches in assessments of alcohol con‐ sumption, or outcome misclassification.

#### *4.3.9. Cigarette smoking*

association of accelerated BMI decline with Alzheimer's disease [79, 80]. Low BMI in late life and weight loss may be related to high risk of dementia and Alzheimer's disease [81], but low BMI and weight loss can be interpreted as markers of preclinical Alzheimer's disease, especially when measured less than 10 years prior to clinical diagnosis [25]. In line with these findings, several follow-up studies of older people suggested that accelerated decline in BMI was associated with future development of Alzheimer's disease [79, 82, 83]. Low BMI in late life was related to a higher risk for Alzheimer's disease over a subsequent 5- to 6 year period [81]. Thus, late-life low BMI and weight loss can be interpreted as markers for preclinical Alzheimer's disease, particularly when measured just a few years prior to clinical

An association of elevated cholesterol at middle life with increased risk of late-life Alzheim‐ er's disease was reported in some studies [53]. Controversial findings have also been report‐ ed on the relation of cholesterol in late life to dementia risk. Some cohort studies found no association or even an inverse association of total cholesterol with dementia risk [84]. A study showed a decline in total cholesterol at least 15 years before dementia onset [85]. Re‐ cently, a bidirectional cholesterol-cognition relationship has been reported. High midlife cholesterol was associated with poorer late-life cognition, but decreasing cholesterol after

Instead of exploring the effect of its subcomponents, several studies have assessed the rela‐ tionship between metabolic syndrome as a whole and the risk of Alzheimer's disease or cog‐ nitive decline. A clustering of interrelated metabolic risk factors such as diabetes, obesity, hypertension and dyslipidaemia has received increasing attention in the past few years. Sev‐ eral components of the metabolic syndrome have been individually related to cognitive out‐ comes. A prospective study found that the metabolic syndrome contributed to cognitive decline [87]. But this finding was not confirmed in a population of the oldest old. The con‐ cept of the metabolic syndrome may be less valid in this age group [88]. Finally, two studies showed that metabolic syndrome was associated with an increased risk of Alzheimer's dis‐

Excessive alcohol intake can cause alcoholic dementia and may increase the risk of vascular dementia. Heavier alcohol intake at middle age was associated with increased risk of latelife dementia [91]. By contrast, increasing evidence suggests that light to moderate alcohol consumption may be associated with a reduced risk of dementia and cognitive decline [92], a similar effect as observed for cardiovascular disease [25]. In a meta-analysis of 15 prospec‐ tive studies on the effect of alcohol on dementia risk, light to moderate alcohol consumption was associated with a reduction in the risk of Alzheimer's disease and dementia [93]. How‐ ever, the role of moderate alcohol consumption in dementia still remains controversial be‐

diagnosis of the disease [17].

*4.3.7. The metabolic syndrome*

ease [89, 90].

*4.3.8. Alcohol consumption*

midlife may reflect poorer cognitive status [86].

*4.3.6. Hyperlipidaemia*

338 Understanding Alzheimer's Disease

The relationship between smoking and cognitive decline remains uncertain. Case-control studies have largely suggested that smoking lowers the risk of Alzheimer's disease [13]. Some prospective studies have found an increased risk of Alzheimer's disease associated with smoking [94]. A meta-analysis that examined the association between smoking and Alzheimer's disease while accounting for tobacco-industry affiliation found that the com‐ bined results of 18 cross-sectional studies without industry affiliations yielded no associa‐ tion [95]. Analysis of 14 cohort studies without tobacco-industry affiliations yielded a significant increase in the risk of Alzheimer's disease [13]. In the Kungsholmen Project, smoking affected survival in Alzheimer's disease cases more than in non-demented subjects, and the protective effect of smoking on the Alzheimer's disease was no longer present when incident Alzheimer's cases were studied [7] suggesting that previously reported association of cigarette smoking with low prevalence of dementia was probably due to survival bias.

#### *4.3.10. Diet and nutrients*

Diets high in fish, fruits and vegetables are high in anti-oxidants and polyunsaturated fatty acids (PUFAs). In some observational studies, high or supplementary intake of vitamins C, E, B6, B12, and folate has been related to a decreased risk of Alzheimer's disease [96, 97]. Indeed, low levels of B12 and folate were found to be related to an increased risk of Alz‐ heimer's disease in a study from the Kungsholmen Project [98]. Investigations on the effect of dietary PUFAs on the risk of cognitive dysfunction proved inconclusive. Several studies showed that the consumption of PUFAs led to reduction in the risk of Alzheimer's disease and dementia, mild cognitive impairment [99]. Population-based studies suggested that moderate to high intake of unsaturated fats at midlife is protective, whereas a moderate in‐ take of saturated fats may increase the risk of dementia and Alzheimer's disease [100, 101], especially among *APOE* ε4 carriers [102, 103]. Fatty acids may affect dementia through vari‐ ous mechanisms such as atherosclerosis and inflammation. Adherence to 'Mediterranean di‐ et' (higher intake of fish, fruits, and vegetables rich in antioxidants) was associated with a reduced risk of Alzheimer's disease independent of vascular pathways [104].

#### **4.4. Psychosocial factors**

Psychological factors include social economic status, education attainment in early life, and work complexity in adult-life and leisure activities. Evidence from epidemiological research has been accumulating that some psychosocial factors and healthy lifestyle may postpone the onset of dementia, possibly by enhancing cognitive reserve.

#### *4.4.1. Social economic status*

A number of studies have found that higher socioeconomic status (SES) is associated with a reduced risk of developing Alzheimer's disease [105-107]. In most of these studies, SES was assessed based on occupational attainment, current income to reflect socioeconomic level in adulthood, or educational attainment. Findings from a prospective study, however, suggest‐ ed that early life socioeconomic status assessed at the household or community level was re‐ lated to level of cognition in late life but not to rate of cognitive decline or risk of Alzheimer's disease [47].

*4.4.4. Mentally stimulating activity*

with a reduced rate of hippocampal atrophy [118].

*4.4.5. Social network and social engagement*

dementia [121].

*4.4.6. Depression*

Various types of mentally demanding activities have been examined in relation to dementia and AD, including knitting, gardening, dancing, playing board games and musical instru‐ ments, reading, social and cultural activities, and watching specific television programs, which often showed a protective effect [113]. Due to the cultural and individual differences in choosing specific activities, some researchers summarize mentally stimulating activities into a composite score, which showed that a cognitive activity score involving participation in seven common activities with information processing as a central component was associ‐ ated with a reduced risk of AD, even after controlling for APOE ε4 allele, medical condi‐ tions, and depressive symptoms [114, 115]. The Swedish Twin Study showed that greater complexity of work, and particularly complex work with people, may reduce the risk of Alz‐ heimer's disease [116]. The Canadian Study of Health and Aging found that high complexi‐ ty of work appeared to be associated with a reduced risk of dementia, but mostly for vascular dementia [117]. In supporting of these findings, the recent neuroimaging study suggested that a high level of complex mental activity across the lifespan was correlated

Epidemiology of Alzheimer's Disease http://dx.doi.org/10.5772/54398 341

A poor social network or social disengagement in late life was associated with an elevated risk of dementia. Evidence from longitudinal observational studies suggests that a poor so‐ cial network or social disengagement is associated with cognitive decline and dementia [119, 120]. The risk for dementia and AD was also increased in older people with increasing social isolation and less frequent and unsatisfactory contacts with relatives and friends. Further‐ more, low social engagement in late life and a decline in social engagement from middle age to late life were associated with a doubly increased risk of developing dementia and AD in late life. Rich social networks and high social engagement imply better social support, lead‐ ing to better access to resources and material goods [123]. Rich and large social networks al‐ so provide affective and intellectual stimulation that could influence cognitive function and different health outcomes through behavioural, psychological, and physiological pathways [122]. Finally, a recent study suggested that low neuroticism in combination with high extra‐ version was the personality trait associated with the lowest dementia risk, and among so‐ cially isolated individuals even low neuroticism alone seemed to decrease the risk of

Recent evidence suggests a strong relationship between depression and Alzheimer's disease. A lifetime history of major depression has been considered as a risk factor for later develop‐ ment of Alzheimer's disease [124, 125]. The presence of depressive symptoms can affect the conversion of mild cognitive impairment to Alzheimer's disease. Neuronal plaques and neu‐ rofibrillary tangles, the two major hallmarks of Alzheimer's disease brain, are more pro‐ nounced in the brains of Alzheimer's disease patients with comorbid depression as compared with Alzheimer's disease patients without depression. On the other hand, neuro‐

#### *4.4.2. High education*

Numerous longitudinal studies have consistently shown that a higher educational achieve‐ ment in early life is associated with a decreased incidence of dementia, and of Alzheimer's disease in particular. Low dementia prevalence among highly educated persons has been re‐ ported by numerous surveys. Educational attainment and lifespan mental activity associat‐ ed with childhood education may reduce the risk of dementia [25]. The cogntive reserve hypothesis has been proposed to interpret this association such that education could en‐ hance neural and cognitive reserve that may provide compensatory mechanisms to cope with degenerative pathological changes in the brain, and therefore delay onset of the de‐ mentia syndrome [17]. Alternatively, educational achievement may be a surrogate or an in‐ dicator of intelligent quotient, early life living environments, and occupational toxic exposure experienced over adulthood [108].

#### *4.4.3. Physical activity*

Basic science and observational evidence on humans strongly supports the hypothesis that increased physical activity prevents the onset of dementia. Regular exercise, even low-inten‐ sity activity such as walking, has been associated with reduced risk of dementia and cogni‐ tive decline [109-111]. In the Kungsholmen Project, the component of physical activity presenting in various leisure activities, rather than sports and any specific physical exercise, was related to a decreased dementia risk [110]. A strong protective effect of regular physical activity in middle age against the development of dementia and Alzheimer's disease in late life was reported, especially for persons with the *APOE* ε4 allele [112]. As it may take years to achieve high levels of physical fitness, brief periods of exercise training may not have sub‐ stantial benefits on cognitive processes, but could still be detectable in the subsets of cogni‐ tive domains that are more sensitive to the age related decrements. Physical activity is important not only in promoting general and vascular health, but also in promoting brain plasticity, and it may also affect several gene transcripts and neurotropic factors that are rel‐ evant for the maintenance of cognitive functions. There is now increasing amounts of trial evidence to support this hypothesis in terms of cognitive benefits in healthy older adults as well as in people at risk for dementia. However, to date there are no RCTs confirm that in‐ creased physical activity prevents dementia.

#### *4.4.4. Mentally stimulating activity*

*4.4.1. Social economic status*

340 Understanding Alzheimer's Disease

Alzheimer's disease [47].

exposure experienced over adulthood [108].

creased physical activity prevents dementia.

*4.4.2. High education*

*4.4.3. Physical activity*

A number of studies have found that higher socioeconomic status (SES) is associated with a reduced risk of developing Alzheimer's disease [105-107]. In most of these studies, SES was assessed based on occupational attainment, current income to reflect socioeconomic level in adulthood, or educational attainment. Findings from a prospective study, however, suggest‐ ed that early life socioeconomic status assessed at the household or community level was re‐ lated to level of cognition in late life but not to rate of cognitive decline or risk of

Numerous longitudinal studies have consistently shown that a higher educational achieve‐ ment in early life is associated with a decreased incidence of dementia, and of Alzheimer's disease in particular. Low dementia prevalence among highly educated persons has been re‐ ported by numerous surveys. Educational attainment and lifespan mental activity associat‐ ed with childhood education may reduce the risk of dementia [25]. The cogntive reserve hypothesis has been proposed to interpret this association such that education could en‐ hance neural and cognitive reserve that may provide compensatory mechanisms to cope with degenerative pathological changes in the brain, and therefore delay onset of the de‐ mentia syndrome [17]. Alternatively, educational achievement may be a surrogate or an in‐ dicator of intelligent quotient, early life living environments, and occupational toxic

Basic science and observational evidence on humans strongly supports the hypothesis that increased physical activity prevents the onset of dementia. Regular exercise, even low-inten‐ sity activity such as walking, has been associated with reduced risk of dementia and cogni‐ tive decline [109-111]. In the Kungsholmen Project, the component of physical activity presenting in various leisure activities, rather than sports and any specific physical exercise, was related to a decreased dementia risk [110]. A strong protective effect of regular physical activity in middle age against the development of dementia and Alzheimer's disease in late life was reported, especially for persons with the *APOE* ε4 allele [112]. As it may take years to achieve high levels of physical fitness, brief periods of exercise training may not have sub‐ stantial benefits on cognitive processes, but could still be detectable in the subsets of cogni‐ tive domains that are more sensitive to the age related decrements. Physical activity is important not only in promoting general and vascular health, but also in promoting brain plasticity, and it may also affect several gene transcripts and neurotropic factors that are rel‐ evant for the maintenance of cognitive functions. There is now increasing amounts of trial evidence to support this hypothesis in terms of cognitive benefits in healthy older adults as well as in people at risk for dementia. However, to date there are no RCTs confirm that in‐

Various types of mentally demanding activities have been examined in relation to dementia and AD, including knitting, gardening, dancing, playing board games and musical instru‐ ments, reading, social and cultural activities, and watching specific television programs, which often showed a protective effect [113]. Due to the cultural and individual differences in choosing specific activities, some researchers summarize mentally stimulating activities into a composite score, which showed that a cognitive activity score involving participation in seven common activities with information processing as a central component was associ‐ ated with a reduced risk of AD, even after controlling for APOE ε4 allele, medical condi‐ tions, and depressive symptoms [114, 115]. The Swedish Twin Study showed that greater complexity of work, and particularly complex work with people, may reduce the risk of Alz‐ heimer's disease [116]. The Canadian Study of Health and Aging found that high complexi‐ ty of work appeared to be associated with a reduced risk of dementia, but mostly for vascular dementia [117]. In supporting of these findings, the recent neuroimaging study suggested that a high level of complex mental activity across the lifespan was correlated with a reduced rate of hippocampal atrophy [118].

#### *4.4.5. Social network and social engagement*

A poor social network or social disengagement in late life was associated with an elevated risk of dementia. Evidence from longitudinal observational studies suggests that a poor so‐ cial network or social disengagement is associated with cognitive decline and dementia [119, 120]. The risk for dementia and AD was also increased in older people with increasing social isolation and less frequent and unsatisfactory contacts with relatives and friends. Further‐ more, low social engagement in late life and a decline in social engagement from middle age to late life were associated with a doubly increased risk of developing dementia and AD in late life. Rich social networks and high social engagement imply better social support, lead‐ ing to better access to resources and material goods [123]. Rich and large social networks al‐ so provide affective and intellectual stimulation that could influence cognitive function and different health outcomes through behavioural, psychological, and physiological pathways [122]. Finally, a recent study suggested that low neuroticism in combination with high extra‐ version was the personality trait associated with the lowest dementia risk, and among so‐ cially isolated individuals even low neuroticism alone seemed to decrease the risk of dementia [121].

#### *4.4.6. Depression*

Recent evidence suggests a strong relationship between depression and Alzheimer's disease. A lifetime history of major depression has been considered as a risk factor for later develop‐ ment of Alzheimer's disease [124, 125]. The presence of depressive symptoms can affect the conversion of mild cognitive impairment to Alzheimer's disease. Neuronal plaques and neu‐ rofibrillary tangles, the two major hallmarks of Alzheimer's disease brain, are more pro‐ nounced in the brains of Alzheimer's disease patients with comorbid depression as compared with Alzheimer's disease patients without depression. On the other hand, neuro‐ degenerative phenomena have been observed in different brain regions of patients with a history of depression. Recent evidence suggests that molecular mechanisms and cascades that underlie the pathogenesis of major depression, such as chronic inflammation and hy‐ per-activation of hypothalamic–pituitary–adrenal (HPA) axis, are also involved in the pathogenesis of Alzheimer's disease [125]. A recent study has shown that depression in‐ creased the risk of dementia among patients with diabetes [126].

ciated with 4.5 times the risk [133, 134]. Moderate head injury is defined as a head injury resulting in loss of consciousness or post-traumatic amnesia lasting more than 30 minutes; if either of these lasts more than 24 hours, the injury is considered severe. These increased risks have not been shown for individuals experiencing mild head injury or any number of common mishaps, such as bumping one's head while exiting a car. Groups that experienced repeated head injuries, such as boxers, football players and combat veterans, may be at in‐ creased risk of dementia, late-life cognitive impairment and evidence of tau tangles (a hall‐ mark of Alzheimer's) at autopsy [135-138]. Additional research is needed to better understand the association between brain injury and increased risk of Alzheimer's disease.

Epidemiology of Alzheimer's Disease http://dx.doi.org/10.5772/54398 343

Meta-analyses and systematic reviews have provided robust evidence that cognitive reserve (a concept combining the benefits of education, occupation, and mental activities) [139], physical activity and exercise [140, 141], midlife obesity [142], alcohol intake [93], and smok‐ ing [142] are the most important modifiable risk factors for Alzheimer's disease. There is in‐ sufficient overall evidence from epidemiological studies to support any association between dietary or supplementary antioxidant or B vitamins and altered risk of incident dementia [143, 144]. Data from several independent time points from a large Swedish epidemiological study suggest that better social networks and social activities might be associated with re‐ duced incidence of Alzheimer's disease [119], but this has not been examined systematically

Many treatable medical conditions have also been associated with an increased risk of Alz‐ heimer's disease, including stroke [145], diabetes [146], midlife hypertension [52], and mid‐ life hypercholesterolemia [147, 148]. Blood pressure and cholesterol both seem to be reduced in late life and in the prodromal to Alzheimer's disease; thus, the difference between midlife and late life is an important distinction. There is probably an important relation between some of these conditions and the lifestyle factors mentioned previously, and interventions to promote healthy living will probably reduce the incidence of diabetes and stroke as well as having other, more direct, effects on dementia. There is limited evidence about the potential effect of management of diabetes or stroke on the risk of subsequent dementia, more inter‐

Less than two decades have passed since the first incidence data for Alzheimer's disease and other dementias were reported, during which there have been many achievements in the understanding of risk and protective factors of Alzheimer's disease. Accumulated evidence from epidemiological research strongly supports a role for lifestyle and cardiovascular risk factors in the pathogenesis and development of dementia. However, none of these factors has been proven to have a causal relation specifically with Alzheimer's disease. Indeed, this topic is further complicated by the fact that the traditional diagnosis of dementia subtypes has been challenged by population-based neuropathological and neuroimaging studies. Re‐ search has shown a range of dementia-associated brain abnormalities from pure vascular le‐

**5. Summary of evidence from systematic review**

in other large epidemiological cohorts [61].

vention trials on this topic are needed (Table 1) [61,149].

#### **4.5. Other factors**

#### *4.5.1. Inflammation*

Inflammation is known to be involved in the atherosclerotic process. Thus, serum inflamma‐ tory makers may be associated with dementia. Some cohort studies found such an associa‐ tion, and C-reactive protein may be the most promising in predicting dementia risk [127]. In addition, long-term use of non-steroidal anti-inflammatory drugs was suggested to be asso‐ ciated with a lower risk of AD [25].

#### *4.5.2. Hormone replacement therapy*

Hormone replacement therapy in postmenopausal women has been frequently reported to be associated with a lower risk of AD. An association between hormone replacement thera‐ py and a reduced risk of dementia and Alzheimer's disease among postmenopausal women had been frequently reported in numerous observational studies until 2004 when, instead of a protective effect, a significantly increased risk of dementia associated with estrogenic ther‐ apy was found in the Women's Health Study [128].

#### *4.5.3. Occupational exposures*

Manual work involving goods production has been associated with an increased risk of AD and dementia. Occupation and occupational exposures (e.g., electromagnetic fields and heavy metals) may play a role in dementia and Alzheimer's disease [129, 130]. Data from the Kungsholmen Project showed that manual work involving goods production was associated with an increased risk of dementia and Alzheimer's disease [130], and specifically a risk ef‐ fect was detected with electromagnetic exposure [129]. Occupational exposure to extremelylow-frequency electromagnetic fields (ELF-EMF) has been related to an increased risk of dementia and AD in a number of follow-up studies [129, 131]. The meta-analysis of epide‐ miological evidence suggests an association between occupational exposure to ELF-EMF and AD [132].

#### *4.5.4. Head trauma and traumatic brain injury*

For many years, head trauma has been suggested as a possible risk factor for Alzheimer's disease, and it has been extensively investigated in several studies, but this possible associa‐ tion still remains controversial. Moderate head injuries are associated with twice the risk of developing Alzheimer's compared with no head injuries, and severe head injuries are asso‐ ciated with 4.5 times the risk [133, 134]. Moderate head injury is defined as a head injury resulting in loss of consciousness or post-traumatic amnesia lasting more than 30 minutes; if either of these lasts more than 24 hours, the injury is considered severe. These increased risks have not been shown for individuals experiencing mild head injury or any number of common mishaps, such as bumping one's head while exiting a car. Groups that experienced repeated head injuries, such as boxers, football players and combat veterans, may be at in‐ creased risk of dementia, late-life cognitive impairment and evidence of tau tangles (a hall‐ mark of Alzheimer's) at autopsy [135-138]. Additional research is needed to better understand the association between brain injury and increased risk of Alzheimer's disease.
