Alzheimer’s disease (AD) is a neurodegenerative disorder of unknown aetiology, with the exception of a small percentage of cases related to mutations of the amyloid precursor protein (APP), presenilins and other, as yet unknown, genes.1,2 For sporadic cases of AD, many environmental and genetic risk factor modifiers have been described, but – with a few exceptions – most of them remain controversial. Most of these studies are observational in different populations,3 since case–control studies, which were very popular in the 1980s, showed bias.4 Unconfirmed associations of environmental risk factors or genetic traits with AD could be due to several factors, such as inclusion of a percentage of patients with erroneous diagnoses (a significant number of patients with clinical diagnoses of AD are found to have mixed pathologies or other diseases at post mortem examination), inadequate size or special characteristics of the sample or excessively permissive statistical evaluation.
Spain has several characteristics that make it adequate for such studies. Although in the past Spain has seen significant waves of immigration, in the last millennium immigration has not occurred at high enough levels to influence the genetic background of its population. Spain also has high-quality standards of universally free healthcare. Several studies have been published as meta-analyses5 or local population studies.6–9 In this article we review some of these and other, more recent, studies.
Environmental Risk Modifiers
A summary of the available data is shown in Table 1, which presents results about environmental modifiers of the risk of AD in other countries as well as in Spain.3,5–14 We shall review briefly the most important results obtained in the studies performed in Spain. The most important studies reviewed in this work are those in Zaragoza and Pamplona,5 Gerona,6 the Basque Country,9 Central Spain7 and Leganes.8 A brief summary of these studies is presented in Table 2.
As in other studies around the world, epidemiological investigations performed in Spain have confirmed the increased risk associated with age in AD. This effect is almost exponential until >90 years of age, when it appears to reduce its impact.10,15
Illiteracy and poor schooling are associated with an increased risk of dementia and AD in most studies in which the population has a mixed (assorted) educational background.3,10,13,14 The same findings are reported in Spain.5–9 However, most of these studies did not differentiate between education and its co-variates, such as low socioeconomic status, possible pre-natal and developmental nutrition, lack of social and familial intellectual stimulation and others.16–19
The majority of population-based studies performed in Spain have shown an increased risk of AD in females.6,8,9 In the Neurological Disorders in Central Spain (NEDICES) study this relationship was not found.7 This has been proposed as the basis for a neuro-protective role of oestrogens, even prompting the use of these compounds in clinical trials, but a very confusing factor is the fact that senile females (around the turn of the millennium this was defined as >65 years of age) had a much lower level of education than contemporary males. Studies such as the Ashkelon study where gender was corrected for by education have not shown a difference in the risk at different ages. As a meta-analysis pointed out,10 there was no gender difference in dementia incidence, but women tended to have a higher incidence of AD in very old age and men tended to have a higher incidence of vascular dementia (VD) at younger ages. Another finding is that the pathological expression of AD could have more clinical relevance in women.20
Cardiovascular Risk Factors
The presence of cardiovascular risk factors has been considered, by definition, as an important criterion for the differentiation between AD and VD.11 However, neuropathological studies have shown that such differentiation is unwarranted.12 Even using the conventional international criteria for the diagnosis of AD and VD, all of the epidemiological studies have shown that high blood pressure, diabetes and previous history of stroke are risk factors for dementia in general, and VD and AD in particular.21–24 It also appears that the risk of these factors is additive.7,24,25 Some meta-analyses have shown that the treatment of high blood pressure reduces the risk of dementia.26
Several studies have shown that physical exercise reduces the risk of dementia and AD.3,27 Again, this co-variates with other social factors. The role of exercise has been downplayed on the basis of considering an excessively sedentary lifestyle as a prodromic symptom of dementia.27 The beneficial effects of exercise in transgenic mice28 and in patients29 do not support this scepticism. Intellectual and social activities are considered protective against dementia and AD.13 There is only one preliminary Spanish study on this topic in Spain.30
Epidemiological Studies of Environmental Risk Factors for Dementia and Alzheimer’s Disease in Spain
A summary of the most important epidemiological studies performed in Spain is presented in Table 2. These studies are difficult to compare because of their different methodologies, but the results obtained are essentially similar.
Epidemiological Studies of Genetic Risk Factors for Dementia and Azheimer’s Disease in Spain
Dozens of studies on genetic risk factors for dementia and AD have been performed in Spain, and a summary of the most important is presented in Table 3. The study performed by Ampuero et al.8 was a population study and the results were validated in a pathological series. The other studies are case–control studies in clinical cohorts of patients without pathological confirmation of the diagnoses.
These studies of different genetic risk factors performed in case– control clinical cohorts are very promising since they provide an enormous amount of data. However, interpretation of the data is difficult due to the lack of definitive diagnoses and to statistical limitations. Therefore, the results require confirmation by other studies, clinical–pathological series and functional investigations.
In summary, the impact of the ApoEε4 allele appears as a significant risk factor for AD, while the other risk modifiers, although they have statistically significant value, did not demonstrate beyond any doubt their clinical relevance. The requirements of the optimal studies of risk factors are summarised in Table 4. ■