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

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‐

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‐

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‐

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

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‐

creased the risk of dementia among patients with diabetes [126].

**4.5. Other factors**

342 Understanding Alzheimer's Disease

*4.5.1. Inflammation*

ciated with a lower risk of AD [25].

*4.5.2. Hormone replacement therapy*

*4.5.3. Occupational exposures*

and AD [132].

apy was found in the Women's Health Study [128].

*4.5.4. Head trauma and traumatic brain injury*

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 in other large epidemiological cohorts [61].

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

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‐ sions at one end to pure Alzheimer's pathologies at the other, with most dementia cases

**Factors Systematic review Results**

**Intervention studies**

RR=relative risk. OR=odds ratio. SHEP=Systolic Hypertension in the Elderly Program. SYST-EUR=Systolic Hypertension in Europe. SCOPE=Study on Cognition and Prognosis in the Elderly. PROSPER=PROspective Study of Pravastatin in the

Population studies have identified many factors that could be important in reducing the risk of dementia, including factors that identify people at risk for dementia (vascular risk factors, depressive symptoms) and factors that may reduce the risk of dementia (cognitive, physical, and social activity, a diet rich in antioxidants and polyunsaturated fatty acids, vascular risk factor control). While early interventional studies have been less conclusive, future trials should continue to examine the effect of risk factor modification on cognitive outcomes. In particular, interventions that combine a number of factors, such as healthy nutrition along with cognitive, social, and physical activity, should be investigated. In the most optimistic view, dementia could be delayed or even prevented by these interventions. At worst, people will improve their overall health, especially their cardiovascular health, and enjoy a more

Despite the specific challenges posed by neurological disorders, such as Alzheimer's disease and other dementias, interventions need to be implemented to verify findings from the

**Table 1.** Meta-analyses or systematic reviews of risk factors for dementia and Alzheimer's disease [61,149]

Four of five longitudinal studies in midlife suggested a significant positive association between high total cho‐ lesterol and incident dementia. For overall difference the RR was 1·4–3·1

Epidemiology of Alzheimer's Disease http://dx.doi.org/10.5772/54398 345

OR 0.89 (95% CI 0.69–1.16) for incident dementia

Neither of the two trials reported significant benefit of statin therapy

Three trials showed no benefit. One trial (the only that selected participants based on increased homocys‐ teine) reported benefit with respect to global function

18 studies, but only five assessed high choles‐ terol specifically in midlife. All five midlife stud‐ ies had over 15 years follow-up and a total of over 15 000 participants

(SHEP, SYST-EUR, and SCOPE) with mean fol‐ low-up of 3·3 years. Only SYST-EUR reported significant benefit

26 340 participants between the two trials (PROSPER and HPS), with follow-up of 3·2 and 5 years. Cognition was measured with different instruments at different timepoints

Four trials in older people without existing cog‐ nitive impairment

Hypertension 12 091 participants between the three trials

Midlife hypercholes‐ terolemia

Statins for prevention of dementia

Vitamins B12 or fo‐ late

Elderly at Risk. HPS=Heart Protection Study.

cognitively and socially engaging life.

**5.1. Intervention strategies against Alzheimer's disease**

being attributable to both vascular disease and neurodegeneration.



RR=relative risk. OR=odds ratio. SHEP=Systolic Hypertension in the Elderly Program. SYST-EUR=Systolic Hypertension in Europe. SCOPE=Study on Cognition and Prognosis in the Elderly. PROSPER=PROspective Study of Pravastatin in the Elderly at Risk. HPS=Heart Protection Study.

**Table 1.** Meta-analyses or systematic reviews of risk factors for dementia and Alzheimer's disease [61,149]

Population studies have identified many factors that could be important in reducing the risk of dementia, including factors that identify people at risk for dementia (vascular risk factors, depressive symptoms) and factors that may reduce the risk of dementia (cognitive, physical, and social activity, a diet rich in antioxidants and polyunsaturated fatty acids, vascular risk factor control). While early interventional studies have been less conclusive, future trials should continue to examine the effect of risk factor modification on cognitive outcomes. In particular, interventions that combine a number of factors, such as healthy nutrition along with cognitive, social, and physical activity, should be investigated. In the most optimistic view, dementia could be delayed or even prevented by these interventions. At worst, people will improve their overall health, especially their cardiovascular health, and enjoy a more cognitively and socially engaging life.

#### **5.1. Intervention strategies against Alzheimer's disease**

sions at one end to pure Alzheimer's pathologies at the other, with most dementia cases

Overweight: Dementia RR 1.26 (95% CI 1.10–1.44); Alz‐ heimer's disease 1.35 (95% CI 1·19–1.54) Obesity: Dementia RR 1.64 (95% CI 1.34-2.00); Alz‐ heimer's disease RR 2.04 (95% CI 1.59-2.62)

Dementia RR 2.2 (95% CI 1.3–3.6)

Dementia RR 0.72 (95% CI 0.60–0.86); Alzheimer's dis‐ ease 0.55 (95% CI 0.36–0.84)

Dementia OR 0.54 (95% CI 0.49–0.59)

Dementia RR 0.74 (95% CI 0.61–0.91); Alzheimer's dis‐ ease 0.72 (0.61–0.86)

Four of five longitudinal studies focusing on midlife hy‐ pertension suggested that it is a significant risk factor for incident dementia (RR 1.24–2.8 in different studies) The biggest differences were reported in studies using 160/95 mm Hg as the threshold for hypertension

12 of 16 studies showed significant association be‐ tween stroke and incident dementia, with overall dou‐ bling of incidence

ease RR 1.39 (95% CI 1.16–1.66)

being attributable to both vascular disease and neurodegeneration.

Meta-analysis of ten studies. Sixteen articles on 15 prospective studies with 3.2-36 years followup

2–25 years follow-up in over 17 000 people. In the four studies the dementia ORs were 3·17 (95% CI 1.37–7.35), 1.42 (1.07–1.89), 1.60 (1.00–2.57), and 1.63 (1.00–2.67)

disease, dementia, or both, with at least 150 000 participants

22 prospective studies with at least 29 000 par‐ ticipants followed up for a median of 7.1 years

up and at least 14 000 participants

with at least 16 000 participants

mainly included patients aged 65 years and over

**Medical conditions**

Diabetes 15 prospective cohort studies Dementia RR 1.47 (95% CI 1.25–1.73); Alzheimer's dis‐

Smoking Meta-analysis of four prospective studies with

Physical activity 13 prospective studies focusing on Alzheimer's

Alcohol 15 longitudinal studies with 2–8 years follow-

Midlife hypertension At least 15 years follow-up in most studies,

Stroke 16 studies with at least 25 000 participants,

Overweight and obe‐ sity

344 Understanding Alzheimer's Disease

Cognitive reserve (in‐ telligence, occupa‐ tion, and education)

**Factors Systematic review Results**

Despite the specific challenges posed by neurological disorders, such as Alzheimer's disease and other dementias, interventions need to be implemented to verify findings from the many population-based observational studies, which suggest that preventive and therapeu‐ tic interventions have great potential [150].

still unclear, we are now able to make more accurate diagnoses than before, and the pattern of dementia distribution has been sufficiently described to guide the planning of medical and social services. Epidemiological studies have shown that vascular risk factors in middle age and later in life significantly contribute to the development and progression of the de‐ mentia syndrome, whereas extensive social network and active engagement in social, physi‐ cal, and mental activities may delay the onset of the dementing disorders. Hence, one of the promising strategies to deal with the tremendous challenge from the epidemic of dementia is to implement appropriate intervention measures from a life-course perspective. Achieving high education in early life and engaging mentally stimulating activity over adulthood to enhance cognitive reserve, and maintaining vascular health by adopting healthy lifestyles and optimally controlling vascular diseases to reduce the burden of vascular lesions in the brain. These preventive measures will enable people to maintain cognitive ability in late life, even though they may have developed a high load of Alzheimer pathologies in their brain.

Epidemiology of Alzheimer's Disease http://dx.doi.org/10.5772/54398 347

Research grants were received from the Swedish council for working life and social re‐ search, the Swedish Research Council in Medicine and the Swedish Brain Power. This study was also supported in part by funds from the Loo and Hans Ostermans Foundation and the Foundation for Geriatric Diseases at Karolinska Institutet, the Gamla Tjänarinnor Founda‐

1 Department of Epidemiology, Tianjin Medical University, Tianjin, P.R., China

2 Aging Research Center, Karolinska Institutet-Stockholm University, Stockholm, Sweden

[1] From the Centers for Disease Control and Prevention. Public health and aging: trends in aging--United States and worldwide. JAMA 2003;289(11):1371-1373.

[2] Kinsella K, Velkoff VA. The demographics of aging. Aging Clin Exp Res 2002;14(3):

3 Department of Neurological and Psychiatric Sciences, University of Florence, Italy

**Acknowledgements**

**Author details**

**References**

159-169.

tion, Demensfonden and the Bertil Stohnes Foundation.

Weili Xu1,2\*, Camilla Ferrari2,3 and Hui-Xin Wang2

\*Address all correspondence to: weili.xu@ki.se

#### *5.1.1. Vascular factors and related disorders*

Most vascular risk factors and related disorders are modifiable or treatable that can serve as targets in the development of primary preventative strategies against dementia. For exam‐ ple, antihypertensive therapy has been shown to reduce the risk of dementia in observatio‐ nal studies, and this finding was partly confirmed by clinical trials. Furthermore, studies have confirmed that obesity and diabetes can be prevented by changing dietary habits and lifestyles, and that health education may help quit smoking. Finally, preventing recurrent cerebrovascular disease and maintaining sufficient cerebral blood perfusion seems to be crit‐ ical for postponing expression of the dementia syndrome in older people. Thus, controlling high blood pressure and obesity, especially from middle age, and preventing diabetes and recurrent stroke could be the primary preventive measures against late-life dementia.

#### *5.1.2. Intervention towards psychosocial factors and lifestyles*

High educational achievements in early life can provide cognitive reserve that benefits the whole life in terms of cognitive health and delaying the onset of late-life dementia. Extensive social networks and active engagements in intellectually stimulating activities such as read‐ ing, doing crosswords, and playing board games may significantly lower the risk of demen‐ tia by providing cognitive reserve or by reducing psychosocial stress. It is likely that mentally and socially integrated lifestyles could postpone the onset of dementia [119]. Regu‐ lar physical exercise may reduce the risk of the dementias resulting from cerebral atheroscle‐ rosis. Leisure activities with all three components of physical, mental, and social activities may have the most beneficial effect on dementia prevention. Many of the risk factors for de‐ mentia, such as hypertension, diabetes, and obesity, may be modified by diet. In addition, a diet high in antioxidants may reduce inflammation, which is associated with the risk of de‐ mentia. Thus, it is reasonable to suggest that the risk of dementia itself could be modified by diet. The treatment of depression also seems to improve cognitive function in people who are depressed. Taking together, the most promising strategy for the primary prevention of dementia may be to encourage people implementing multiple preventative measures throughout the life course, including high educational attainment in childhood and early adulthood, an active control of vascular factors (e.g., smoking) and disorders (e.g., hyperten‐ sion and diabetes) in adulthood, and maintenance of mentally, physically, and socially ac‐ tive lifestyles during middle age and later in life.

#### **6. Conclusions**

Alzheimer's disease is a major cause of functional dependence, institutionalisation, and mortality among elderly people. Population-based studies have made a great contribution to our knowledge of Alzheimer's disease. Although many aspects of Alzheimer's disease are still unclear, we are now able to make more accurate diagnoses than before, and the pattern of dementia distribution has been sufficiently described to guide the planning of medical and social services. Epidemiological studies have shown that vascular risk factors in middle age and later in life significantly contribute to the development and progression of the de‐ mentia syndrome, whereas extensive social network and active engagement in social, physi‐ cal, and mental activities may delay the onset of the dementing disorders. Hence, one of the promising strategies to deal with the tremendous challenge from the epidemic of dementia is to implement appropriate intervention measures from a life-course perspective. Achieving high education in early life and engaging mentally stimulating activity over adulthood to enhance cognitive reserve, and maintaining vascular health by adopting healthy lifestyles and optimally controlling vascular diseases to reduce the burden of vascular lesions in the brain. These preventive measures will enable people to maintain cognitive ability in late life, even though they may have developed a high load of Alzheimer pathologies in their brain.
