L Fratiglioni, Aging Research Center, Karolinska Institutet, Gävlegatan 16, S -113 30 Stockholm, Sweden. E-mail: firstname.lastname@example.org, Phone: +46-86-905-818, Fax: +46-86-906-889.
Dementia is an acquired highly disabling syndrome common among elderly people. Alzheimer's disease is the most frequent type of dementia, and its prevalence is rapidly increasing due to the aging of populations. Therefore, the need to find effective preventive means is pressing. Population studies allow identification of risk/protective factors for dementia/Alzheimer's disease, thus leading to preventive strategies that can be implemented in the general population to reduce the incidence of this disorder. Presented here is an overview of the main findings of epidemiological studies on nutritional factors and nutrition-related pathological conditions, as related to dementia and Alzheimer's disease.
Brain aging is characterized by the progressive and gradual accumulation over time of detrimental changes in structure and function, which leads to an increased risk of age-related brain disorders, such as dementia. Dementia is a clinical syndrome characterized by multiple cognitive deficits severe enough to interfere with daily functioning, including social and professional activities. Dementia, together with hypertension, is the most common chronic disorder in persons aged 75 years and older1 and is one of the major causes of disability, institutionalization, and death.2–4 Due to the aging of populations worldwide, dementia has become an emerging public health issue not only in developed countries but also in less developed regions. Currently, more than 24 million people in the world have dementia, but this number will double in 20 years.5
It is well known that dementia syndrome can be induced by many different underlying diseases and that a differential diagnosis may be difficult for several reasons. Alzheimer's disease (AD) is considered the most common cause of dementia, accounting for 60–70% of all dementia cases, while vascular dementia is the second most frequent type.6 AD as well as other dementia subtypes shows heterogeneity and overlap in clinical and pathological features. Different dementing disorders may make a common contribution or interact in causing dementia symptoms. Thus, rather than viewing, for example, AD and vascular dementia as dichotomous entities, it may be more relevant to consider the role of their additive or synergistic interactions in producing dementia syndrome.7 The combination of pathological changes in the brains of old people due to AD and vascular dementia is extremely common, making mixed dementia probably the most common form of dementia in advanced age. When the presence of vascular comorbidity is taken into account to reclassify dementia subtypes, only 47% of cases previously diagnosed as AD are confirmed, whereas 53% are classified as mixed dementia cases.8 Following this new perspective, this review will focus on dementia syndrome rather than on specific dementing disorders.
The etiology of dementia has been studied extensively over the last decade with the ultimate goal of identifying efficacious prevention and treatment strategies. All this effort has led to the broad consensus that dementing disorders are caused by several interrelated mechanisms in which the interaction of genetic and environmental factors plays the major role.6 The development and clinical manifestation of dementia syndrome in old age may be explained by individual differences in environmental and social factors experienced not only in late or adult life (such as life habits, medical disorders, and occupational complexity) but also in childhood and youth.6 Several researchers have adopted a “life-course perspective” when studying dementia risk and its major determinants. This approach seeks to identify time windows when exposures have their greatest effect on outcome and to determine whether cumulative exposures could have integrative or additive effects over the life course. The concept of “time period at exposure” might be highly relevant for chronic disorders with a long period of latency, such as dementia. A certain factor might increase the risk of the disease if a subject is exposed during a specific time period, whereas the same factor may show a different effect in other life periods, due to interactions with other factors or to selective survival.
In contrast with the well-known age-related cognitive decline in nondemented subjects that starts in young adulthood, dementia is very uncommon before the age of 60 years, and prevalence and incidence rise exponentially only after 70 years of age. This suggests the pathological processes in the brain need to accumulate to a certain extent that can cause cognitive impairment sufficiently severe to become a clinically manifested dementia syndrome. This level of cognitive impairment constitutes a threshold that marks the clinical onset of dementia. Avoiding or postponing this threshold represents one of the major goals in dementia research. In recent years, it has become possible to delineate clear etiological hypotheses and to identify some possible preventive strategies against dementia.
PREVENTION OF DEMENTIA: CURRENT EVIDENCE
Old age and genetic susceptibility are the only well-established risk factors for dementia, but other hypotheses have been suggested and explored in longitudinal population-based studies such as the Kungsholmen Project.9 In Figure 1 the major etiological hypotheses for dementia are summarized together with the related factors that have been investigated. Factors can increase (risk factor) or decrease (protective factor) the risk of dementia and can be active in different periods of the lifespan. In this life-course model, four life periods are considered. Among these hypotheses, strong epidemiological evidence supports the genetic, vascular, and psychosocial hypotheses in dementia as well as the notion that active engagement in mental, physical, and social activities in old age may postpone the onset of dementia by increasing the cognitive reserve.
First-degree relatives of AD patients have a higher lifetime risk of developing AD than the general population or relatives of nondemented subjects. Both genetic and environmental factors contribute to the phenomenon of familial aggregation. The ApoE ε4 allele is the only established susceptibility gene for both early- and late-onset AD. The risky effect of the ApoE ε4 allele decreases with increasing age, and after the age of 75 years 15–20% of AD cases are attributable to the ApoE genotype. Familial aggregation of dementia and AD can be only partially explained by ApoE polymorphism, suggesting the potential involvement of other genes. Indeed, several candidate genes (e.g., insulin-degrading enzyme and angiotensin-I converting enzyme gene) have been investigated, but the reports are sporadic and findings are inconsistent.
Numerous studies suggest vascular risk factors, such as midlife hypertension, diabetes, and cerebrovascular disease, contribute to the development of dementia. Based on the vascular hypothesis, controlling high blood pressure in middle age, avoiding midlife obesity, and appropriately treating diabetes have been proposed to be the major intervention actions against dementia. In the Kungsholmen Project of people aged 75 years and older, high systolic pressure, low diastolic pressure, low pulse pressure, diabetes and prediabetes, stroke, and heart failure were identified as relevant risk factors for dementia and AD. In a recent study, the independent as well as the combined effect of these vascular factors on dementia were verified by aggregating the factors in two risk profiles on the basis of two major biological mechanisms: the atherosclerotic and hypoperfusion hypotheses.10 All components of the two vascular profiles were significantly or marginally associated with an increased risk of dementia. The risk of dementia was increased with increasing scores of atherosclerotic and hypoperfusion profile in a dose-response manner; subjects with an atherosclerotic or hypoperfusion profile score ≥ 2 had an approximately twofold increased risk for dementia. There was no evidence of statistical interaction between vascular profiles and use of blood-pressure-lowering drugs and ApoE genotype.
Evidence from both epidemiological and biological studies indicates that factors acting at different periods across the life course and of an intellectually stimulating nature may contribute to increasing the neural reserve; this may, in turn, promote functionally more efficient cognitive networks to cope with brain pathology and delay the onset of clinical manifestations of dementia. Such factors include high education, adult-life occupational work complexity as well as late-life rich social network, and intellectually stimulating activities.11,12 Although physical exercise may reduce the risk of brain damage due to atherosclerosis, the relevance of physical activity itself remains a subject of debate, as most physical activities also include social and mental components. Complex leisure activities with physical, mental, and social components seem to have the most beneficial effect in reducing the risk of dementia.11 In a recent study, low neuroticism in combination with high extraversion was identified as the personality trait associated with the lowest dementia risk.13 The most likely outcome of a mentally, physically, and socially active life, as it relates to a reduced risk of dementia, is to postpone the onset of the dementia syndrome: Even delaying dementia onset by 5 years would reduce the prevalence of dementia by half and substantially decrease the number of dementia cases in the community.
DIETARY AND NUTRITIONAL FACTORS IN DEMENTIA
As shown in Figure 1, dietary factors play a relevant role in the development of dementia through at least two pathways: vascular mechanisms and oxidative stress. Current epidemiological evidence is summarized in Table 1.
Table 1. Summary of the main longitudinal studies on dietary and diet-related factors and dementia.
Nutritional and diet-related factors
Studies reporting an association
Studies reporting no association
Diet and vascular risk in dementia
High serum cholesterol
Midlife (positive association): Alonso et al. (2009)16; Kivipelto et al. (2002)14; Solomon et al. (2007)24; Whitmer et al. (2005)15 Late life (negative association): Mielke et al. (2005)21; Reitz et al. (2004)22; Romas et al. (1999)23; Stewart et al. (2007)25
Midlife: Kalmijn et al. (2000)17; Tan et al. (2003)18 Late life: Hayden et al. (2006)19; Li et al. (2004)20
Saturated, polyunsaturated, and fish-related fats
Saturated fat (risk factor): Kalmijn et al. (1997)28; Laitinen et al. (2006)29; Morris et al. (2003)30 Polyunsaturated and fish-related fats (protective factor): Barberger-Gateau et al. (2007)32; Huang et al. (2005)33; Morris et al. (2003)30; Schaefer et al. (2006)34
Saturated fat: Barberger-Gateau et al. (2002)31; Engelhart et al. (2002)35 Polyunsaturated and fish-related fats: Devore et al. (2009)36; Engelhart et al. (2002)35; Kroger et al. (2009)37
Diabetes and prediabetes
Akomolafe et al. (2006)38; Arvanitakis et al. (2004)39; Leibson et al. (1997)40; Luchsinger et al. (2001)41; Ott et al. (1999)42; Xu et al. (2004)43, (2007)46, (2009)45
Obesity or overweight
Midlife (positive association): Chiang et al. (2007)54; Fitzpatrick et al. (2009)47; Hassing et al. (2009)51; Kivipelto et al. (2005)48; Rosengren et al. (2005)49; Whitmer et al. (2005)50 Late life (negative association): Atti et al. (2008)55; Dahl et al. (2008)56; Fitzpatrick et al. (2009)47; Stewart et al. (2005)52; West et al. (2009)57
Midlife: Alonso et al. (2009)16; Stewart et al. (2005)52
Vitamin B6, B12, folate, and homocysteine
Fischer et al. (2008)62; Kivipelto et al. (2009)70; Luchsinger et al. (2007)65; Maxwell et al. (2002)63; Ravaglia et al. (2005)71; Seshadri et al. (2002)72; Wang et al. (2001)64
Aisen et al. (2008)74; Eussen et al. (2006)68; Luchsinger et al. (2004)73; McMahon et al. (2006)75; Morris et al. (2006)66
Diet and oxidative stress in dementia
Antioxidant vitamins (C, E)
Engelhart et al. (2002)77; Helmer et al. (2003)86; Morris et al. (2005)78; Zandi et al. (2004)79
Kang et al. (2008)87; Laurin et al. (2004)80; Luchsinger et al. (2003)81; Masaki et al. (2000)82
Mediterranean diet, fruit and vegetables
Barberger-Gateau et al. (2007)32; Dai et al. (2006)90; Scarmeas et al. (2006)91; (2009)92,93
Eskelinen et al. (2009)99 (midlife, coffee drinking, protective effect); Lindsay et al. (2002)97; Maia et al. (2002)96
Eskelinen et al. (2009)99 (midlife, tea drinking); Ritchie et al. (2007)95; Tyas et al. (2001)98
DIET AND VASCULAR RISK IN DEMENTIA
Dietary and (high) serum cholesterol
An association between elevated serum cholesterol levels in midlife and increased risk of late-life AD has been reported from some studies14–16 but not confirmed by others.17,18 Controversial findings were also reported when serum cholesterol was examined in late life. Several cohort studies with a relatively short period of follow-up found no association of late-life total cholesterol level with risk of AD and dementia19,20 or even an association of high total cholesterol with decreased AD risk.21–23 The importance of the pattern of change in cholesterol levels after midlife has been recently highlighted by two studies with long follow-up periods. These studies found that a decline in plasma total cholesterol after midlife may be associated with the risk of cognitive decline, dementia, and AD in late life.24,25 These findings suggest a bidirectional relationship exists between serum total cholesterol and dementia; high total serum cholesterol in midlife seems to be a risk factor for dementia and AD in advanced age, while decreasing serum cholesterol after midlife may reflect ongoing disease processes and represent a marker of early stages in the development of dementia and AD.
The use of statins (cholesterol-lowering drugs) in relation to dementia has been investigated in several community studies, but with mixed findings. Some observational studies suggest they have a protective effect, while others did not, and clinical trials of the use of statins for the prevention of cognitive decline or dementia mainly reported no effects.26,27
Unsaturated fats and fish
Fatty acids could be involved in the development of dementia through various mechanisms such as atherosclerosis and inflammation. High intake of foods with rich saturated fats in association with an elevated risk of dementia and cognitive decline is suggested by some community-based prospective studies,28–30 but not by others.31 On the other hand, a diet with high polyunsaturated and fish-related fats is known to be associated with a low risk of vascular diseases; thus, it may be plausible to extend the beneficial effects to the prevention of dementia. In support of this hypothesis, high intake of fish and omega-3 polyunsaturated fatty acid has shown to be associated with a decreased risk of dementia.30,32,33 In the follow-up study of the Framingham cohort, a high level of plasma docosahexaenoic acid was associated with a lower risk of AD and dementia,34 and the consumption of more than two servings of fish per week was also associated with a 50% reduced risk of dementia. Plasma docosahexaenoic acid was significantly correlated with fish intake in this cohort. By contrast, in the Rotterdam study cohort, neither high intake of total and saturated fats nor low intake of polyunsaturated fatty acids was associated with the risk of dementia and its main subtypes.35,36 Similarly, no association between omega-3 fatty acids and risk of dementia was found in the Canadian Study of Health and Aging.37 In the Three-City Study, the relationship between plasma levels of docosahexaenoic acid and incident dementia was not confirmed, while a lower risk of dementia in subjects with higher plasma concentrations of eicosapentaenoic acid was reported.32
Diabetes mellitus and prediabetes
Dietary factors appear to play a relevant role in diabetes and impaired glucose tolerance. Increased risk of both vascular and degenerative dementias among persons with diabetes was reported from several longitudinal studies38–43 and confirmed by a systematic review.44 The risky effect seems to be stronger when diabetes occurs at midlife rather than in late life.45 Borderline diabetes (prediabetes) or impaired glucose tolerance is also linked to an increased risk of dementia and AD in very old people.46 Such an association may reflect a direct effect of hyperglycemia on neurodegenerative changes in the brain or an effect of hyperinsulinemia, or it may be due to the diabetes-related comorbidities such as hypertension and dyslipidemia. Other pathophysiological mechanisms through which diabetes could increase the risk of dementia include oxidative stress, advanced glycation end-products, and inflammatory cytokines.
Obesity or overweight
Obesity has been investigated intensively in relation to dementia risk. From these studies, a lifespan-dependent association pattern emerges such that a midlife higher body mass index (BMI) is a risk factor for late-life dementia and AD, whereas an accelerated decline in BMI during late life may anticipate the occurrence of dementia. A higher BMI at the age of around 50 years was related to increased risk of dementia in late life in several studies.47–51 However, this was not confirmed in a cohort of Japanese-American men; instead, a greater decline in BMI was detected in this group approximately 10 years prior to dementia onset.52 One longitudinal study with a long follow-up period found a gender-specific relationship between BMI and dementia incidence: for men, being underweight at 30, 40, or 45 years increased the risk of developing dementia, while for women, obesity (BMI > 30) at the same ages was related to increased incidence of dementia.53 Another study found a J-shaped relationship between midlife BMI and dementia risk, with both underweight and overweight subjects having increased risk of dementia.54 In advanced age, a positive association between obesity (BMI > 30) and a reduced risk of dementia has been suggested by a longitudinal study,47 whereas more studies found that being overweight or obese (BMI ≥ 25) in late life was related to a reduced risk of developing cognitive decline, dementia, and AD.55–58 In line with this finding, a low BMI in late life has been related to a higher risk of dementia developing over a subsequent period of 5–6 years,47,59 and other follow-up studies of elderly people suggest accelerated decline in BMI is associated with subsequent development of dementia.55,60,61 Weight loss may result from predementia apathy, reduced olfactory function, difficulty in eating, or inadequate nutrition due to cognitive impairment or incipient dementia. In this context, low BMI and weight loss in advanced age can be interpreted as markers for preclinical dementia.
Homocysteine and vitamins B6, B12, and folate
Inconsistent results have been reported for the association of vitamins B12, B6, and folate with dementia. Some longitudinal studies suggested an inverse association of low serum vitamin B12 and folate with increased risk of dementia and AD,62–64 and one survey showed that high folate intake may decrease the risk of AD, independently of vitamin B6 and B1265; however, another investigation did not find any association between dietary intakes of folate, vitamin B12, and vitamin B6 with incident AD.66 Experimental studies support the hypothesis of a protective effect of folate against cognitive deterioration.67 However, a Cochrane systematic review and randomized clinical trials concluded that folic acid and vitamin B12 supplementations have no benefits on cognition, even though folate plus vitamin B12 is effective at reducing serum homocysteine.68,69 Hyperhomocysteinemia is a known risk factor for cardiac and cerebrovascular diseases, and it may contribute to dementia through vascular mechanisms or neurotoxic effects. An association between high serum homocysteine and increased risk of dementia and cognitive decline is suggested in several cohort studies70–72 but not confirmed by others.73 Recent controlled clinical trials do not support the hypothesis that homocysteine lowering with high-dose B vitamin and folate supplements improves cognitive performance or slows cognitive decline in individuals with mild-to-moderate AD.74,75
DIET AND OXIDATIVE STRESS IN DEMENTIA
Oxidative stress is generally accepted as a central process in dementia and AD pathophysiology,76 and antioxidant micronutrients have been investigated in relation to dementia and AD. Some follow-up studies have reported a decrease in dementia risk associated with increasing dietary or supplementary intake of vitamins E and C.77–79 However, other studies showed dietary or supplemental intake of vitamin E or other antioxidants (vitamin C, carotenoids) in either middle age or late life was not associated with the risk of dementia.80–82 In some studies, both demented and cognitively impaired persons have been shown to have, in comparison with cognitively healthy persons, reduced concentrations of plasma antioxidant micronutrients,83,84 whereas plasma levels of vitamins A and E were not associated with dementia and cognitive decline in the Rotterdam Study.85 In the PAQUID (Personnes Agées Quid) study, an increased risk for dementia in subjects with lower vitamin E (α-tocopherol) plasma levels was reported,86 while another prospective study did not find a relation between plasma levels of several antioxidants (α- and γ-tocopherol, carotenoids, and retinol) and dementia when antioxidant levels were measured in women in their mid 60s and cognitive function was assessed 10 years later.87 Finally, randomized clinical trials with relatively short-term use of vitamin E supplementation in dementia prevention and therapy provided conflicting results.88 This could be explained, at least in part, by the fact that only α-tocopherol has been used, while the vitamin E family includes eight natural vitamin E forms, some of which seem to have stronger neuroprotective properties.89
A balanced intake of micro- and macronutrients through diet could be more effective than supplements in terms of neuroprotection. Several community studies found high consumption of fruit and vegetables to be associated with a reduced risk of dementia and AD.32,90 A composite dietary pattern evaluated in relation to the risk of AD and dementia is the Mediterranean diet, which is characterized by high intakes of legumes, cereals, and fruit and vegetables rich in antioxidants, high intakes of unsaturated fatty acids and fish, and low intakes of red meat and poultry, often accompanied by low-to-moderate intake of wine. This Mediterranean-type dietary pattern may act against cognitive impairment and dementia through cerebrovascular mechanisms. In support of this hypothesis, a few follow-up studies have shown that stricter adherence to the Mediterranean-type diet is associated with reduced risk of dementia and AD91,92; it is also associated with a lower risk of developing mild cognitive impairment as well as a reduction in the risk of conversion from mild cognitive impairment to AD.93 However, a French study found no association between higher adherence to a Mediterranean diet and risk of incident dementia.94
Coffee and tea
Caffeine-containing beverages, like coffee and tea, have been hypothesized to be neuroprotective both for the presence of caffeine and because they are a source of antioxidants. Despite positive results of experimental studies, observational studies on long-term coffee and tea consumption and the risk of cognitive decline and dementia are limited and have produced inconsistent results. The Three-Cities Study showed a protective role for high caffeine intake in maintaining cognitive abilities in women but found no association with dementia or AD incidence over 4 years.95 In a case-control study, subjects with AD had a lower average daily intake of caffeine during the 20 years that preceded the diagnosis,96 and a longitudinal study suggested daily coffee consumption was associated with a lower risk of developing AD, while no association with tea consumption was detected.97 Another study showed no association between coffee or tea use and incidence of AD in elderly subjects.98 A recent long-follow-up longitudinal study of a Finnish cohort showed that coffee intake at midlife was associated with a reduced risk of dementia in late life when subjects were compared with those who drank no or only little coffee; the lowest risk for dementia was found in people who drank 3–5 cups per day.99 In the same study, tea drinking in midlife was not associated with risk of dementia.
Preventing or postponing the onset of dementia and delaying or slowing its progression would lead to a consequent improvement of health status and quality of life in the elderly. Indeed, even delaying dementia onset by 5 years would reduce the prevalence of dementia by half and substantially decrease the burden of the disease in the community; this would confer great benefits at both the individual and the societal levels. Epidemiology is the leading research area in assessing protective and risk factors for age-related cognitive decline and dementia, and its ultimate objectives are to develop efficacious strategies toward primary prevention and to reduce the incidence of this disorder or to delay its onset and progression. Several risk and protective factors for dementia and AD have been investigated in population studies. While the scientific evidence is still inconsistent for some of the associated factors, evidence is strong enough for others (e.g., vascular and dietary factors), which can lead to preventive strategies that can be developed and implemented in the general population. Based on the evidence concerning nutritional factors and disorders related to diet, possible strategies for primary prevention at this time include avoiding midlife obesity and appropriately treating diabetes. Intervention studies have also demonstrated that diabetes can be prevented by changing lifestyles in terms of dietary habits and physical activities.100
Some studies also show that people who maintain tight control over their blood glucose levels tend to score better on tests of cognitive function than those with poorly controlled diabetes. Thus, the intervention measures targeting diabetes could also reduce the risk of dementia. Active use of these intervention strategies over the life course, together with other primary intervention measures (e.g., optimal control of other vascular factors, such as hypertension, and engagement in social, physical, and mentally stimulating activities), should dramatically improve one's chances of retaining a highly functional brain in late life.
Funding: This work was supported in part by grants from the Swedish Council for Working Life and Social Research, the Swedish Research Council in Medicine, the Swedish Brain Power Initiatives, the Alzheimer Foundation in Sweden, and the Gamla Tjänarinnor Foundation.
Declaration of interest. The authors have no relevant interests to declare.