**2. Observational studies**

Vascular dementia (VaD), mainly due to cerebrovascular diseases (CVD), is the second most frequent type of dementia [5, 6]. This current classification of dementia types is being recon‐ sidered in light of recent neuropathological and neuroimaging studies, which have shown a range of dementia-associated brain abnormalities from pure vascular lesions at one end to pure AD pathologies at the other, with most dementia cases being attributable to both CVD and AD. In fact, AD and CVD-related changes often coexist in the brain of older adults with dementia and mild cognitive impairment (MCI) [7, 8]. Also, both types of lesions are detected in the brain of cognitively normal elderly people, highlighting the importance of mixed pathologies in increasing the risk of late-life dementia [9]. The co-occurrence of AD and CVD is consistent with the evidence that AD and VaD share several risk and protective factors, including cardiovascular and lifestyle related factors. Overall, this implies that dementia syndrome is a valid target for prevention, especially from the public health perspective.

Prevention is traditionally divided into three levels: primary, secondary, and tertiary preven‐ tion. Primary prevention aims to reduce the incidence of the disease by eliminating or treating specific risk factors, which may decrease or delay the development of dementia. Secondary prevention aims to early detection of the disease, before any symptom has emerged, when treatment could stop its progression. Tertiary prevention aims to reduce the impact of

Regarding primary prevention, both observational and interventional epidemiological studies have been conducted for dementia and AD. On the other hand, in the field of AD the devel‐ opment of pharmacological interventions has been mainly limited to a tertiary prevention level, since the diagnostic criteria currently in use for AD (National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association, NINCDS-ADRDA - criteria) identify the presence of the disease only when AD is severe enough to cause a dementia syndrome [10]. Thus, the majority of anti-AD drugs have been tested in subjects already in the symptomatic stage of the disease, and so far no drug has shown the ability to stop the disease progression (i.e. disease-modifying effect) [11]. However, several studies have shown that the pathophysiological process of AD begins years, if not decades, before the diagnosis of Alzheimer's dementia and individuals generally experience a gradual impairment of cognitive functions, which can progress to a dementia syndrome

Recent advances in neuroimaging, cerebrospinal fluid (CSF) assays, and other techniques now provide the ability to detect evidence of the AD pathophysiological process in vivo, but the diagnostic criteria currently in use do not take into account these biomarkers. Three interna‐ tional workgroups promoted by the American National Institute of Aging (NIA) and the American Alzheimer's Association recently proposed new diagnostic guidelines to identify dementia due to AD, MCI due to AD, and preclinical AD [15-17]. These new criteria formalize the different clinical stages of AD and incorporate biomarkers (genetic, biochemical, neuroi‐ maging) that can be detected in vivo and are believed to reflect AD pathology. These diagnostic criteria are now being validated and can be revised as long as new findings from research on biomarkers in AD will clarify the link between AD pathophysiology and the AD clinical syndrome. These criteria offer the opportunity to identify subjects who can be target of

complications and disability of long-term diseases.

452 Understanding Alzheimer's Disease

[12-14].

Several community-based prospective studies of aging and health have been carried out in different countries since the 80s'. These studies have provided relevant information on the aetiology of dementia and AD, and have led to the identification of possible preventive strategies. Evidence from these observational studies has shown that dementia is a multifac‐ torial disorder caused by several interrelated mechanisms in which the interaction of genetic and environmental factors plays the major role (Table 1). The pathways that lead from different risk factors to dementia are not fully understood, but several etiological hypotheses have been proposed: the vascular hypothesis, inflammatory hypothesis, oxidative-stress hypothesis, toxic hypothesis and psychosocial hypothesis [18, 19]. These theories highlight potential links of various risk factors to both the vascular and the neurodegenerative brain pathologies that can cause dementia, supporting the validity of dementia syndrome as target for prevention [6, 20].

#### **2.1. Non-modifiable risk factors for Alzheimer's disease**

Both modifiable and non-modifiable risk factors have been identified for dementia and AD, and while for some factors the scientific evidence is quite robust, for others the results are still inconclusive.

#### *2.1.1. Age*

Increasing age is a well-established risk factor for dementia, which is a common disorders after 75 years of age, but rare before age 60. The incidence rates of dementia increase exponentially with advancing age. In Europe, approximately two per 1,000 person-years become demented among people aged 65-69 years, and the incidence increases to 70 to 80 per 1,000 person-years for people 90 years or over [21, 22]. It is still unclear if the incidence of dementia continues to increase even in the oldest old or reaches a plateau at a certain age. The Cache County Study found that the incidence of dementia increased with age, peaked, and then started to decline at extreme old ages for both men and women. However, some meta-analyses and large-scale studies in Europe provided no evidence for the potential decline in the incidence of dementia among the oldest old [21, 22]. Table 1


*APOE*: apolipoprotein E. BMI: body mass index. *CLU*: clusterin. *CR1*: complement component receptor 1. *DYRK1A*: dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A. GSK3β: glycogen synthase kinase-3beta. HRT: hormone replacement therapy. NSAIDs: nonsteroidal anti-inflammatory drugs. *PICALM*: phosphatidylinositol binding clathrin assembly protein. PUFA: polyunsaturated fatty acid. SES: socioeconomic status. *TOMM40*: translocase of outer mitochondrial membrane 40 homolog.

6

*2.1.2. Familial aggregation*

to the *APOE* ε4 allele [25-28].

factors and neurotransmitters [32].

according to specific genetic risk profiles.

*2.1.3. Genes*

Familial aggregation is another important risk factor for late life dementia and AD. First-degree relatives of AD patients have a higher lifetime risk for developing AD than relatives of nondemented people or the general population (Table 1) [21, 22]. It is likely that shared genetic and environmental factors contribute to the familial aggregation. The amount of risk of AD

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The Apolipoprotein E *(APOE)* ε4 allele is the only established genetic risk factor for both earlyand late-onset AD; it is a susceptibility gene, being neither necessary nor sufficient for the development of AD. The risk of AD increases with increasing number of the ε4 alleles in a dose-dependent manner, but the risk effect decreases with increasing age. Individuals with two *APOE* ε4 alleles have a more than seven times increased risk of developing AD compared with those with *APOE* ε3 alleles and approximately 15 to 20 percent of AD cases are attributable

Other genes have been related to increased risk of late life AD, but the association is less consistent. These are mainly genes involved in the metabolism and processing of the amyloid precursor protein (APP) and Aβ, as well as tau protein, including the *GSK3β*, *DYRK1A*, *Tau*, and *CLU* genes [25]. Until now, mutations in APP have not been implicat‐ ed in the late-onset form of AD, with the exception of the rare variant, N660Y, which was recently identified in one case from a late-onset AD family [29]. A recent study identi‐ fied a mutation in the *APP* gene that can be protective against AD and age-related cognitive decline. This mutation is associated with a reduced production of amyloidogenic pepti‐ des [30]. Other genes that have been associated with increased risk of AD are *TOMM40*, *CR1* and *PICALM*. The *TOMM40* gene is located in a region of chromosome 19, which is in linkage disequilibrium with *APOE*, and its polymorphism affects the age on onset of AD in subjects with an *APOE* genotype [31]. *CR1* is involved in the complement cascade, while *PICALM* encodes a protein that is involved in clathrin-mediated endocytosis, an essential step in the intracellular trafficking of proteins and lipids such as nutrients, growth

Several aspects challenge the identification of genetic risk factors for late life AD, including the fact that risk conferred by a single gene is generally small, and for some genes is the combination of risk alleles that is relevant for a significant change of the overall risk. Also, the heterogeneous and mixed nature of brain pathology causing dementia, particularly coexisting CVD, makes it more difficult to identify genetic risk factors for AD. Nevertheless, the identi‐ fication of genetic risk factors for late onset AD can have implication for preventive and therapeutic strategies. In fact, it has been shown that the *APOE ε4* allele can modulate the effect of lifestyle related risk factors [33] and influence the effect of pharmacological treatment for AD [34]. It is thus possible that future preventive and therapeutic measures will be tailored

that is attributable to genetics is estimated to be around 70% [25].

**Table 1.** Proposed risk and protective factors for dementia and Alzheimer's disease

#### *2.1.2. Familial aggregation*

Familial aggregation is another important risk factor for late life dementia and AD. First-degree relatives of AD patients have a higher lifetime risk for developing AD than relatives of nondemented people or the general population (Table 1) [21, 22]. It is likely that shared genetic and environmental factors contribute to the familial aggregation. The amount of risk of AD that is attributable to genetics is estimated to be around 70% [25].

#### *2.1.3. Genes*

6

at extreme old ages for both men and women. However, some meta-analyses and large-scale studies in Europe provided no evidence for the potential decline in the incidence of dementia

**Increased risk** 

*midlife* 

*Genetic and environmental factors in* 

*Vascular factors/diseases in late-life*  Higher risk in individuals with brain hypoperfusion profile: chronic heart failure, low pulse pressure, low diastolic

Higher risk in individuals with atherosclerosis profile: high systolic pressure, diabetes mellitus or prediabetes, stroke

*Genetic and environmental factors in* 

*Environmental factors in midlife* High work complexity modulates the increased dementia risk due to low

High education reduces the negative

*Genetic and environmental factors in late-*

Active leisure activities or absence of vascular risk factors reduces the risk due

Physical activity counteracts the risk due

*Vascular factors in midlife* Hypertension, obesity, hypercholesterolemia and physical inactivity have an additive effect when

they co-occur

pressure

**Decreased risk** 

to *APOE*ε4

education

to *APOE*ε4

*life* 

effect of *APOE*ε4

*midlife* 

*APOE*ε4 magnifies the effect of high alcohol intake, smoking, physical inactivity and high intake of saturate fat

**Risk factors Protective factors Combined effects** 

**Psychosocial factors**  High education and SES High work complexity Rich social network and social

engagement

Physical activity

Mediterranean diet

Antihypertensive drugs

*APOE*: apolipoprotein E. BMI: body mass index. *CLU*: clusterin. *CR1*: complement component receptor 1. *DYRK1A*: dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A. GSK3β: glycogen synthase kinase-3beta. HRT: hormone replacement therapy. NSAIDs: nonsteroidal anti-inflammatory drugs. *PICALM*: phosphatidylinositol binding clathrin assembly protein. PUFA: polyunsaturated fatty acid. SES: socioeconomic status. *TOMM40*:

related fats Vitamin B6, B12, folate Antioxidant vitamins (A, C, E)

Vitamin D

**Drugs**  Statins

> HRT NSAIDs

**Lifestyle**

**Diet** 

Mentally stimulating activity

Polyunsaturated (PUFA) and fish-

**Genetic**  *APP* 

among the oldest old [21, 22].

454 Understanding Alzheimer's Disease

Familial aggregation *APOE* ε4 *APP GSK3β DYRK1A Tau CLU TOMM40 PICALM CR1* 

Table 1

**Age Genetic** 

**Vascular** 

**Lifestyle**  Smoking High alcohol intake

**Diet** 

**Others**  Depression Occupational exposure Traumatic brain injury Infective agents (Herpes Simplex Virus Type I, Clamydophila pneumoniae, Spirochetes)

Saturated fats Homocysteine

Cerebrovascular lesions Cardiovascular diseases Diabetes mellitus and pre-diabetes *Midlife positive association but late-life* 

High serum cholesterol

High BMI (overweight and obesity)

translocase of outer mitochondrial membrane 40 homolog.

**Table 1.** Proposed risk and protective factors for dementia and Alzheimer's disease

*negative association*  Hypertension

The Apolipoprotein E *(APOE)* ε4 allele is the only established genetic risk factor for both earlyand late-onset AD; it is a susceptibility gene, being neither necessary nor sufficient for the development of AD. The risk of AD increases with increasing number of the ε4 alleles in a dose-dependent manner, but the risk effect decreases with increasing age. Individuals with two *APOE* ε4 alleles have a more than seven times increased risk of developing AD compared with those with *APOE* ε3 alleles and approximately 15 to 20 percent of AD cases are attributable to the *APOE* ε4 allele [25-28].

Other genes have been related to increased risk of late life AD, but the association is less consistent. These are mainly genes involved in the metabolism and processing of the amyloid precursor protein (APP) and Aβ, as well as tau protein, including the *GSK3β*, *DYRK1A*, *Tau*, and *CLU* genes [25]. Until now, mutations in APP have not been implicat‐ ed in the late-onset form of AD, with the exception of the rare variant, N660Y, which was recently identified in one case from a late-onset AD family [29]. A recent study identi‐ fied a mutation in the *APP* gene that can be protective against AD and age-related cognitive decline. This mutation is associated with a reduced production of amyloidogenic pepti‐ des [30]. Other genes that have been associated with increased risk of AD are *TOMM40*, *CR1* and *PICALM*. The *TOMM40* gene is located in a region of chromosome 19, which is in linkage disequilibrium with *APOE*, and its polymorphism affects the age on onset of AD in subjects with an *APOE* genotype [31]. *CR1* is involved in the complement cascade, while *PICALM* encodes a protein that is involved in clathrin-mediated endocytosis, an essential step in the intracellular trafficking of proteins and lipids such as nutrients, growth factors and neurotransmitters [32].

Several aspects challenge the identification of genetic risk factors for late life AD, including the fact that risk conferred by a single gene is generally small, and for some genes is the combination of risk alleles that is relevant for a significant change of the overall risk. Also, the heterogeneous and mixed nature of brain pathology causing dementia, particularly coexisting CVD, makes it more difficult to identify genetic risk factors for AD. Nevertheless, the identi‐ fication of genetic risk factors for late onset AD can have implication for preventive and therapeutic strategies. In fact, it has been shown that the *APOE ε4* allele can modulate the effect of lifestyle related risk factors [33] and influence the effect of pharmacological treatment for AD [34]. It is thus possible that future preventive and therapeutic measures will be tailored according to specific genetic risk profiles.

#### **2.2. Modifiable risk and protective factors for Alzheimer's disease**

Different modifiable factors have been proposed to play a role in late life dementia and AD, including nutritional factors (i.e., diet and nutritional supplements), social or economic factors, medical conditions and lifestyle related factors (e.g., smoking habit, physical activity, etc.) (Table 1). A report commissioned by the National institute of Health (NIH) to the Agency for Healthcare Research and Quality (AHRQ) was published in 2010, and concluded that current research evidence on many risk and protective factors for cognitive decline and AD is not of sufficient strength, thus recommendations for preventing these conditions cannot be made [35, 36]. Another previous review yielded similar conclusions [37]. These negative perspectives have been criticized, since there is consistent and robust epidemiological evidence that use of antihypertensive medications, cessation of smoking and increasing physical activity produces cognitive benefits in older adults [38]. Furthermore, the analytical strategy used in the Evidence Based Review carried out by the AHRQ did not take into account the life-course perspective [39]. Observational longitudinal studies have shown that the risk of late-life dementia and AD is determined by exposures to multiple factors experienced over the life-span and that the effect of specific risk/protective factors largely depends on age [39]. Thus, a life-course perspective is relevant for chronic disorders with a long latent period (such as dementia). It allows the identification of time windows when exposures have their greatest effect on outcome and assessment of whether cumulative exposures could have multiplicative or additive effects over the life course [40]. Age-dependent associations with AD have been suggested for several aging-related medical conditions. For example, elevated blood pressure, body mass index (BMI) and total cholesterol levels at a young age and in middle age (<65 years) have been associated with an increased risk of dementia and AD, whereas having lower values in late life (age >75 years) has been also associated with subsequent development of dementia/ AD [41-46].

Regarding serum total cholesterol, the importance of the pattern of change in cholesterol levels after midlife has been shown by two studies with a long follow-up, reporting that a decline in plasma total cholesterol after midlife may be associated with the risk of cognitive decline, dementia and AD in late life [56, 57]. These findings suggest that high total serum cholesterol in midlife seems to be a risk factor for dementia and AD in advanced age, while decreasing serum cholesterol after midlife may reflect ongoing disease processes and represent a marker of early stages in the development of dementia and AD. The use of statins (cholesterol-lowering drugs) in relation to dementia has been investigated in several community studies, with mixed findings. Some observational studies suggest a protective effect, while others did not, and clinical trials using statins for prevention of cognitive decline or dementia mainly reported no effects [6, 58]. Diabetes mellitus has been associated with increased risk of dementia and AD over adult life, but the risk is stronger when diabetes occurs in mid-life than in late-life [59]. Also pre-diabetes, impaired glucose regulation, and impaired insulin secretion have been associated with

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Cerebrovascular lesions and cardiovascular diseases have been shown to be risk factors for dementia and AD. Several population-based studies reveal an approximately two- to four-fold increased risk of incident dementia associated with clinical stroke (post-stroke dementia) [61, 62]. It is probable that an association of clinical stroke with AD is rarely reported due to the fact that a history of stroke is part of the current criteria for excluding the diagnosis of AD. However, asymptomatic cerebrovascular lesions such as silent brain infarcts and white matter lesions have been associated with an increased risk of dementia and AD [63, 64], although the association with AD is likely to be due to the inclusion of mixed dementia cases. The Cardiovascular Health Study found that cardiovascular disease was associated with an increased incidence of dementia, with the highest risk seen among people with peripheral arterial disease, suggesting that extensive peripheral atherosclerosis is a risk factor for dementia [65]. Atrial fibrillation, heart failure, and severe atherosclerosis measured with ankle-to-brachial index are also associated with the

**2. Environmental and other factors**: Current smoking is another major risk factor for dementia and AD, and based on the worldwide prevalence of smoking, about 14% of all AD cases are potentially attributable to this risk factor [70]. Although it is not entirely clear whether depression is a risk factor for or a preclinical symptom of dementia, studies with long-term follow-up support the risk-factor hypothesis [71]. Other conditions have been proposed as risk factors for dementia and AD, but the evidence is still sparse. These include occupational exposure, traumatic brain injury and infections. Occupational exposure to heavy metals such as aluminum and mercury has been suggested to be a risk factor for AD; even high consumption of aluminum from drinking water has been associated with an elevated risk of AD and dementia [6, 72]. In addition, occupational exposure to extremely-low-frequency electromagnetic fields (ELF-EMFs) has been related

and increased risk of dementia and AD [60].

increased risk of dementia and AD [66-69].

to an increased risk of dementia and AD [73, 74].

#### *2.2.1. Risk factors*

**1. Vascular risk factors and disorders**: An association of elevated blood pressure in midlife with an increased risk of dementia and AD later in life has been reported in several population-based studies [41, 47], while follow-up studies of late-life blood pressure and risk of dementia yield mixed results, largely depending on the length of follow-up. The short-term follow-up studies (e.g., less than 3 years) often found no association or even an inverse association between blood pressure and risk of dementia and AD [41]. However, studies of very old people (i.e., 75 + years) with a longer follow-up period (i.e., more than 6 years) also revealed an increased risk of dementia associated with low blood pressure [48], suggesting that among very old people low blood pressure may also contribute to the development of dementia, possibly by influencing cerebral blood perfusion.

For BMI, the bidirectional association with dementia and AD has been shown in several studies, and longitudinal studies of elderly people have associated accelerated decline in BMI with subsequent development of dementia. This implies that low BMI and weight loss in advanced age can be interpreted as markers for preclinical dementia [45, 46, 49-55]. Regarding serum total cholesterol, the importance of the pattern of change in cholesterol levels after midlife has been shown by two studies with a long follow-up, reporting that a decline in plasma total cholesterol after midlife may be associated with the risk of cognitive decline, dementia and AD in late life [56, 57]. These findings suggest that high total serum cholesterol in midlife seems to be a risk factor for dementia and AD in advanced age, while decreasing serum cholesterol after midlife may reflect ongoing disease processes and represent a marker of early stages in the development of dementia and AD. The use of statins (cholesterol-lowering drugs) in relation to dementia has been investigated in several community studies, with mixed findings. Some observational studies suggest a protective effect, while others did not, and clinical trials using statins for prevention of cognitive decline or dementia mainly reported no effects [6, 58]. Diabetes mellitus has been associated with increased risk of dementia and AD over adult life, but the risk is stronger when diabetes occurs in mid-life than in late-life [59]. Also pre-diabetes, impaired glucose regulation, and impaired insulin secretion have been associated with and increased risk of dementia and AD [60].

**2.2. Modifiable risk and protective factors for Alzheimer's disease**

AD [41-46].

*2.2.1. Risk factors*

456 Understanding Alzheimer's Disease

perfusion.

Different modifiable factors have been proposed to play a role in late life dementia and AD, including nutritional factors (i.e., diet and nutritional supplements), social or economic factors, medical conditions and lifestyle related factors (e.g., smoking habit, physical activity, etc.) (Table 1). A report commissioned by the National institute of Health (NIH) to the Agency for Healthcare Research and Quality (AHRQ) was published in 2010, and concluded that current research evidence on many risk and protective factors for cognitive decline and AD is not of sufficient strength, thus recommendations for preventing these conditions cannot be made [35, 36]. Another previous review yielded similar conclusions [37]. These negative perspectives have been criticized, since there is consistent and robust epidemiological evidence that use of antihypertensive medications, cessation of smoking and increasing physical activity produces cognitive benefits in older adults [38]. Furthermore, the analytical strategy used in the Evidence Based Review carried out by the AHRQ did not take into account the life-course perspective [39]. Observational longitudinal studies have shown that the risk of late-life dementia and AD is determined by exposures to multiple factors experienced over the life-span and that the effect of specific risk/protective factors largely depends on age [39]. Thus, a life-course perspective is relevant for chronic disorders with a long latent period (such as dementia). It allows the identification of time windows when exposures have their greatest effect on outcome and assessment of whether cumulative exposures could have multiplicative or additive effects over the life course [40]. Age-dependent associations with AD have been suggested for several aging-related medical conditions. For example, elevated blood pressure, body mass index (BMI) and total cholesterol levels at a young age and in middle age (<65 years) have been associated with an increased risk of dementia and AD, whereas having lower values in late life (age >75 years) has been also associated with subsequent development of dementia/

**1. Vascular risk factors and disorders**: An association of elevated blood pressure in midlife with an increased risk of dementia and AD later in life has been reported in several population-based studies [41, 47], while follow-up studies of late-life blood pressure and risk of dementia yield mixed results, largely depending on the length of follow-up. The short-term follow-up studies (e.g., less than 3 years) often found no association or even an inverse association between blood pressure and risk of dementia and AD [41]. However, studies of very old people (i.e., 75 + years) with a longer follow-up period (i.e., more than 6 years) also revealed an increased risk of dementia associated with low blood pressure [48], suggesting that among very old people low blood pressure may also contribute to the development of dementia, possibly by influencing cerebral blood

For BMI, the bidirectional association with dementia and AD has been shown in several studies, and longitudinal studies of elderly people have associated accelerated decline in BMI with subsequent development of dementia. This implies that low BMI and weight loss in advanced age can be interpreted as markers for preclinical dementia [45, 46, 49-55].

Cerebrovascular lesions and cardiovascular diseases have been shown to be risk factors for dementia and AD. Several population-based studies reveal an approximately two- to four-fold increased risk of incident dementia associated with clinical stroke (post-stroke dementia) [61, 62]. It is probable that an association of clinical stroke with AD is rarely reported due to the fact that a history of stroke is part of the current criteria for excluding the diagnosis of AD. However, asymptomatic cerebrovascular lesions such as silent brain infarcts and white matter lesions have been associated with an increased risk of dementia and AD [63, 64], although the association with AD is likely to be due to the inclusion of mixed dementia cases. The Cardiovascular Health Study found that cardiovascular disease was associated with an increased incidence of dementia, with the highest risk seen among people with peripheral arterial disease, suggesting that extensive peripheral atherosclerosis is a risk factor for dementia [65]. Atrial fibrillation, heart failure, and severe atherosclerosis measured with ankle-to-brachial index are also associated with the increased risk of dementia and AD [66-69].

**2. Environmental and other factors**: Current smoking is another major risk factor for dementia and AD, and based on the worldwide prevalence of smoking, about 14% of all AD cases are potentially attributable to this risk factor [70]. Although it is not entirely clear whether depression is a risk factor for or a preclinical symptom of dementia, studies with long-term follow-up support the risk-factor hypothesis [71]. Other conditions have been proposed as risk factors for dementia and AD, but the evidence is still sparse. These include occupational exposure, traumatic brain injury and infections. Occupational exposure to heavy metals such as aluminum and mercury has been suggested to be a risk factor for AD; even high consumption of aluminum from drinking water has been associated with an elevated risk of AD and dementia [6, 72]. In addition, occupational exposure to extremely-low-frequency electromagnetic fields (ELF-EMFs) has been related to an increased risk of dementia and AD [73, 74].

Traumatic brain injury has been extensively investigated as a possible risk factor for AD. The meta-analysis of case-control studies supported an association between a history of head injury and the increased risk of AD [75]. In contrast, some longitudinal studies found that AD was not associated with head trauma or only associated with severe traumatic head injury [76]. The role of viral and bacterial organisms in the development of chronic neurodegeneration is long established. Thus, Treponema pallidum and HIV, in particular, have been associated with the development of dementia. Other infections in the central nervous system (CNS), particularly Herpes Simplex Virus Type 1, Chlamydophila pneumoniae and several types of Spirochetes, have been suggested as possible aetiological agents in the development of sporadic AD, but with little consistent evidence. It has also been suggested that peripheral infections may have a role in accelerating neurodegener‐ ation in AD by activating already primed microglial cells within the CNS [77].

tocotrienols, named as α, β, γ, and δ [96]. Each congener shows different biological properties potentially relevant for neuroprotection. These include antioxidant and antiinflammatory activity and modulation of signaling pathways involved in neurodegener‐ ation [96, 97]. Most investigation of vitamin E in relation to dementia and AD has focused primarily only on α-tocopherol, with conflicting findings. Overall, studies investigating vitamin E intake only from supplements found no association with dementia/AD risk [89, 98-101], or a reduced incidence was found only for the combined use of vitamin E and C supplements [102, 103]. On the other hand, studies examining vitamin E dietary intake consistently report a reduced risk of dementia/AD in individuals with high vitamin E intake [84, 85, 104-106]. This might be explained by the fact that while vitamin E supple‐ ments contain only α-tocopherol, dietary intake can provide a balanced combination of different forms of vitamin E, which can be more relevant for neuroprotection. Recent studies seem to support this hypothesis: a multicenter European study found that both AD and MCI were associated with low plasma tocopherols and tocotrienols levels [107]. Further, in the Swedish Kungsholmen Project a decreased AD risk was found in subjects

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with high plasma levels of total tocopherols and total tocotrienols [108].

homocysteine levels [122, 123].

*2.2.3. Combined effect*

already being tested as a therapeutic agent in AD [127].

Vitamin B12 and folate are essential micronutrients that are part of the homocysteine metabolic cycle, and both vitamin B12 and folate deficiencies can result in increased total homocysteine levels, which may lead to a variety of disorders including cardiovascular and cerebrovascular conditions. Several studies reported and increased risk of dementia/ AD, worse cognitive functioning and structural brain changes in individuals with low levels of vitamin B12, holotranscobalamin (the biologically active fraction of vitamin B12) or folate, or high levels of total homocysteine [109-115]. Other studies did not confirm these findings, but methodological differences (e.g., different follow-up duration, implementing the study after mandatory folic acid fortification, etc.) could account for the discrepancy [116-119]. Reviews of RCTs concluded that supplementations of folic acid and vitamin B12 had no benefits on cognition in healthy or cognitively impaired older people, although they were effective in reducing serum homocysteine levels [120, 121]. A more recent RCT testing the efficacy of B vitamins (B6, B12, folate) in subjects with MCI reported beneficial effects of the supplementation, in terms of reduced rate of brain atrophy and cognitive decline, which were more evident in subjects with elevated

Vitamin D is a secosteroid hormone that is suggested to have neuroprotective effects that include regulation of neuronal calcium homeostasis, as well as antioxidant, neurotrophic and anti-inflammatory properties. Few recent longitudinal studies found a reduced risk of cognitive decline or AD in subjects with higher blood levels or higher dietary intake of vitamin D [124-126]. Despite the epidemiological evidence is still weak vitamin D is

Cumulative and combined exposure to different risk factors can lead to modified effects on dementia/AD risk (Table 1). In the Finnish Cardiovascular Risk Factors, Aging, and Dementia

#### *2.2.2. Protective factors*


tocotrienols, named as α, β, γ, and δ [96]. Each congener shows different biological properties potentially relevant for neuroprotection. These include antioxidant and antiinflammatory activity and modulation of signaling pathways involved in neurodegener‐ ation [96, 97]. Most investigation of vitamin E in relation to dementia and AD has focused primarily only on α-tocopherol, with conflicting findings. Overall, studies investigating vitamin E intake only from supplements found no association with dementia/AD risk [89, 98-101], or a reduced incidence was found only for the combined use of vitamin E and C supplements [102, 103]. On the other hand, studies examining vitamin E dietary intake consistently report a reduced risk of dementia/AD in individuals with high vitamin E intake [84, 85, 104-106]. This might be explained by the fact that while vitamin E supple‐ ments contain only α-tocopherol, dietary intake can provide a balanced combination of different forms of vitamin E, which can be more relevant for neuroprotection. Recent studies seem to support this hypothesis: a multicenter European study found that both AD and MCI were associated with low plasma tocopherols and tocotrienols levels [107]. Further, in the Swedish Kungsholmen Project a decreased AD risk was found in subjects with high plasma levels of total tocopherols and total tocotrienols [108].

Vitamin B12 and folate are essential micronutrients that are part of the homocysteine metabolic cycle, and both vitamin B12 and folate deficiencies can result in increased total homocysteine levels, which may lead to a variety of disorders including cardiovascular and cerebrovascular conditions. Several studies reported and increased risk of dementia/ AD, worse cognitive functioning and structural brain changes in individuals with low levels of vitamin B12, holotranscobalamin (the biologically active fraction of vitamin B12) or folate, or high levels of total homocysteine [109-115]. Other studies did not confirm these findings, but methodological differences (e.g., different follow-up duration, implementing the study after mandatory folic acid fortification, etc.) could account for the discrepancy [116-119]. Reviews of RCTs concluded that supplementations of folic acid and vitamin B12 had no benefits on cognition in healthy or cognitively impaired older people, although they were effective in reducing serum homocysteine levels [120, 121]. A more recent RCT testing the efficacy of B vitamins (B6, B12, folate) in subjects with MCI reported beneficial effects of the supplementation, in terms of reduced rate of brain atrophy and cognitive decline, which were more evident in subjects with elevated homocysteine levels [122, 123].

Vitamin D is a secosteroid hormone that is suggested to have neuroprotective effects that include regulation of neuronal calcium homeostasis, as well as antioxidant, neurotrophic and anti-inflammatory properties. Few recent longitudinal studies found a reduced risk of cognitive decline or AD in subjects with higher blood levels or higher dietary intake of vitamin D [124-126]. Despite the epidemiological evidence is still weak vitamin D is already being tested as a therapeutic agent in AD [127].

#### *2.2.3. Combined effect*

Traumatic brain injury has been extensively investigated as a possible risk factor for AD. The meta-analysis of case-control studies supported an association between a history of head injury and the increased risk of AD [75]. In contrast, some longitudinal studies found that AD was not associated with head trauma or only associated with severe traumatic head injury [76]. The role of viral and bacterial organisms in the development of chronic neurodegeneration is long established. Thus, Treponema pallidum and HIV, in particular, have been associated with the development of dementia. Other infections in the central nervous system (CNS), particularly Herpes Simplex Virus Type 1, Chlamydophila pneumoniae and several types of Spirochetes, have been suggested as possible aetiological agents in the development of sporadic AD, but with little consistent evidence. It has also been suggested that peripheral infections may have a role in accelerating neurodegener‐

ation in AD by activating already primed microglial cells within the CNS [77].

onset of dementia, possibly by increasing the cognitive reserve [81].

inconsistent approaches of alcohol assessments [6].

**1. Psychosocial factors**: Protective factors for dementia and AD have also been identified, including high education and socioeconomic status (SES) in early life as well as a number of factors in adult life: high work complexity, rich social network, social engagement, mentally-stimulating activity, non-smoking and regular physical exercise [6, 78, 79]. Living with a partner during mid-life has been associated with reduced risk of cognitive impairment and dementia later in life, suggesting that being in a relationship entails cognitive and social challenges that can increase the cognitive reserve [80]. Even at old ages the active engagement in mental, physical and social activities may postpone the

**2. Lifestyle and diet**: In addition, several follow-up studies reported a decreased risk of dementia and AD associated with healthy dietary patterns and nutritional factors, such as high adherence to a Mediterranean diet or dietary intake of antioxidants (e.g., vitamins E and C) and ω-3 polyunsaturated fatty acid (PUFA, often measured as fish consumption) [82-86], although some negative results have been also reported [87-90]. Light-to-moder‐ ate alcohol intake (e.g., 1-3 drinks per day) has been associated to a reduced incidence of dementia and AD [6, 91, 92], while heavy alcohol consumption at midlife has been associated to an increased risk of dementia/AD, especially among *APOE* ε4 carriers [93]. Alcohol may have beneficial influences on several cardiovascular factors, including lipid and lipoprotein levels, inflammatory and hemostatic factors. Indeed, moderate alcohol drinking has been related to a reduced risk of cardiovascular diseases, and may be associated with fewer brain infarcts [6]. However, it has been also suggested that the apparent cognitive benefits of light-to-moderate alcohol intake could be due to potential biases that result from methodological limitations of the observational studies such as information bias, confounding of socioeconomic status and healthy lifestyles, and

**3. Vitamins**: The micronutrient vitamin E is the main lipid-soluble, chain-breaking, nonenzymatic antioxidant in the human body [94], and is essential for normal neurological functions [95]. Vitamin E includes eight natural congeners: four tocopherols and four

*2.2.2. Protective factors*

458 Understanding Alzheimer's Disease

Cumulative and combined exposure to different risk factors can lead to modified effects on dementia/AD risk (Table 1). In the Finnish Cardiovascular Risk Factors, Aging, and Dementia study (CAIDE), the risk of dementia has been evaluated in relation to a score (CAIDE Dementia Risk Score) combining mid-life risk factors, including low education and cardiovascular factors (i.e., hypertension, obesity, hypercholesterolemia, physical inactivity). The risk of dementia increased as the score increased in a dose-response trend, making it possible to identify individuals who can greatly benefit from preventive intervention that targets vascular risk factors [128]. Similar findings have been reported for late-life exposures: in the Swedish Kungsholmen Project, the cumulative effect of vascular risk factors and vascular diseases on dementia/AD risk has been investigated in people aged 75+ years. These factors were aggre‐ gated according to two pathophysiological hypotheses: the brain hypoperfusion profile, defined by chronic heart failure, low pulse pressure, and low diastolic pressure, and the atherosclerosis profile, which included high systolic pressure, diabetes mellitus or prediabetes, and stroke. In both profiles, dementia/AD risk increased with increasing scores in a doseresponse manner, suggesting a synergy of vascular risk factors in promoting dementia/AD also in advanced age [129]. The American Cardiovascular Health Cognition Study developed a Late-life Dementia Risk Index, and also its brief version, which groups older adults in the three categories of low, moderate, and high risk of developing dementia. Both versions of the index support the cumulative effect of different factors in determining the risk of dementia after the age of 65 years. These indices include information from different domains, including demographic factors (age), genetic (presence of the *APOE* ε4 allele), lifestyle (BMI<18.5, lack of alcohol consumption), comorbid vascular conditions (internal carotid artery thickening, angina, coronary artery by-pass surgery, stroke, peripheral artery disease), evidence of brain abnormalities showed by magnetic resonance imaging (MRI) (white matter diseases or enlarged ventricles), cognitive test scores and physical performances [130, 131].

studies points at different modifiable factors that can be managed in order to prevent or delay dementia onset. Moreover, epidemiological findings strongly suggest that the life-course approach model and the multifactorial nature of dementia and AD should be considered when

Prevention of Alzheimer's Disease: Intervention Studies

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Different medications, including statins, antihypertensive drugs, estrogens alone or in combination with progestin (hormone replacement therapy, HRT), nonsteroidal anti-inflam‐ matory drugs (NSAIDs), and nutraceuticals (vitamin B12, C, E, folate, Ginkgo biloba) have been tested as primary or secondary prevention measures for dementia and AD in subjects with normal cognition or MCI. In general, for all these compounds the protective effects suggested by observational studies have not been confirmed in RCTs, the results of which are inconsistent or even suggest a detrimental effect on cognition (e.g., NSAIDs, HRT) [120, 134-136]. Few interventional studies implementing non-pharmacological approaches have been carried out. Among them some RCTs on cognitive training and physical activity provided encouraging results, which need further confirmation [134, 137]. It is possible that the negative results from the RCTs done so far reflect the real inefficacy of the tested strategies in preventing dementia and AD. However, the apparent contradiction of results from observational and

**1.** The intervention was done outside the time-window when management of a risk factor would reduce dementia risk: several risk factors exert their effect mainly during mid-life, whereas RCTs have been done in older adults. This is the case for vascular risk factors, which seem to be more relevant when the exposure occurs during mid-life. Moreover, the HRT research suggests that estrogens may have beneficial, neutral, or detrimental effects on the brain depending on age at treatment, type of menopause (natural versus medically or surgically induced) or stage of menopause [138]. This concept, called the "window of opportunity hypothesis" is in agreement with the life-course approach model. There is evidence of neuroprotective effects of estrogens in women before the age of natural menopause and in the early postmenopausal stage (50-60 years), while estrogens initiated in late postmenopause (65-79 years) increase the risk of cognitive impairment and dementia [138-142]. The large-scale RCT of the Women's Health Initiative Memory Study (WHI-MS) showed that estrogens therapy alone or in combination with progestin was associated with a two-fold increased risk for dementia and MCI [139, 140]. The WHI-MS study enrolled women aged 65-79 years, who were given the HRT many years after the onset of natural or surgical menopause. In contrast, the Kronos Early Estrogen Prevention Study (KEEPS) tested the HRT in recently menopausal women (mean age 53 years; enrolment within three years after menopause), reporting beneficial effects [141]. In fact, the use of the HRT in the KEEPS participants has been associated with the improvement of markers of cardiovascular risk, anxiety and depression, without adverse effects on

interventional studies could be explained by several factors:

planning any preventive strategy.

**3. Interventional studies**

**3.1. Current evidence**

The combined effect of genetic-environmental or environmental-environmental joint expo‐ sures may also lead to the attenuation of the dementia risk. Population-based studies suggest an effect modification for the *APOE* ε4 allele, the most important genetic risk factor for sporadic AD. *APOE* ε4 carriers seem more vulnerable to risk factors like alcohol drinking, smoking, physical inactivity and high intake of saturate fat, indicating that people with genetic suscept‐ ibility may reduce their initial AD risk by lifestyle interventions (i.e., physical activity, sufficient intake of PUFA, and avoiding excess alcohol drinking and smoking) [33]. The protective effect of lifestyle in *APOE* ε4 carriers seem to be present also in advanced age: in the Swedish Kungsholmen Project, subjects aged 75+ years who were *APOE* ε4 carriers, but with high education, active leisure activities, or good vascular health (i.e., absence of vascular risk factors), had a reduced risk of dementia and AD, as well as a delayed time of onset of the disease [132]. Further, it has been shown that high education may reduce dementia risk among *APOE* ε4 allele carriers [133].

Regarding the interactions among modifiable risk factors, results from the Kungsholmen Project suggested that complexity of work with data and people was related to a decreased dementia risk and that the highest level of work complexity may modulate the increased dementia risk due to low education [78].

In conclusion, even though the evidence for some risk and protective factors in dementia and AD is still scarce, and their role needs to be further clarified, findings from observational studies points at different modifiable factors that can be managed in order to prevent or delay dementia onset. Moreover, epidemiological findings strongly suggest that the life-course approach model and the multifactorial nature of dementia and AD should be considered when planning any preventive strategy.
