Alzheimer's disease prevention: A way forward

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"figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1626 "Ancho" => 2575 "Tamanyo" => 155312 ] ] "descripcion" => array:1 [ "en" => "References on the prevention of Alzheimer's disease." ] ] ] "textoCompleto" => "BackgroundThe prevalence of dementia is high in the over 60-year-old population (5–7%), and the most common form is Alzheimer's disease (AD) (65–80%).<a class="elsevierStyleCrossRefs" href="#bib0405">1–3</a> Dementia and AD constitute a real public health problem,<a class="elsevierStyleCrossRef" href="#bib0420">4</a> with a predicted increase in the immediate future due to the aging of the population, increased survival, which will result in increased demand for medical and social care.<a class="elsevierStyleCrossRefs" href="#bib0420">4–6</a> The problem is compounded by a lack of immediate perspectives for healing and the distinct lack of progress in developing effective drugs.<a class="elsevierStyleCrossRefs" href="#bib0435">7,8</a>In the last 3 decades, significant effort has been dedicated to clinical, basic and experimental (mice transgenic) research into AD, which has led to numerous therapeutic trials with a countless number of drugs that have required large investments, resulting in cognitive and behavioral benefits of low intensity and duration.<a class="elsevierStyleCrossRef" href="#bib0440">8</a> Nonpharmacological therapies for AD have also shown slight efficacy during the time they are performed but are difficult to implement and have not substantially changed outcomes.<a class="elsevierStyleCrossRefs" href="#bib0445">9,10</a> Drugs tested both in primary (preclinical AD) and secondary (predementia cognitive decline or mild cognitive impairment [MCI]) prevention have not been successfull.<a class="elsevierStyleCrossRefs" href="#bib0440">8,11</a> In this less than encouraging situation, long-term data from population cohorts have shown a reduction in the incidence rate and prevalence of dementia and EA.<a class="elsevierStyleCrossRefs" href="#bib0460">12,13</a> Various studies have calculated that if the main risk factors (RFs) for dementia and AD could be suppressed, their incidence rate could be cut by a third.<a class="elsevierStyleCrossRefs" href="#bib0460">12,14</a> These optimistic data have led to investment in research on the preventive aspects of AD, both individual and societal (public health), in the United States of America<a class="elsevierStyleCrossRef" href="#bib0475">15</a> and in the European Union, through the establishment of the European Dementia Prevention Initiative.<a class="elsevierStyleCrossRef" href="#bib0480">16</a> We should therefore be aware of the possibilities for preventing AD,<a class="elsevierStyleCrossRefs" href="#bib0460">12–19</a> given that they provide a way forward.Current concept of Alzheimer's disease: a lack of unanimityThere is relative unanimity in that AD is a neurodegenerative disease resulting from the accumulation of misfolded proteins: the beta-amyloid (βA) peptide, which is found in the extracellular senile plaques (SP), and the hyperphosphorylated tau protein, which is established in fibrillar accumulations in the neuronal soma, constituting neurofibrillary degeneration (NFD) or neurofibrillary tangles.<a class="elsevierStyleCrossRef" href="#bib0500">20</a> There are 2 types of AD: (1) the familial form (FAD), which is usually early onset, produced by less prevalent monogenic abnormalities (1% of AD cases) in 1 of the 3 genes (amyloid precursor protein gene, PS1 or PS2); and (2) the sporadic or idiopathic AD (SAD), in which 99% of cases fit and is most commonly senile.<a class="elsevierStyleCrossRef" href="#bib0505">21</a> FAD has been interpreted as a βA deposit disease. The products of altered genes induce the toxic brain deposit, which triggers an “amyloid cascade” that is responsible for the other abnormalities. This hypothesis, however, has been postulated for both types of AD.<a class="elsevierStyleCrossRef" href="#bib0510">22</a> However, the biological substrate of SAD appears to differ from that of FAD, which would explain the failure of antiamyloid therapies.<a class="elsevierStyleCrossRefs" href="#bib0500">20,23</a>For SAD, genetic RFs have also been described (one of which, the E4 allele of the apolipoprotein E gene, is almost universal except in sub-Saharan Africans), as well as numerous susceptibility alleles (of risk and protection) (see <a id="intr0015" class="elsevierStyleInterRef" href="http://www.alzgene.org/">www.alzgene.org</a>, which updates the references to these alleles). There are also poorly understood hereditary traits that are possibly due to epigenetic mechanisms.<a class="elsevierStyleCrossRefs" href="#bib0520">24,25</a> SAD is therefore a complex neurodegenerative disease, influenced by polygenic and epigenetic mechanisms<a class="elsevierStyleCrossRef" href="#bib0525">25</a> and by environmental factors. There is certain unanimity on the pathogenic mechanisms that lead to the clinical expression of SAD. AD (both FAD and SAD) are believed to be the consequence of the slow (decades) and progressive accumulation of NFD and SPs that, when they exceed a certain brain reserve threshold (brain size and neuron quantity) and cognitive threshold (complexity of neural network associated with intelligence and education), manifest insidiously as dementia.<a class="elsevierStyleCrossRef" href="#bib0530">26</a> Other disorders affect SAD, including neuronal and synaptic loss, hippocampal atrophy, vascular abnormalities and age-related changes, which add up to its adverse effect on the cognitive reserve.<a class="elsevierStyleCrossRefs" href="#bib0535">27–30</a> However, there is no agreement on the primary molecular processes of SAD, whose range extends from mechanisms that hold a vascular hypothesis<a class="elsevierStyleCrossRef" href="#bib0555">31</a> to cellular lesions by oxidation, cell cycle abnormalities<a class="elsevierStyleCrossRef" href="#bib0560">32</a> and systemic mechanisms.<a class="elsevierStyleCrossRef" href="#bib0565">33</a>From a clinical perspective, there is greater consensus on the diagnostic criteria. In 1984, McKhann et al., along with several AD associations such as the National Institute of Neurological Disorders and Stroke/Alzheimer's disease and Related Disorders Association, agreed on a series of criteria (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>) that enabled the diagnosis of AD to be classified as possible (when present in the absence of another dementia etiology); probable (when certain clinical characteristics are added to the previous situation); and defined (probable symptoms and histological confirmation).<a class="elsevierStyleCrossRef" href="#bib0570">34</a> This classification has been shown effective in pathological studies (good sensitivity and moderate specificity)<a class="elsevierStyleCrossRef" href="#bib0575">35</a> and has been employed for more than 25 years for the clinical diagnosis. However, the lack of a pathological gold standard<a class="elsevierStyleCrossRefs" href="#bib0535">27–30</a> and the lack of efficacy in the immunoactive therapies (although they remove the βA deposits in SAD)<a class="elsevierStyleCrossRef" href="#bib0580">36</a> have resulted in an update to this classification,<a class="elsevierStyleCrossRef" href="#bib0585">37</a> which currently includes a prodromal SAD phase (MCI) and the construct (only for research purposes) of preclinical AD.<a class="elsevierStyleCrossRefs" href="#bib0590">38,39</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Preclinical AD is defined as the absence of cognitive decline, with positive biomarkers in cerebrospinal fluid (reduction of βA and increase in tau) or detection of βA accumulation in the brain through magnetic resonance imaging or contrast-enhanced positron emission tomography. A number of authors also accept subclinical memory loss. The purpose of this definition is to be able to test drugs both in stages of predementia (MCI) and at-risk preclinical AD.<a class="elsevierStyleCrossRefs" href="#bib0585">37–40</a> The introduction of biomarkers in AD has not yet standardized either the techniques or the importance of its various findings (neuroimaging or biochemical) nor are they a guarantee of progression to AD.<a class="elsevierStyleCrossRef" href="#bib0600">40</a>Historical perspective of Alzheimer's diseaseAt the start of the 20th century, dementia was an uncommon condition that typically appeared in senescence (the mean life expectancy of the population was scarcely above 40 years). The condition was believed to be caused by a deficient cerebrovascular supply (once secondary causes, such as progressive general paralysis, had been ruled out).Alois Alzheimer described a case of dementia in 1907 in a 51-year-old woman (presenile for being younger than 65 years) whose brain showed a new lesion, the NFD. The other histological trait characteristic of dementia in senescence, SPs, was described by Fischer (a member of the Pick school in Prague, a rival of the Frankfurt school headed by Kraepelin and Alzheimer). For a number of authors, the birth of AD was due to the historical quirk of Kraepelin (powerful head of the Frankfurt school) who wanted a professorship and a new disease, presenile dementia, for his disciple Alzheimer.<a class="elsevierStyleCrossRefs" href="#bib0605">41,42</a> It has been suggested that the initial case could have been leukodystrophy.<a class="elsevierStyleCrossRef" href="#bib0615">43</a> Kraepelin had an essentialist concept of mental diseases. He considered them clinical conditions and natural diseases and separate from each other, a concept that has been communicated over time.<a class="elsevierStyleCrossRef" href="#bib0610">42</a> The separation of senile and presenile dementia of Alzheimer persisted up to the end of the 60s, when a number of studies<a class="elsevierStyleCrossRef" href="#bib0620">44</a> showed that pathologically, both types of dementia (presenile and senile) were indistinguishable if they present SPs and NFD. It was thus agreed in 1978, during a meeting of specialists in the US National Institutes of Health.<a class="elsevierStyleCrossRef" href="#bib0625">45</a> AD would have a specific clinical condition that includes memory loss and slow, progressive cognitive decline, with no motor signs and with a histology characterized by the presence of SPs and NFD. This Cartesian separation of AD dementia from the other types of senile dementia has been questioned in the 21st century by community pathological studies.<a class="elsevierStyleCrossRefs" href="#bib0535">27–30</a> In these studies, what is diagnosed as SAD is a heterogeneous condition with 75–80% of cases with mixed lesions (vascular, type AD and others) and very few pure cases (vascular, type AD and other neurodegenerative diseases).<a class="elsevierStyleCrossRefs" href="#bib0535">27,29,30</a>Alzheimer's disease or dementia-Alzheimer syndrome?There is no pathological gold standard for AD. The criterion of the presence of SPs and NFD is insufficient,<a class="elsevierStyleCrossRefs" href="#bib0535">27–30</a> despite the position held by a number of authors.<a class="elsevierStyleCrossRef" href="#bib0630">46</a> Neither the clinical condition nor the recent biological or neuroimaging biomarkers have the capacity to establish an unequivocal diagnosis.<a class="elsevierStyleCrossRefs" href="#bib0495">19,40</a> This situation greatly complicates the diagnosis of SAD as a well-defined nosological condition. In reality, we often only have a diagnosis of SAD based on probabilistic clinical and pathological criteria.<a class="elsevierStyleCrossRefs" href="#bib0570">34,37</a> SPs and NFD are not specific to AD. SPs can be found in a third of elderly persons with normal cognition, as can NFD, whose intensity increases with aging and can be found in other diseases (Down syndrome, various parkinsonisms, dementia pugilistica and other rarer neurodegenerative disease).<a class="elsevierStyleCrossRefs" href="#bib0535">27–30</a> As has been discussed previously, the histology of AD (NFD and SP) is rarely unique. AD is often found intermixed with histological traits from other neurodegenerative disorders (such as α-synuclein deposits, a phenomenon accentuated in individuals older than 80 years<a class="elsevierStyleCrossRefs" href="#bib0535">27–30</a>) and other not fully characterized disorders.<a class="elsevierStyleCrossRefs" href="#bib0540">28–47</a> Numerous authors also consider SPs and NFD a terminal pathological result common to several types of dementia; that is, residual biological lesions of previous dysmetabolic processes and with no causal pathophysiological capacity.<a class="elsevierStyleCrossRefs" href="#bib0555">31–33,36,48,49</a> This viewpoint, coupled with the clinical-pathological discrepancy of AD-type lesions (10–15% of patients with histopathology findings of AD but no dementia and another 10–15% of cases of dementia or clinical SAD with no underlying disease to explain it) has caused a shift in opinion.<a class="elsevierStyleCrossRefs" href="#bib0540">28,47</a> SAD should be considered a dementia-Alzheimer syndrome and not a well differentiated condition as Kraepelin thought. Senile cognitive decline, MCI and AD-dementia constitute a continuum in which clear separations are contrived.<a class="elsevierStyleCrossRefs" href="#bib0650">50,51</a>Pathophysiology: abolition of the amyloid hypothesis?The amyloid hypothesis has been the dominant explanation for the pathophysiology of AD. The finding of disorders in the gene for the amyloid precursor protein, the precursor of βA in FAD, originated this hypothesis, which, in essence, predicts that the accumulation of βA is toxic for the brain and generates NFD and other abnormalities.<a class="elsevierStyleCrossRef" href="#bib0505">21</a> The inability of transgenic mice studies to reproduce human AD (with associated neuron loss) and the failure of immune therapy against the accumulation of βA<a class="elsevierStyleCrossRef" href="#bib0580">36</a> has resulted in 2 conflicting schools of thought: one that considers that this hypothesis is uncertain (although the accumulation of βA can be an epiphenomenon associated with SAD)<a class="elsevierStyleCrossRefs" href="#bib0555">31–33,36,48</a> and the other, which holds that preclinical therapy (against the accumulation of βA) could be effective and that this theory should not be rejected without this test.<a class="elsevierStyleCrossRefs" href="#bib0505">21,38,39</a> To complicate the issue further, studies with various animal models have shown that βA, tau and α-synuclein can be transmitted transcellularly; i.e., that its propagation would be analogous to that which occurs in prion diseases (caused by misfolded proteins). This finding has led to the suggestion of similar mechanisms for protein accumulation in neurodegenerative disease, although there is no evidence of transmission of AD among humans.<a class="elsevierStyleCrossRef" href="#bib0660">52</a> It is not surprising that, in this context of lack of pathophysiological knowledge, it is difficult to envision a curative treatment that impedes (or eliminates) the formation of AD lesions, and primary prevention is seriously considered the best option.<a class="elsevierStyleCrossRefs" href="#bib0460">12–14,16,19,51</a>Prevention of Alzheimer's disease and its biological plausibilitySeveral observations have indicated that the incidence and prevalence (relative to the existing group of elderly persons) of dementia is decreasing in developed countries. The first study on this issue, which proceeded from the Long Term Care Study conducted in the US between 1982 and 2004, observed a reduction in the functional disability in the elderly, caused essentially by a decrease in mixed dementia.<a class="elsevierStyleCrossRef" href="#bib0665">53</a> Several additional studies confirmed the reduction in cognitive impairment and dementia in The Netherlands,<a class="elsevierStyleCrossRef" href="#bib0670">54</a> Spain,<a class="elsevierStyleCrossRef" href="#bib0675">55</a> Sweden<a class="elsevierStyleCrossRef" href="#bib0680">56</a> and England.<a class="elsevierStyleCrossRef" href="#bib0685">57</a> All of these studies have shown a decrease in dementia in the younger cohorts during the period 1990-2008. It is worth noting that a study in Danish nonagenarians (1910 and 1915 cohorts) reported that the youngest (born in 1915) were cognitively better and had greater survival.<a class="elsevierStyleCrossRef" href="#bib0690">58</a> In 2016, the Framingham study (children of the first cohort) showed a clear reduction in the incidence of dementia over 3 decades (primary prevention result).<a class="elsevierStyleCrossRef" href="#bib0695">59</a> A neuropathological finding in Switzerland from a 30-year follow-up agreed with the clinical data: in the last years of this period, the brain βA burden decreased.<a class="elsevierStyleCrossRef" href="#bib0700">60</a> It is logical to assume, by analogy with what occurs in other diseases, that progress in controlling the RFs of dementia and AD is responsible for this decrease. Thus, historical data indicate the benefit of controlling the RFs of infectious diseases (e.g., the number of tuberculosis cases decreased significantly before the emergence of streptomycin due to improved public health and hygiene)<a class="elsevierStyleCrossRef" href="#bib0705">61</a> and vascular and lifestyle RFs (reducing the incidence of noncommunicable diseases, such as ischemic heart disease, stroke and breast cancer).<a class="elsevierStyleCrossRef" href="#bib0710">62</a> The same relationship for SAD is biologically plausible,<a class="elsevierStyleCrossRefs" href="#bib0710">62,63</a> although we will have to wait for the results of experimental clinical trials currently underway, whose initial results are encouraging.<a class="elsevierStyleCrossRefs" href="#bib0480">16,19</a>Risk factors and preventive factors of sporadic Alzheimer's disease and dementiaThere has been an increase in publications on preventing AD since the beginning of this century (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>), although they are heterogeneous in terms of their analysis objectives (cognitive impairment, dementia and SAD) and analyzed RFs/preventive factors (PFs).<a class="elsevierStyleCrossRefs" href="#bib0460">12–19</a> A synthesis of RFs and PFs in AD is presented in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>, although it does not differentiate as to whether the RFs and PFs correspond to dementia in general or to SAD in particular, given that numerous studies do not make this distinction. This scheme is followed by a simple description, starting with the nonpreventable items and continuing with the more potentially modifiable. Additionally, the RFs and PFs have been reported over the course of a lifetime to show that SAD is a chronic disease in which intergenerational and prenatal factors are involved.<a class="elsevierStyleCrossRefs" href="#bib0710">62,63</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Aging is a universal RF in cognitive impairment, dementia and AD,<a class="elsevierStyleCrossRefs" href="#bib0465">13–23</a> but it is doubtful that the female sex is an RF for SAD (although SAD is more prevalent in women due to their greater longevity). However, the slight increase in the incidence rate in women in a number of cohorts could be due to their lower educational level compared with men or to the greater selective mortality of this condition in adulthood.<a class="elsevierStyleCrossRefs" href="#bib0720">64,65</a> Regardless, age and sex (as with genetics) are not modifiable factors, although they can be attenuated by epigenetic changes (see <a id="intr0020" class="elsevierStyleInterRef" href="http://www.nida.nih.gov/">www.nida.nih.gov</a>).<a class="elsevierStyleCrossRefs" href="#bib0525">25,66</a> A number of familial factors can be important. Among them, the degree of maternal education appears the most relevant,<a class="elsevierStyleCrossRefs" href="#bib0730">66,67</a> although not on its own given that SAD, as with other complex diseases, starts its gestation in the womb (Baker hypothesis). This hypothesis underlines the significant role of poor fetal nutrition and low birth weight in the subsequent development of diseases (vascular, diabetes and others)<a class="elsevierStyleCrossRefs" href="#bib0525">25,66,67</a> and has been refined by a scientific movement that has analyzed the importance of factors in gestation and the first era of infancy (developmental plasticity) and the epigenetic mechanisms that regulate them. This movement (scientific associations and journals) has provided animal studies (including primates) and has launched pediatric cohorts to study their hypothesis (see, <a id="intr0025" class="elsevierStyleInterRef" href="http://www.dohadsoc.org/">www.dohadsoc.org</a>). Their main theoretical premise is that there is an intergenerational transmission (epigenetics) of physiological susceptibility to certain diseases that manifest in later life.<a class="elsevierStyleCrossRef" href="#bib0740">68</a> Their practical observations include low education (less than 8 years of studies and especially illiteracy) is an RF for dementia and SAD, detectable in populations that at the beginning of the 20th century had high illiteracy rates such as the Spanish, which was apparent in the Spanish NEDICES study<a class="elsevierStyleCrossRef" href="#bib0745">69</a> [see <a id="intr0030" class="elsevierStyleInterRef" href="http://www.ciberned.es/estudio">www.ciberned.es/estudio</a> NEDICES]. Education is a consistent RF/PF in the reviews on the topic,<a class="elsevierStyleCrossRefs" href="#bib0460">12–14,16–19,69</a> particularly in developed countries, and is included in a systematic review (education and dementia).<a class="elsevierStyleCrossRef" href="#bib0750">70</a> Nevertheless, this relationship is complex. Education can be a marker of low socioeconomic status (poor nutrition and intellectual stimulation in brain development or pediatric stages) or form part of the cognitive reserve.<a class="elsevierStyleCrossRef" href="#bib0530">26</a> Education is also a shifting factor, which can increase at various periods of life. In the NEDICES cohort, verbal intelligence was better able to predict cognitive performance that years of study or socioeconomic status.<a class="elsevierStyleCrossRef" href="#bib0755">71</a> Education has a biological effect on the brain (increase in synaptic connections and others), which constitutes the cognitive reserve that impedes or delays the clinical manifestation of dementia.<a class="elsevierStyleCrossRef" href="#bib0530">26</a>Most population cohorts have shown that the main vascular RFs present in adulthood (obesity, arterial hypertension, diabetes, metabolic syndrome, smoking, heart disease and stroke) are RFs for the onset of dementia and SAD in the elderly,<a class="elsevierStyleCrossRefs" href="#bib0460">12,13,16–18</a> although it is debated whether vascular lesions in the brain are synergistic or promoters of SAD.<a class="elsevierStyleCrossRefs" href="#bib0650">50,69,72</a> Of these RFs, uncontrolled arterial hypertension is the primary RF, because it not only occurs in middle age but also in old age.<a class="elsevierStyleCrossRefs" href="#bib0485">17,73</a>Physical activity is a PF of dementia and SAD for which there is almost unanimous agreement.<a class="elsevierStyleCrossRefs" href="#bib0470">14,16–18</a> As has been stated by the World Health Organization and several state health agencies, physical inactivity is the fourth leading RF for disease in the world, and it lowers defenses against various cardiovascular and other chronic diseases.<a class="elsevierStyleCrossRef" href="#bib0770">74</a> There are abundant studies in the literature concerning physical inactivity as a RF for SAD, even in old age (for example, data from the NEDICES cohort show that the elderly who engage in physical exercise had a lower risk of dementia than those who were sedentary).<a class="elsevierStyleCrossRef" href="#bib0775">75</a> There are experimental and anthropological data that support its biological plausibility.<a class="elsevierStyleCrossRef" href="#bib0780">76</a>Other RFs/PFs require more studies to demonstrate their preventive capacity in SAD, given that despite the abundant observational data, there are few trials that support them.<a class="elsevierStyleCrossRef" href="#bib0490">18</a> Nevertheless, diet, social integration and participation in social and cognitive activities over one's lifetime, even in old age, have been indicated as PFs for dementia and SAD.<a class="elsevierStyleCrossRefs" href="#bib0780">76,77</a> Diet is more difficult to investigate, given that it changes over the course of one's life and is subject to cultural determinants and socioeconomic status. On this subject, the studies are very heterogeneous, but the more recent ones suggest that diets rich in fruits, vegetables, proteins of plant origin, fish, omega-3 fatty acids, olive oil and little meat, such as the Mediterranean diet (and other healthy diets such as Dietary Approaches to Stop Hypertension and the Japanese diet), are associated with a lower incidence of cardiovascular disease and cognitive decline. It is logical to assume that these diets would lower the incidence of SAD, although data are more scarce on this subject.<a class="elsevierStyleCrossRef" href="#bib0790">78</a> The tests showing that a regular intake of coffee, moderate quantities of alcohol, green tea or chocolate are PFs for dementia and SAD are less apparent.<a class="elsevierStyleCrossRefs" href="#bib0470">14,78</a> Severe head trauma is a RF for dementia and possibly AD. Sensory deficits (blindness, deafness), sleep disorders and depression can be RFs or the initial manifestations of SAD.<a class="elsevierStyleCrossRefs" href="#bib0480">16–19</a> Exposure to toxins (insecticides and others) appears to be a RF in the genesis of SAD and other neurodegenerative diseases.<a class="elsevierStyleCrossRefs" href="#bib0480">16–18,79</a> There are numerous studies that have indicated that poor systemic health is associated with cognitive impairment/dementia and SAD. This association could be explained as a lack of vitality associated with aging but could be a RF.<a class="elsevierStyleCrossRef" href="#bib0565">33</a>Population trials in preventing dementia and Alzheimer's diseasePrimary prevention trials for SAD are not a pipe dream and are underway in the US and Europe. The European trials are being conducted under the auspices of the European Dementia Prevention Initiative (see <a id="intr0035" class="elsevierStyleInterRef" href="http://www.edpi.org/">www.edpi.org</a>),<a class="elsevierStyleCrossRef" href="#bib0480">16</a> with the international collaboration of 3 countries that include 3 large population cohorts. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), which introduced multidimensional actions (nutritional, vascular RF control and others), is a randomized study with 1200 participants in a 7-year follow-up. The Prevention of Dementia by Intensive Vascular Care (preDIVA) study is sponsored by the University of Amsterdam and consists of the 6-year follow-up of a cohort of 3534 individuals in whom 2 types of therapies are being assessed: a control group with standard treatment and another with a specific therapy (nurses who monitor drug therapy, lifestyle and cardiovascular RFs). The French Multidomain Alzheimer Prevention (MAPT) study conducts a 3-year intervention years and a subsequent 5-year follow-up of a cohort of 1600 participants older than 70 years, with mainly nutrition and physical activity counseling. Additionally, there is the Healthy Aging Through Internet Counselling in the Elderly (HATICE), an online project that provides therapeutic counseling (randomized) in 3 participating countries (Finland, The Netherlands and France) (<a id="intr0040" class="elsevierStyleInterRef" href="http://www.edpi.org/">www.edpi.org</a>). Only the FINGER study has promising preliminary data: the treated group had better performance on cognitive tests than the control group.<a class="elsevierStyleCrossRef" href="#bib0800">80</a>In conclusion, the accumulated data indicate that SAD is not a clinical-pathological condition as well differentiated as believed from the time of Kraepelin to 2 decades ago. SAD is beginning to be thought of as a clinical condition that encompasses a set of conditions, which include SPs, NFD, vascular lesions (macroscopic and microscopic) and neurodegenerative disease of various types, which gestate in the brain for several decades and clinically manifest in old age. Genetic, epigenetic and environmental factors are involved in the establishment of SAD. The condition's inner pathophysiology is unknown, and it is therefore unlikely that a drug to impede or delay its onset will appear within the foreseeable future. In this scenario, an early preventive approach is necessary. The control of likely RFs (education, physical activity and vascular and lifestyle RFs such as diet and tobacco) should be performed from childhood, a period during which the greatest brain growth occurs. The control of RFs/PFs has biological plausibility and a number of reliable observations,<a class="elsevierStyleCrossRefs" href="#bib0695">59,60</a> although it has not been confirmed in trials. Several trials are underway that control numerous RFs, drug-associated or not, and their initial results are promising.Conflicts of interestThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:15 [ 0 => array:3 [ "identificador" => "xres763846" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec765218" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres763845" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec765217" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Current concept of Alzheimer's disease: a lack of unanimity" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Historical perspective of Alzheimer's disease" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Alzheimer's disease or dementia-Alzheimer syndrome?" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Pathophysiology: abolition of the amyloid hypothesis?" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Prevention of Alzheimer's disease and its biological plausibility" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Risk factors and preventive factors of sporadic Alzheimer's disease and dementia" ] 11 => array:2 [ "identificador" => "sec0040" "titulo" => "Population trials in preventing dementia and Alzheimer's disease" ] 12 => array:2 [ "identificador" => "sec0045" "titulo" => "Conflicts of interest" ] 13 => array:2 [ "identificador" => "xack254109" "titulo" => "Acknowledgements" ] 14 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-01-25" "fechaAceptado" => "2016-05-09" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec765218" "palabras" => array:6 [ 0 => "Alzheimer's disease" 1 => "Alzheimer's syndrome" 2 => "Dementia" 3 => "Prevention of dementia" 4 => "Risk factors" 5 => "Alzheimer's disease prevention trials" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec765217" "palabras" => array:6 [ 0 => "Enfermedad de Alzheimer" 1 => "Síndrome de Alzheimer" 2 => "Demencia" 3 => "Prevención de la demencia" 4 => "Factores de riesgo" 5 => "Ensayos de prevención de la enfermedad de Alzheimer" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "This review proposes a more optimistic view of Alzheimer's disease (AD), in contrast to that contributed by the ageing of the population and the failure of potentially curative therapies (vaccines and others). Treatment failure is likely due to the fact that AD gestates in the brain for decades but manifests in old age. This review updates the concept of AD and presents the results of recent studies that show that primary prevention can reduce the incidence and delay the onset of the disease. Half of all cases of AD are potentially preventable through education, the control of cardiovascular risk factors, the promotion of healthy lifestyles and specific drug treatments. These approaches could substantially reduce the future incidence rate of this disease." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Esta revisión propone una visión más optimista de la enfermedad de Alzheimer (EA), en contraposición a la que el envejecimiento poblacional y el fracaso de terapias potencialmente curativas (vacunas y otras) han contribuido a ofrecer. El fracaso terapéutico se debe, verosímilmente, a que la EA se gesta en el cerebro durante décadas, aunque se manifieste en la vejez. En esta revisión se actualiza el concepto de EA y se recogen los resultados de estudios recientes que muestran que la prevención primaria podría reducir la incidencia, o retrasar la aparición de la EA. La mitad de los casos de EA pueden ser potencialmente prevenibles mediante la educación, el control de los factores de riesgo cardiovascular, la promoción de estilos de vida saludables y algunos tratamientos farmacológicos que podrían conseguir una reducción sustancial de su incidencia en el futuro." ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Bermejo-Pareja F, Llamas-Velasco S, Villarejo-Galende A. Prevención de la enfermedad de Alzheimer: un camino a seguir. Rev Clin Esp. 2016;216:495–503." ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "Extension of the conference Healthcare research into Alzheimer's disease: A promising Future, of FBP, in the III International Symposium “Developments in Healthcare Research into Alzheimer's Disease”. Salamanca. Spain. June. 2015." ] ] "multimedia" => array:3 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Source: <a class="elsevierStyleInterRef" id="intr0005" href="http://www.ncbi.nlm.nih.gov/pubmed/">http://www.ncbi.nlm.nih.gov/pubmed/</a> accessed January 2015." "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1626 "Ancho" => 2575 "Tamanyo" => 155312 ] ] "descripcion" => array:1 [ "en" => "References on the prevention of Alzheimer's disease." ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "AD, Alzheimer's disease; CSF, cerebrospinal fluid; CT, computed tomography; EEG, electroencephalogram; NINCDS-ADRDA, National Institute of Neurological Disorders and Stroke/Alzheimer's disease and Related Disorders Association.Sources: McKhann et al.<a class="elsevierStyleCrossRef" href="#bib0570">34</a> and McKhann et al.<a class="elsevierStyleCrossRef" href="#bib0585">37</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Probable AD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Presence of dementia (documented with neuropsychological tests) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Progressive evolution \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lack of impaired consciousness (alert) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Start between 40 and 90 years \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Absence of other diseases that could explain the dementia \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">The diagnosis is strengthened by the presence of \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Progressive impairment of cortical functions \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Family history of dementia \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">No biochemical abnormalities in the CSF \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Normal EEG or with nonspecific changes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cerebral atrophy in the brain CT \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Data that make the diagnosis unlikely \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sudden onset \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Early motor focal findings (seizures, paresis, gait disorders) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Possible AD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Progressive dementia in the absence of other causes that could explain the condition \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Can occur in the presence of a systemic or cerebral disorder that provokes dementia but of unlikely causality in this case \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">In research studies, in the presence of a severe and progressive isolated cognitive deficiency and lacking other identifiable causes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AD determined or defined \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Data of probable AD plus histological evidence of AD \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1261823.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Criteria for the diagnosis of Alzheimer's disease (NINCDS-ADRDA)." ] ] 2 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "AD, Alzheimer's disease; BMI, body mass index; PF, protection factors; RF, risk factors; VRF, vascular risk factors." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Unmodifiable \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age, sex and brain size \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Parental: maternal education \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Genetics: ApoE4 and other uncommon alleles, family history of sporadic AD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Partially modifiable \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Epigenetic: environment–gene interactions (poorly understood) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Modifiable \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Fetal RFs: maternal hyponutrition, low birth weight? \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Childhood and adolescent RFs: low educational level, low socioeconomic level, obesity \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Adulthood and old age \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">VRF: BMI (obesity), diabetes mellitus<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a>, arterial hypertension, smoking, arteriosclerosis, stroke, heart disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">. Lifestyle: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">- PF: physical activity, continuing education, intellectual and social activity \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">- Nutritional: high intake of n-3 fatty acids, Mediterranean diet and other healthy diets? Coffee intake and moderate alcohol intake? \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">- Diseases: general anesthesia? Severe head trauma, poor general health? Depression? \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">- Miscellaneous: high homocysteine levels? \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sensory disorders: blindness, deafness? and social isolation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Environmental toxins: pesticides and others \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1261822.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "A number of studies specify that it is insulin-resistant diabetes. 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Alzheimer's disease prevention: A way forward

Prevención de la enfermedad de Alzheimer: un camino a seguir

F. Bermejo-Parejaa,b,c, S. Llamas-Velascoa,d,

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laisset@hotmail.com

Corresponding author.

, A. Villarejo-Galendec,d

a Imas12 (Instituto de Investigación Hospital Universitario 12 de Octubre), Madrid, Spain

b Cátedra Extraordinaria de Alzheimer y enfermedades Neurodegenerativas, Departamento de Medicina, Facultad de Medicina, Universidad Complutense, Madrid, Spain

c CIBERNED, Instituto de Investigación Carlos III, Madrid, Spain

d Departamento de Neurología, Hospital Universitario 12 de Octubre, Madrid, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall">The prevalence of dementia is high in the over 60-year-old population &#40;5&#8211;7&#37;&#41;&#44; and the most common form is Alzheimer&#39;s disease &#40;AD&#41; &#40;65&#8211;80&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">1&#8211;3</span></a> Dementia and AD constitute a real public health problem&#44;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">4</span></a> with a predicted increase in the immediate future due to the aging of the population&#44; increased survival&#44; which will result in increased demand for medical and social care&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">4&#8211;6</span></a> The problem is compounded by a lack of immediate perspectives for healing and the distinct lack of progress in developing effective drugs&#46;<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">7&#44;8</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In the last 3 decades&#44; significant effort has been dedicated to clinical&#44; basic and experimental &#40;mice transgenic&#41; research into AD&#44; which has led to numerous therapeutic trials with a countless number of drugs that have required large investments&#44; resulting in cognitive and behavioral benefits of low intensity and duration&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">8</span></a> Nonpharmacological therapies for AD have also shown slight efficacy during the time they are performed but are difficult to implement and have not substantially changed outcomes&#46;<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">9&#44;10</span></a> Drugs tested both in primary &#40;preclinical AD&#41; and secondary &#40;predementia cognitive decline or mild cognitive impairment &#91;MCI&#93;&#41; prevention have not been successfull&#46;<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">8&#44;11</span></a> In this less than encouraging situation&#44; long-term data from population cohorts have shown a reduction in the incidence rate and prevalence of dementia and EA&#46;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">12&#44;13</span></a> Various studies have calculated that if the main risk factors &#40;RFs&#41; for dementia and AD could be suppressed&#44; their incidence rate could be cut by a third&#46;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">12&#44;14</span></a> These optimistic data have led to investment in research on the preventive aspects of AD&#44; both individual and societal &#40;public health&#41;&#44; in the United States of America<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">15</span></a> and in the European Union&#44; through the establishment of the European Dementia Prevention Initiative&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">16</span></a> We should therefore be aware of the possibilities for preventing AD&#44;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">12&#8211;19</span></a> given that they provide a way forward&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Current concept of Alzheimer&#39;s disease&#58; a lack of unanimity</span><p id="par0015" class="elsevierStylePara elsevierViewall">There is relative unanimity in that AD is a neurodegenerative disease resulting from the accumulation of misfolded proteins&#58; the beta-amyloid &#40;&#946;A&#41; peptide&#44; which is found in the extracellular senile plaques &#40;SP&#41;&#44; and the hyperphosphorylated tau protein&#44; which is established in fibrillar accumulations in the neuronal soma&#44; constituting neurofibrillary degeneration &#40;NFD&#41; or neurofibrillary tangles&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">20</span></a> There are 2 types of AD&#58; &#40;1&#41; the familial form &#40;FAD&#41;&#44; which is usually early onset&#44; produced by less prevalent monogenic abnormalities &#40;1&#37; of AD cases&#41; in 1 of the 3 genes &#40;amyloid precursor protein gene&#44; PS1 or PS2&#41;&#59; and &#40;2&#41; the sporadic or idiopathic AD &#40;SAD&#41;&#44; in which 99&#37; of cases fit and is most commonly senile&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">21</span></a> FAD has been interpreted as a &#946;A deposit disease&#46; The products of altered genes induce the toxic brain deposit&#44; which triggers an &#8220;amyloid cascade&#8221; that is responsible for the other abnormalities&#46; This hypothesis&#44; however&#44; has been postulated for both types of AD&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">22</span></a> However&#44; the biological substrate of SAD appears to differ from that of FAD&#44; which would explain the failure of antiamyloid therapies&#46;<a class="elsevierStyleCrossRefs" href="#bib0500"><span class="elsevierStyleSup">20&#44;23</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">For SAD&#44; genetic RFs have also been described &#40;one of which&#44; the E4 allele of the apolipoprotein E gene&#44; is almost universal except in sub-Saharan Africans&#41;&#44; as well as numerous susceptibility alleles &#40;of risk and protection&#41; &#40;see <a id="intr0015" class="elsevierStyleInterRef" href="http://www.alzgene.org/">www&#46;alzgene&#46;org</a>&#44; which updates the references to these alleles&#41;&#46; There are also poorly understood hereditary traits that are possibly due to epigenetic mechanisms&#46;<a class="elsevierStyleCrossRefs" href="#bib0520"><span class="elsevierStyleSup">24&#44;25</span></a> SAD is therefore a complex neurodegenerative disease&#44; influenced by polygenic and epigenetic mechanisms<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">25</span></a> and by environmental factors&#46; There is certain unanimity on the pathogenic mechanisms that lead to the clinical expression of SAD&#46; AD &#40;both FAD and SAD&#41; are believed to be the consequence of the slow &#40;decades&#41; and progressive accumulation of NFD and SPs that&#44; when they exceed a certain brain reserve threshold &#40;brain size and neuron quantity&#41; and cognitive threshold &#40;complexity of neural network associated with intelligence and education&#41;&#44; manifest insidiously as dementia&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">26</span></a> Other disorders affect SAD&#44; including neuronal and synaptic loss&#44; hippocampal atrophy&#44; vascular abnormalities and age-related changes&#44; which add up to its adverse effect on the cognitive reserve&#46;<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">27&#8211;30</span></a> However&#44; there is no agreement on the primary molecular processes of SAD&#44; whose range extends from mechanisms that hold a vascular hypothesis<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">31</span></a> to cellular lesions by oxidation&#44; cell cycle abnormalities<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">32</span></a> and systemic mechanisms&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">33</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">From a clinical perspective&#44; there is greater consensus on the diagnostic criteria&#46; In 1984&#44; McKhann et al&#46;&#44; along with several AD associations such as the National Institute of Neurological Disorders and Stroke&#47;Alzheimer&#39;s disease and Related Disorders Association&#44; agreed on a series of criteria &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41; that enabled the diagnosis of AD to be classified as <span class="elsevierStyleItalic">possible</span> &#40;when present in the absence of another dementia etiology&#41;&#59; <span class="elsevierStyleItalic">probable</span> &#40;when certain clinical characteristics are added to the previous situation&#41;&#59; and <span class="elsevierStyleItalic">defined</span> &#40;probable symptoms and histological confirmation&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">34</span></a> This classification has been shown effective in pathological studies &#40;good sensitivity and moderate specificity&#41;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">35</span></a> and has been employed for more than 25 years for the clinical diagnosis&#46; However&#44; the lack of a pathological gold standard<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">27&#8211;30</span></a> and the lack of efficacy in the immunoactive therapies &#40;although they remove the &#946;A deposits in SAD&#41;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">36</span></a> have resulted in an update to this classification&#44;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">37</span></a> which currently includes a prodromal SAD phase &#40;MCI&#41; and the construct &#40;only for research purposes&#41; of preclinical AD&#46;<a class="elsevierStyleCrossRefs" href="#bib0590"><span class="elsevierStyleSup">38&#44;39</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">Preclinical AD is defined as the absence of cognitive decline&#44; with positive biomarkers in cerebrospinal fluid &#40;reduction of &#946;A and increase in tau&#41; or detection of &#946;A accumulation in the brain through magnetic resonance imaging or contrast-enhanced positron emission tomography&#46; A number of authors also accept subclinical memory loss&#46; The purpose of this definition is to be able to test drugs both in stages of predementia &#40;MCI&#41; and at-risk preclinical AD&#46;<a class="elsevierStyleCrossRefs" href="#bib0585"><span class="elsevierStyleSup">37&#8211;40</span></a> The introduction of biomarkers in AD has not yet standardized either the techniques or the importance of its various findings &#40;neuroimaging or biochemical&#41; nor are they a guarantee of progression to AD&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">40</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Historical perspective of Alzheimer&#39;s disease</span><p id="par0035" class="elsevierStylePara elsevierViewall">At the start of the 20th century&#44; dementia was an uncommon condition that typically appeared in senescence &#40;the mean life expectancy of the population was scarcely above 40 years&#41;&#46; The condition was believed to be caused by a deficient cerebrovascular supply &#40;once secondary causes&#44; such as progressive general paralysis&#44; had been ruled out&#41;&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Alois Alzheimer described a case of dementia in 1907 in a 51-year-old woman &#40;presenile for being younger than 65 years&#41; whose brain showed a new lesion&#44; the NFD&#46; The other histological trait characteristic of dementia in senescence&#44; SPs&#44; was described by Fischer &#40;a member of the Pick school in Prague&#44; a rival of the Frankfurt school headed by Kraepelin and Alzheimer&#41;&#46; For a number of authors&#44; the birth of AD was due to the historical quirk of Kraepelin &#40;powerful head of the Frankfurt school&#41; who wanted a professorship and a new disease&#44; presenile dementia&#44; for his disciple Alzheimer&#46;<a class="elsevierStyleCrossRefs" href="#bib0605"><span class="elsevierStyleSup">41&#44;42</span></a> It has been suggested that the initial case could have been leukodystrophy&#46;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">43</span></a> Kraepelin had an essentialist concept of mental diseases&#46; He considered them clinical conditions and natural diseases and separate from each other&#44; a concept that has been communicated over time&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">42</span></a> The separation of senile and presenile dementia of Alzheimer persisted up to the end of the 60s&#44; when a number of studies<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">44</span></a> showed that pathologically&#44; both types of dementia &#40;presenile and senile&#41; were indistinguishable if they present SPs and NFD&#46; It was thus agreed in 1978&#44; during a meeting of specialists in the US National Institutes of Health&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">45</span></a> AD would have a specific clinical condition that includes memory loss and slow&#44; progressive cognitive decline&#44; with no motor signs and with a histology characterized by the presence of SPs and NFD&#46; This Cartesian separation of AD dementia from the other types of senile dementia has been questioned in the 21st century by community pathological studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">27&#8211;30</span></a> In these studies&#44; what is diagnosed as SAD is a heterogeneous condition with 75&#8211;80&#37; of cases with mixed lesions &#40;vascular&#44; type AD and others&#41; and very few pure cases &#40;vascular&#44; type AD and other neurodegenerative diseases&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">27&#44;29&#44;30</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Alzheimer&#39;s disease or dementia-Alzheimer syndrome&#63;</span><p id="par0045" class="elsevierStylePara elsevierViewall">There is no pathological gold standard for AD&#46; The criterion of the presence of SPs and NFD is insufficient&#44;<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">27&#8211;30</span></a> despite the position held by a number of authors&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">46</span></a> Neither the clinical condition nor the recent biological or neuroimaging biomarkers have the capacity to establish an unequivocal diagnosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">19&#44;40</span></a> This situation greatly complicates the diagnosis of SAD as a well-defined nosological condition&#46; In reality&#44; we often only have a diagnosis of SAD based on probabilistic clinical and pathological criteria&#46;<a class="elsevierStyleCrossRefs" href="#bib0570"><span class="elsevierStyleSup">34&#44;37</span></a> SPs and NFD are not specific to AD&#46; SPs can be found in a third of elderly persons with normal cognition&#44; as can NFD&#44; whose intensity increases with aging and can be found in other diseases &#40;Down syndrome&#44; various parkinsonisms&#44; dementia pugilistica and other rarer neurodegenerative disease&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">27&#8211;30</span></a> As has been discussed previously&#44; the histology of AD &#40;NFD and SP&#41; is rarely unique&#46; AD is often found intermixed with histological traits from other neurodegenerative disorders &#40;such as &#945;-synuclein deposits&#44; a phenomenon accentuated in individuals older than 80 years<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">27&#8211;30</span></a>&#41; and other not fully characterized disorders&#46;<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">28&#8211;47</span></a> Numerous authors also consider SPs and NFD a terminal pathological result common to several types of dementia&#59; that is&#44; residual biological lesions of previous dysmetabolic processes and with no causal pathophysiological capacity&#46;<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">31&#8211;33&#44;36&#44;48&#44;49</span></a> This viewpoint&#44; coupled with the clinical-pathological discrepancy of AD-type lesions &#40;10&#8211;15&#37; of patients with histopathology findings of AD but no dementia and another 10&#8211;15&#37; of cases of dementia or clinical SAD with no underlying disease to explain it&#41; has caused a shift in opinion&#46;<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">28&#44;47</span></a> SAD should be considered a dementia-Alzheimer syndrome and not a well differentiated condition as Kraepelin thought&#46; Senile cognitive decline&#44; MCI and AD-dementia constitute a continuum in which clear separations are contrived&#46;<a class="elsevierStyleCrossRefs" href="#bib0650"><span class="elsevierStyleSup">50&#44;51</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Pathophysiology&#58; abolition of the amyloid hypothesis&#63;</span><p id="par0050" class="elsevierStylePara elsevierViewall">The amyloid hypothesis has been the dominant explanation for the pathophysiology of AD&#46; The finding of disorders in the gene for the amyloid precursor protein&#44; the precursor of &#946;A in FAD&#44; originated this hypothesis&#44; which&#44; in essence&#44; predicts that the accumulation of &#946;A is toxic for the brain and generates NFD and other abnormalities&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">21</span></a> The inability of transgenic mice studies to reproduce human AD &#40;with associated neuron loss&#41; and the failure of immune therapy against the accumulation of &#946;A<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">36</span></a> has resulted in 2 conflicting schools of thought&#58; one that considers that this hypothesis is uncertain &#40;although the accumulation of &#946;A can be an epiphenomenon associated with SAD&#41;<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">31&#8211;33&#44;36&#44;48</span></a> and the other&#44; which holds that preclinical therapy &#40;against the accumulation of &#946;A&#41; could be effective and that this theory should not be rejected without this test&#46;<a class="elsevierStyleCrossRefs" href="#bib0505"><span class="elsevierStyleSup">21&#44;38&#44;39</span></a> To complicate the issue further&#44; studies with various animal models have shown that &#946;A&#44; tau and &#945;-synuclein can be transmitted transcellularly&#59; i&#46;e&#46;&#44; that its propagation would be analogous to that which occurs in prion diseases &#40;caused by misfolded proteins&#41;&#46; This finding has led to the suggestion of similar mechanisms for protein accumulation in neurodegenerative disease&#44; although there is no evidence of transmission of AD among humans&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">52</span></a> It is not surprising that&#44; in this context of lack of pathophysiological knowledge&#44; it is difficult to envision a curative treatment that impedes &#40;or eliminates&#41; the formation of AD lesions&#44; and primary prevention is seriously considered the best option&#46;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">12&#8211;14&#44;16&#44;19&#44;51</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Prevention of Alzheimer&#39;s disease and its biological plausibility</span><p id="par0055" class="elsevierStylePara elsevierViewall">Several observations have indicated that the incidence and prevalence &#40;relative to the existing group of elderly persons&#41; of dementia is decreasing in developed countries&#46; The first study on this issue&#44; which proceeded from the Long Term Care Study conducted in the US between 1982 and 2004&#44; observed a reduction in the functional disability in the elderly&#44; caused essentially by a decrease in mixed dementia&#46;<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">53</span></a> Several additional studies confirmed the reduction in cognitive impairment and dementia in The Netherlands&#44;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">54</span></a> Spain&#44;<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">55</span></a> Sweden<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">56</span></a> and England&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">57</span></a> All of these studies have shown a decrease in dementia in the younger cohorts during the period 1990-2008&#46; It is worth noting that a study in Danish nonagenarians &#40;1910 and 1915 cohorts&#41; reported that the youngest &#40;born in 1915&#41; were cognitively better and had greater survival&#46;<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">58</span></a> In 2016&#44; the Framingham study &#40;children of the first cohort&#41; showed a clear reduction in the incidence of dementia over 3 decades &#40;primary prevention result&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">59</span></a> A neuropathological finding in Switzerland from a 30-year follow-up agreed with the clinical data&#58; in the last years of this period&#44; the brain &#946;A burden decreased&#46;<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">60</span></a> It is logical to assume&#44; by analogy with what occurs in other diseases&#44; that progress in controlling the RFs of dementia and AD is responsible for this decrease&#46; Thus&#44; historical data indicate the benefit of controlling the RFs of infectious diseases &#40;e&#46;g&#46;&#44; the number of tuberculosis cases decreased significantly before the emergence of streptomycin due to improved public health and hygiene&#41;<a class="elsevierStyleCrossRef" href="#bib0705"><span class="elsevierStyleSup">61</span></a> and vascular and lifestyle RFs &#40;reducing the incidence of noncommunicable diseases&#44; such as ischemic heart disease&#44; stroke and breast cancer&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">62</span></a> The same relationship for SAD is biologically plausible&#44;<a class="elsevierStyleCrossRefs" href="#bib0710"><span class="elsevierStyleSup">62&#44;63</span></a> although we will have to wait for the results of experimental clinical trials currently underway&#44; whose initial results are encouraging&#46;<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">16&#44;19</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Risk factors and preventive factors of sporadic Alzheimer&#39;s disease and dementia</span><p id="par0060" class="elsevierStylePara elsevierViewall">There has been an increase in publications on preventing AD since the beginning of this century &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#44; although they are heterogeneous in terms of their analysis objectives &#40;cognitive impairment&#44; dementia and SAD&#41; and analyzed RFs&#47;preventive factors &#40;PFs&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">12&#8211;19</span></a> A synthesis of RFs and PFs in AD is presented in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#44; although it does not differentiate as to whether the RFs and PFs correspond to dementia in general or to SAD in particular&#44; given that numerous studies do not make this distinction&#46; This scheme is followed by a simple description&#44; starting with the nonpreventable items and continuing with the more potentially modifiable&#46; Additionally&#44; the RFs and PFs have been reported over the course of a lifetime to show that SAD is a chronic disease in which intergenerational and prenatal factors are involved&#46;<a class="elsevierStyleCrossRefs" href="#bib0710"><span class="elsevierStyleSup">62&#44;63</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">Aging is a universal RF in cognitive impairment&#44; dementia and AD&#44;<a class="elsevierStyleCrossRefs" href="#bib0465"><span class="elsevierStyleSup">13&#8211;23</span></a> but it is doubtful that the female sex is an RF for SAD &#40;although SAD is more prevalent in women due to their greater longevity&#41;&#46; However&#44; the slight increase in the incidence rate in women in a number of cohorts could be due to their lower educational level compared with men or to the greater selective mortality of this condition in adulthood&#46;<a class="elsevierStyleCrossRefs" href="#bib0720"><span class="elsevierStyleSup">64&#44;65</span></a> Regardless&#44; age and sex &#40;as with genetics&#41; are not modifiable factors&#44; although they can be attenuated by epigenetic changes &#40;see <a id="intr0020" class="elsevierStyleInterRef" href="http://www.nida.nih.gov/">www&#46;nida&#46;nih&#46;gov</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0525"><span class="elsevierStyleSup">25&#44;66</span></a> A number of familial factors can be important&#46; Among them&#44; the degree of maternal education appears the most relevant&#44;<a class="elsevierStyleCrossRefs" href="#bib0730"><span class="elsevierStyleSup">66&#44;67</span></a> although not on its own given that SAD&#44; as with other complex diseases&#44; starts its gestation in the womb &#40;Baker hypothesis&#41;&#46; This hypothesis underlines the significant role of poor fetal nutrition and low birth weight in the subsequent development of diseases &#40;vascular&#44; diabetes and others&#41;<a class="elsevierStyleCrossRefs" href="#bib0525"><span class="elsevierStyleSup">25&#44;66&#44;67</span></a> and has been refined by a scientific movement that has analyzed the importance of factors in gestation and the first era of infancy &#40;developmental plasticity&#41; and the epigenetic mechanisms that regulate them&#46; This movement &#40;scientific associations and journals&#41; has provided animal studies &#40;including primates&#41; and has launched pediatric cohorts to study their hypothesis &#40;see&#44; <a id="intr0025" class="elsevierStyleInterRef" href="http://www.dohadsoc.org/">www&#46;dohadsoc&#46;org</a>&#41;&#46; Their main theoretical premise is that there is an intergenerational transmission &#40;epigenetics&#41; of physiological susceptibility to certain diseases that manifest in later life&#46;<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">68</span></a> Their practical observations include low education &#40;less than 8 years of studies and especially illiteracy&#41; is an RF for dementia and SAD&#44; detectable in populations that at the beginning of the 20th century had high illiteracy rates such as the Spanish&#44; which was apparent in the Spanish NEDICES study<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">69</span></a> &#91;see <a id="intr0030" class="elsevierStyleInterRef" href="http://www.ciberned.es/estudio">www&#46;ciberned&#46;es&#47;estudio</a> NEDICES&#93;&#46; Education is a consistent RF&#47;PF in the reviews on the topic&#44;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">12&#8211;14&#44;16&#8211;19&#44;69</span></a> particularly in developed countries&#44; and is included in a systematic review &#40;education and dementia&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">70</span></a> Nevertheless&#44; this relationship is complex&#46; Education can be a marker of low socioeconomic status &#40;poor nutrition and intellectual stimulation in brain development or pediatric stages&#41; or form part of the cognitive reserve&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">26</span></a> Education is also a shifting factor&#44; which can increase at various periods of life&#46; In the NEDICES cohort&#44; verbal intelligence was better able to predict cognitive performance that years of study or socioeconomic status&#46;<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">71</span></a> Education has a biological effect on the brain &#40;increase in synaptic connections and others&#41;&#44; which constitutes the cognitive reserve that impedes or delays the clinical manifestation of dementia&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">26</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Most population cohorts have shown that the main vascular RFs present in adulthood &#40;obesity&#44; arterial hypertension&#44; diabetes&#44; metabolic syndrome&#44; smoking&#44; heart disease and stroke&#41; are RFs for the onset of dementia and SAD in the elderly&#44;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">12&#44;13&#44;16&#8211;18</span></a> although it is debated whether vascular lesions in the brain are synergistic or promoters of SAD&#46;<a class="elsevierStyleCrossRefs" href="#bib0650"><span class="elsevierStyleSup">50&#44;69&#44;72</span></a> Of these RFs&#44; uncontrolled arterial hypertension is the primary RF&#44; because it not only occurs in middle age but also in old age&#46;<a class="elsevierStyleCrossRefs" href="#bib0485"><span class="elsevierStyleSup">17&#44;73</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Physical activity is a PF of dementia and SAD for which there is almost unanimous agreement&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">14&#44;16&#8211;18</span></a> As has been stated by the World Health Organization and several state health agencies&#44; physical inactivity is the fourth leading RF for disease in the world&#44; and it lowers defenses against various cardiovascular and other chronic diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0770"><span class="elsevierStyleSup">74</span></a> There are abundant studies in the literature concerning physical inactivity as a RF for SAD&#44; even in old age &#40;for example&#44; data from the NEDICES cohort show that the elderly who engage in physical exercise had a lower risk of dementia than those who were sedentary&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0775"><span class="elsevierStyleSup">75</span></a> There are experimental and anthropological data that support its biological plausibility&#46;<a class="elsevierStyleCrossRef" href="#bib0780"><span class="elsevierStyleSup">76</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Other RFs&#47;PFs require more studies to demonstrate their preventive capacity in SAD&#44; given that despite the abundant observational data&#44; there are few trials that support them&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">18</span></a> Nevertheless&#44; diet&#44; social integration and participation in social and cognitive activities over one&#39;s lifetime&#44; even in old age&#44; have been indicated as PFs for dementia and SAD&#46;<a class="elsevierStyleCrossRefs" href="#bib0780"><span class="elsevierStyleSup">76&#44;77</span></a> Diet is more difficult to investigate&#44; given that it changes over the course of one&#39;s life and is subject to cultural determinants and socioeconomic status&#46; On this subject&#44; the studies are very heterogeneous&#44; but the more recent ones suggest that diets rich in fruits&#44; vegetables&#44; proteins of plant origin&#44; fish&#44; omega-3 fatty acids&#44; olive oil and little meat&#44; such as the Mediterranean diet &#40;and other healthy diets such as Dietary Approaches to Stop Hypertension and the Japanese diet&#41;&#44; are associated with a lower incidence of cardiovascular disease and cognitive decline&#46; It is logical to assume that these diets would lower the incidence of SAD&#44; although data are more scarce on this subject&#46;<a class="elsevierStyleCrossRef" href="#bib0790"><span class="elsevierStyleSup">78</span></a> The tests showing that a regular intake of coffee&#44; moderate quantities of alcohol&#44; green tea or chocolate are PFs for dementia and SAD are less apparent&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">14&#44;78</span></a> Severe head trauma is a RF for dementia and possibly AD&#46; Sensory deficits &#40;blindness&#44; deafness&#41;&#44; sleep disorders and depression can be RFs or the initial manifestations of SAD&#46;<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">16&#8211;19</span></a> Exposure to toxins &#40;insecticides and others&#41; appears to be a RF in the genesis of SAD and other neurodegenerative diseases&#46;<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">16&#8211;18&#44;79</span></a> There are numerous studies that have indicated that poor systemic health is associated with cognitive impairment&#47;dementia and SAD&#46; This association could be explained as a lack of vitality associated with aging but could be a RF&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">33</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Population trials in preventing dementia and Alzheimer&#39;s disease</span><p id="par0085" class="elsevierStylePara elsevierViewall">Primary prevention trials for SAD are not a pipe dream and are underway in the US and Europe&#46; The European trials are being conducted under the auspices of the European Dementia Prevention Initiative &#40;see <a id="intr0035" class="elsevierStyleInterRef" href="http://www.edpi.org/">www&#46;edpi&#46;org</a>&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">16</span></a> with the international collaboration of 3 countries that include 3 large population cohorts&#46; The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability &#40;FINGER&#41;&#44; which introduced multidimensional actions &#40;nutritional&#44; vascular RF control and others&#41;&#44; is a randomized study with 1200 participants in a 7-year follow-up&#46; The Prevention of Dementia by Intensive Vascular Care &#40;preDIVA&#41; study is sponsored by the University of Amsterdam and consists of the 6-year follow-up of a cohort of 3534 individuals in whom 2 types of therapies are being assessed&#58; a control group with standard treatment and another with a specific therapy &#40;nurses who monitor drug therapy&#44; lifestyle and cardiovascular RFs&#41;&#46; The French Multidomain Alzheimer Prevention &#40;MAPT&#41; study conducts a 3-year intervention years and a subsequent 5-year follow-up of a cohort of 1600 participants older than 70 years&#44; with mainly nutrition and physical activity counseling&#46; Additionally&#44; there is the Healthy Aging Through Internet Counselling in the Elderly &#40;HATICE&#41;&#44; an online project that provides therapeutic counseling &#40;randomized&#41; in 3 participating countries &#40;Finland&#44; The Netherlands and France&#41; &#40;<a id="intr0040" class="elsevierStyleInterRef" href="http://www.edpi.org/">www&#46;edpi&#46;org</a>&#41;&#46; Only the FINGER study has promising preliminary data&#58; the treated group had better performance on cognitive tests than the control group&#46;<a class="elsevierStyleCrossRef" href="#bib0800"><span class="elsevierStyleSup">80</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">In conclusion&#44; the accumulated data indicate that SAD is not a clinical-pathological condition as well differentiated as believed from the time of Kraepelin to 2 decades ago&#46; SAD is beginning to be thought of as a clinical condition that encompasses a set of conditions&#44; which include SPs&#44; NFD&#44; vascular lesions &#40;macroscopic and microscopic&#41; and neurodegenerative disease of various types&#44; which gestate in the brain for several decades and clinically manifest in old age&#46; Genetic&#44; epigenetic and environmental factors are involved in the establishment of SAD&#46; The condition&#39;s inner pathophysiology is unknown&#44; and it is therefore unlikely that a drug to impede or delay its onset will appear within the foreseeable future&#46; In this scenario&#44; an early preventive approach is necessary&#46; The control of likely RFs &#40;education&#44; physical activity and vascular and lifestyle RFs such as diet and tobacco&#41; should be performed from childhood&#44; a period during which the greatest brain growth occurs&#46; The control of RFs&#47;PFs has biological plausibility and a number of reliable observations&#44;<a class="elsevierStyleCrossRefs" href="#bib0695"><span class="elsevierStyleSup">59&#44;60</span></a> although it has not been confirmed in trials&#46; Several trials are underway that control numerous RFs&#44; drug-associated or not&#44; and their initial results are promising&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conflicts of interest</span><p id="par0095" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">This review proposes a more optimistic view of Alzheimer&#39;s disease &#40;AD&#41;&#44; in contrast to that contributed by the ageing of the population and the failure of potentially curative therapies &#40;vaccines and others&#41;&#46; Treatment failure is likely due to the fact that AD gestates in the brain for decades but manifests in old age&#46; This review updates the concept of AD and presents the results of recent studies that show that primary prevention can reduce the incidence and delay the onset of the disease&#46; Half of all cases of AD are potentially preventable through education&#44; the control of cardiovascular risk factors&#44; the promotion of healthy lifestyles and specific drug treatments&#46; These approaches could substantially reduce the future incidence rate of this disease&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Esta revisi&#243;n propone una visi&#243;n m&#225;s optimista de la enfermedad de Alzheimer &#40;EA&#41;&#44; en contraposici&#243;n a la que el envejecimiento poblacional y el fracaso de terapias potencialmente curativas &#40;vacunas y otras&#41; han contribuido a ofrecer&#46; El fracaso terap&#233;utico se debe&#44; veros&#237;milmente&#44; a que la EA se gesta en el cerebro durante d&#233;cadas&#44; aunque se manifieste en la vejez&#46; En esta revisi&#243;n se actualiza el concepto de EA y se recogen los resultados de estudios recientes que muestran que la prevenci&#243;n primaria podr&#237;a reducir la incidencia&#44; o retrasar la aparici&#243;n de la EA&#46; La mitad de los casos de EA pueden ser potencialmente prevenibles mediante la educaci&#243;n&#44; el control de los factores de riesgo cardiovascular&#44; la promoci&#243;n de estilos de vida saludables y algunos tratamientos farmacol&#243;gicos que podr&#237;an conseguir una reducci&#243;n sustancial de su incidencia en el futuro&#46;</p></span>"
      ]
    ]
    "NotaPie" => array:2 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Please cite this article as&#58; Bermejo-Pareja F&#44; Llamas-Velasco S&#44; Villarejo-Galende A&#46; Prevenci&#243;n de la enfermedad de Alzheimer&#58; un camino a seguir&#46; Rev Clin Esp&#46; 2016&#59;216&#58;495&#8211;503&#46;</p>"
      ]
      1 => array:2 [
        "etiqueta" => "&#9734;&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Extension of the conference <span class="elsevierStyleItalic">Healthcare research into Alzheimer&#39;s disease&#58; A promising Future</span>&#44; of FBP&#44; in the III International Symposium &#8220;<span class="elsevierStyleItalic">Developments in Healthcare Research into Alzheimer&#39;s Disease</span>&#8221;&#46; Salamanca&#46; Spain&#46; June&#46; 2015&#46;</p>"
      ]
    ]
    "multimedia" => array:3 [
      0 => array:8 [
        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "fuente" => "Source&#58; <a class="elsevierStyleInterRef" id="intr0005" href="http://www.ncbi.nlm.nih.gov/pubmed/">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;</a> accessed January 2015&#46;"
        "figura" => array:1 [
          0 => array:4 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">References on the prevention of Alzheimer&#39;s disease&#46;</p>"
        ]
      ]
      1 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
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            "identificador" => "at1"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">AD&#44; Alzheimer&#39;s disease&#59; CSF&#44; cerebrospinal fluid&#59; CT&#44; computed tomography&#59; EEG&#44; electroencephalogram&#59; NINCDS-ADRDA&#44; National Institute of Neurological Disorders and Stroke&#47;Alzheimer&#39;s disease and Related Disorders Association&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Sources&#58; McKhann et al&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">34</span></a> and McKhann et al&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">37</span></a></p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Probable AD</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Presence of dementia &#40;documented with neuropsychological tests&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Progressive evolution</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Lack of impaired consciousness &#40;alert&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Start between 40 and 90 years</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Absence of other diseases that could explain the dementia</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">The diagnosis is strengthened by the presence of</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Progressive impairment of cortical functions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Family history of dementia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>No biochemical abnormalities in the CSF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Normal EEG or with nonspecific changes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Cerebral atrophy in the brain CT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Data that make the diagnosis unlikely</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Sudden onset&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Early motor focal findings &#40;seizures&#44; paresis&#44; gait disorders&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Possible AD</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Progressive dementia in the absence of other causes that could explain the condition</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Can occur in the presence of a systemic or cerebral disorder that provokes dementia but of unlikely causality in this case</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">In research studies&#44; in the presence of a severe and progressive isolated cognitive deficiency and lacking other identifiable causes</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">AD determined or defined</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Data of probable AD plus histological evidence of AD</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Criteria for the diagnosis of Alzheimer&#39;s disease &#40;NINCDS-ADRDA&#41;&#46;</p>"
        ]
      ]
      2 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
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        "tabla" => array:3 [
          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">AD&#44; Alzheimer&#39;s disease&#59; BMI&#44; body mass index&#59; PF&#44; protection factors&#59; RF&#44; risk factors&#59; VRF&#44; vascular risk factors&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Unmodifiable</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age&#44; sex and brain size&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Parental&#58;</span> maternal education&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Genetics&#58;</span> ApoE4 and other uncommon alleles&#44; family history of sporadic AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Partially modifiable</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Epigenetic&#58;</span> environment&#8211;gene interactions &#40;poorly understood&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Modifiable</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Fetal RFs&#58;</span> maternal hyponutrition&#44; low birth weight&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Childhood and adolescent RFs&#58;</span> low educational level&#44; low socioeconomic level&#44; obesity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Adulthood and old age</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>VRF&#58; BMI &#40;obesity&#41;&#44; diabetes mellitus<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&#44; arterial hypertension&#44; smoking&#44; arteriosclerosis&#44; stroke&#44; heart disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#46; Lifestyle&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>- PF&#58; physical activity&#44; continuing education&#44; intellectual and social activity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>- Nutritional&#58; high intake of n-3 fatty acids&#44; Mediterranean diet and other healthy diets&#63; Coffee intake and moderate alcohol intake&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>- Diseases&#58; general anesthesia&#63; Severe head trauma&#44; poor general health&#63; Depression&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>- Miscellaneous&#58; high homocysteine levels&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Sensory disorders&#58; blindness&#44; deafness&#63; and social isolation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Environmental toxins&#58; pesticides and others&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">A number of studies specify that it is insulin-resistant diabetes&#46;</p> <p class="elsevierStyleNotepara" id="npar0010">Sources&#58; <a class="elsevierStyleCrossRefs" href="#bib0470">14&#8211;24</a>&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Main risk factors and preventive factors in sporadic Alzheimer&#39;s disease&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:80 [
            0 => array:3 [
              "identificador" => "bib0405"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The global prevalence of dementia&#58; a systematic review and metaanalysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "M&#46; Prince"
                            1 => "R&#46; Bryce"
                            2 => "E&#46; Albanese"
                            3 => "A&#46; Wimo"
                            4 => "W&#46; Ribeiro"
                            5 => "P&#46;C&#46; Ferri"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jalz.2012.11.007"
                      "Revista" => array:6 [
                        "tituloSerie" => "Alzheimers Dement"
                        "fecha" => "2013"
                        "volumen" => "9"
                        "paginaInicial" => "63"
                        "paginaFinal" => "75"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23305823"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0410"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Consistency of clinical diagnosis of dementia in NEDICES&#44; a population-based longitudinal study in Spain"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "F&#46; Bermejo-Pareja"
                            1 => "J&#46; Benito-Le&#243;n"
                            2 => "S&#46; Vega"
                            3 => "J&#46; Olazar&#225;n"
                            4 => "M&#46; de Toledo"
                            5 => "J&#46; D&#237;az-Guzm&#225;n"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1177/0891988709335794"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Geriatr Psychiatry Neurol"
                        "fecha" => "2009"
                        "volumen" => "22"
                        "paginaInicial" => "246"
                        "paginaFinal" => "255"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19417217"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0415"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prevalence of dementia and major dementia subtypes in Spanish populations&#58; a reanalysis of dementia prevalence surveys&#44; 1990&#8211;2008"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; De Pedro-Cuesta"
                            1 => "J&#46; Virues-Ortega"
                            2 => "S&#46; Vega"
                            3 => "M&#46; Seijo-Martinez"
                            4 => "P&#46; Saz"
                            5 => "F&#46; Rodriguez"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/1471-2377-9-55"
                      "Revista" => array:5 [
                        "tituloSerie" => "BMC Neurol"
                        "fecha" => "2009"
                        "volumen" => "9"
                        "paginaInicial" => "55"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19840375"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0420"
              "etiqueta" => "4"
              "referencia" => array:1 [
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Article information

ISSN: 22548874
Original language: English

DOI:10.1016/j.rceng.2016.06.006

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