Home > News > Environmental and Genetic Risk Factors for Alzheimer’s Disease in Spain
Alzheimer's Disease & Dementia
Read Time: 4 mins

Environmental and Genetic Risk Factors for Alzheimer’s Disease in Spain

Published Online: June 4th 2011 European Neurological Review, 2009;4(2):125-128 DOI: http://doi.org/10.17925/ENR.2009.04.02.125
Authors: Israel Ampuero, Félix Bermejo-Pareja, Guillermo García Ribas, Justo García de Yébenes
Quick Links:
Abstract
Article
Article Information
Abstract:
Overview

Alzheimer’s disease is a complex neurodegenerative disorder of unknown aetiology, and an important number of cases are sporadic. To date, only some of the genetic and environmental risk factors for Alzheimer’s disease have been identified. It is very important to understand the role of environmental and genetic risk factors in Alzheimer’s disease in order to develop therapeutic strategies. For sporadic cases of Alzheimer’s disease, many environmental and genetic risk factor modifiers have been described, but – with a few exceptions – most of them remain controversial. In this article we review some studies of these risk factors in a Spanish population to identify a few directives for future studies.

Keywords

Alzheimer’s disease, environmental risk factor, genetic risk factor, age, education, cardiovascular risk factors, Spanish population

Article:

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.

Age

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

Education

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

Gender

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

Lifestyle

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. ■

Article Information:
Disclosure

The authors have no conflicts of interest to declare.

Correspondence

Justo García de Yébenes, Servicio de Neurología, Hospital Universitario ‘Ramón y Cajal’, Carretera de Colmenar, km 9,1, Madrid 28034, Spain. E: jgyebenes@yahoo.com

Received

2009-01-07T00:00:00

References

  1. Goate AM, Molecular genetics of Alzheimer’s disease, Geriatrics, 1997;52(Suppl. 2):S9–12.
  2. Grimaldi LM, Casadei VM, Ferri C, et al., Association of early-onset Alzheimer’s disease with an interleukin-1alpha gene polymorphism, Ann Neurol, 2000;47:361–5.
  3. Patterson C, Feightner J, Garcia A, MacKnight C, General risk factors for dementia: A systematic evidence review, Alzheimers Dement, 2007;3:341–7.
  4. Mortimer JA, The epidemiology of Alzheimer’s disease: beyond risk factors. In: Iqbal K, et al., Research advances in Alzheimer’s disease and related disorders, Chichester: Wiley, 1995;3–14.
  5. Fratiglioni L, Launer LJ, Andersen K, et al., Incidence of dementia and major subtypes in Europe: A collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group, Neurology, 2000;54(11 Suppl. 5): S10–15.
  6. López-Pousa S, Vilalta-Franch J, Llinás-Regla J, et al., Incidence of dementia in a rural community in Spain: the Girona cohort study, Neuroepidemiology, 2004;23: 170–77.
  7. Bermejo-Pareja F, Benito-León J, Vega S, et al., Neurological Disorders in Central Spain (NEDICES) Study Group. Incidence and subtypes of dementia in three elderly populations of central Spain, J Neurol Sci, 2008;264: 63–72.
  8. Ampuero I, Ros R, Royuela A, et al., Risk factors for dementia of Alzheimer type and aging-associated cognitive decline in a Spanish population based sample, and in brains with pathology confirmed Alzheimer’s disease, J Alzheimers Dis, 2008;14:179–91.
  9. Fernández Martínez M, Castro Flores J, Pérez de Las Heras S, et al., Risk factors for dementia in the epidemiological study of Munguialde County (Basque Country—Spain), BMC Neurol, 2008;8:39.
  10. Jorm AF, Jolley D, The incidence of dementia: a meta-analysis, Neurology, 1998;51:728–33.
  11. Launer LJ, Pathophysiology: an epidemiological perspective. In: Gauthier (ed.), Clinicial diagnosis and management of Alzheimer disease, Informa Healthcare, Abingdon, 2007;27–38.
  12. Brayne C, The elephant in the room – healthy brains in later life, epidemiology and public health, Nat Rev Neurosci, 2007;8:233–9.
  13. Coley N, Andrieu S, Gardette V, et al., Dementia prevention: methodological explanations for inconsistent results, Epidemiol Rev, 2008;30:35–66.
  14. Kalaria RN, Maestre GE, Arizaga R, et al., Alzheimer’s disease and vascular dementia in developing countries: prevalence, management, and risk factors, Lancet Neurol, 2008;7:812–26.
  15. Carrillo-Alcalá ME, Bermejo-Pareja F, Dementia in nonagenarians. Systematic review of population-based studies with Spanish data, Rev Neurol, 2008;47:347–54.
  16. Karp A, Kåreholt I, Qiu S, et al., Relation of education and occupation-based socioeconomic status to incident Alzheimer’s Disease, Am J Epidemiol, 2004;159:175–83.
  17. Mortimer JA, Borenstein AR, Gosche KM, Snowdon DA, Very early detection of Alzheimer neuropathology and the role of brain reserve in modifying its clinical expression, J Geriatr Psychiatry Neurol, 2005;18:218–23.
  18. Roe CM, Xiong C, Miller JP, Morris JC, Education and Alzheimer disease without dementia: support for the cognitive reserve hypothesis, Neurology, 2007;68:223–8.
  19. Del Ser T, Hachinski V, Merskey H, An autopsy-verified study of the effect of education on degenerative dementia, Brain, 1999;122(Pt 12):2309–19.
  20. Barnes LL, Wilson RS, Bienias JL, et al., Sex differences in the clinical manifestations of Alzheimer Disease pathology, Arch Gen Psychiatry, 2005;62:685–91.
  21. Skoog I, Gustafson D, Hypertension, hypertension clustering factors and Alzheimer’s disease, Neurol Res, 2003; 25:675–80.
  22. Stampfer MJ, Cardiovascular disease and Alzheimer’s disease: common links, J Intern Med, 2006;260:211–23.
  23. Biessels GJ, Staekenborg S, Brunner E, et al., Risk of dementia in diabetes mellitus: a systematic review, Lancet Neurol, 2006;5:64–74.
  24. Purnell C, Gao S, Callahan CM, Cardiovascular Risk Factors and Incident Alzheimer Disease: A Systematic Review of the Literature, Alzheimer Dis Assoc Disord, 2009;23(1):1–10.
  25. Luchsinger JA, Reitz C, Honig LS, et al., Aggregation of vascular risk factors and risk of incident Alzheimer disease, Neurology, 2005;65:545–51.
  26. Peters R, Beckett N, Forette F, et al., HYVET investigators.Incident dementia and blood pressure lowering in the Hypertension in the Very Elderly Trial cognitive function assessment (HYVET-COG): a double-blind, placebo controlled trial, Lancet Neurol, 2008;7:683–9.
  27. Laurin D, Verreault R, Lindsay J, et al., Physical activity and risk of cognitive impairment and dementia in elderly persons, Arch Neurol, 2001;58:498–504.
  28. Cracchiolo JR, Mori T, Nazian SJ, et al., Enhanced cognitive activity – over and above social or physical activity – is required to protect Alzheimer’s mice against cognitive impairment, reduce Abeta deposition, and increase synaptic immunoreactivity, Neurobiol Learn Mem, 2007;88:277–94.
  29. Lautenschlager NT, Cox KL, Flicker L, et al., Effect of physical activity on cognitive function in older adults at risk for Alzheimers, JAMA, 2008300:1027–37.
  30. Bermejo-Pareja F, Benito-León J, Vega S, Physical activity and risk of dementia in elderly persons: A populationbased study, Alzheimer Dis Assoc Disorders, 2006;(Suppl. 2): S100.
  31. Mateo I, Sánchez-Juan P, Rodríguez-Rodríguez E, et al., 14-3-3 zeta and tau genes interactively decrease Alzheimer’s disease risk, Dement Geriatr Cogn Disord, 2008;25(4):317–20.
  32. Combarros O, Sánchez-Juan P, Riancho JA, et al., Aromatase and interleukin-10 genetic variants interactively modulate Alzheimer’s disease risk, Neural Transm, 2008;115(6):863–7.
  33. Mateo I, Llorca J, Infante J, et al., Gene-gene interaction between 14-3-3 zeta and butyrylcholinesterase modulates Alzheimer’s disease risk, Eur J Neurol, 2008;15(3):219–22.
  34. Rodríguez-Rodríguez E, Sánchez-Juan P, et al., Interaction between CD14 and LXR beta genes modulates Alzheimer’s disease risk, J Neurol Sci, 2008;264(1–2):97–9.
  35. Llorca J, Rodríguez-Rodríguez E, Dierssen-Sotos T, et al., Meta-analysis of genetic variability in the beta-amyloid production, aggregation and degradation metabolic pathways and the risk of Alzheimer’s disease, Acta Neurol Scand, 2008;117(1):1–14.
  36. Rodríguez-Rodríguez E, Mateo I, Llorca J, et al., Association of genetic variants of ABCA1 with Alzheimer’s disease risk, Am J Med Genet B Neuropsychiatr Genet, 2007;144B(7): 964–8.
  37. Combarros O, Llorca J, Sánchez-Juan P, et al., Interaction between prion protein and interleukin-1A genes increases early-onset Alzheimer’s disease risk, J Neurol, 2007;254(1): 115–17.
  38. Combarros O, Riancho JA, Arozamena J, et al., Interaction between estrogen receptor-alpha and butyrylcholinesterase genes modulates Alzheimer’s disease risk, J Neurol, 2007;254(9):1290–92.
  39. Infante J, Llorca J, Mateo I, et al., Interaction between poly(ADP-ribose) polymerase 1 and interleukin 1A genes is associated with Alzheimer’s disease risk, Dement Geriatr Cogn Disord, 2007;23(4):215–18.
  40. Mateo I, Infante J, Llorca J, et al., Association between glycogen synthase kinase-3beta genetic polymorphism and late-onset Alzheimer’s disease, Dement Geriatr Cogn Disord, 2006;21(4):228–32.
  41. Mateo I, Infante J, Rodríguez E, et al., Interaction between dopamine beta-hydroxylase and interleukin genes increases Alzheimer’s disease risk, J Neurol Neurosurg Psychiatry, 2006;77(2):278–9.
  42. Rodríguez E, Mateo I, Llorca J, et al., Genetic interaction between two apolipoprotein E receptors increases Alzheimer’s disease risk, J Neurol, 2006;253(6):801–3.
  43. Combarros O, Infante J, Llorca J, et al., Interaction between interleukin-6 and intercellular adhesion molecule-1 genes and Alzheimer’s disease risk, J Neurol, 2005;252(4):485–7.
  44. Infante J, Sanz C, Fernández-Luna JL, et al., Gene-gene interaction between interleukin-6 and interleukin-10 reduces AD risk, Neurology, 2004;63(6):1135–6.
  45. Corder EH, Saunders AM, Strittmatter WJ, et al., Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families, Science, 1993;261(5123):828–9.

Further Resources

Share this Article
Related Content In Alzheimer's Disease & Dementia
  • Copied to clipboard!
    accredited arrow-down-editablearrow-downarrow_leftarrow-right-bluearrow-right-dark-bluearrow-right-greenarrow-right-greyarrow-right-orangearrow-right-whitearrow-right-bluearrow-up-orangeavatarcalendarchevron-down consultant-pathologist-nurseconsultant-pathologistcrosscrossdownloademailexclaimationfeedbackfiltergraph-arrowinterviewslinkmdt_iconmenumore_dots nurse-consultantpadlock patient-advocate-pathologistpatient-consultantpatientperson pharmacist-nurseplay_buttonplay-colour-tmcplay-colourAsset 1podcastprinter scenerysearch share single-doctor social_facebooksocial_googleplussocial_instagramsocial_linkedin_altsocial_linkedin_altsocial_pinterestlogo-twitter-glyph-32social_youtubeshape-star (1)tick-bluetick-orangetick-red tick-whiteticktimetranscriptup-arrowwebinar Department Location NEW TMM Corporate Services Icons-07NEW TMM Corporate Services Icons-08NEW TMM Corporate Services Icons-09NEW TMM Corporate Services Icons-10NEW TMM Corporate Services Icons-11NEW TMM Corporate Services Icons-12Salary £ TMM-Corp-Site-Icons-01TMM-Corp-Site-Icons-02TMM-Corp-Site-Icons-03TMM-Corp-Site-Icons-04TMM-Corp-Site-Icons-05TMM-Corp-Site-Icons-06TMM-Corp-Site-Icons-07TMM-Corp-Site-Icons-08TMM-Corp-Site-Icons-09TMM-Corp-Site-Icons-10TMM-Corp-Site-Icons-11TMM-Corp-Site-Icons-12TMM-Corp-Site-Icons-13TMM-Corp-Site-Icons-14TMM-Corp-Site-Icons-15TMM-Corp-Site-Icons-16TMM-Corp-Site-Icons-17TMM-Corp-Site-Icons-18TMM-Corp-Site-Icons-19TMM-Corp-Site-Icons-20TMM-Corp-Site-Icons-21TMM-Corp-Site-Icons-22TMM-Corp-Site-Icons-23TMM-Corp-Site-Icons-24TMM-Corp-Site-Icons-25TMM-Corp-Site-Icons-26TMM-Corp-Site-Icons-27TMM-Corp-Site-Icons-28TMM-Corp-Site-Icons-29TMM-Corp-Site-Icons-30TMM-Corp-Site-Icons-31TMM-Corp-Site-Icons-32TMM-Corp-Site-Icons-33TMM-Corp-Site-Icons-34TMM-Corp-Site-Icons-35TMM-Corp-Site-Icons-36TMM-Corp-Site-Icons-37TMM-Corp-Site-Icons-38TMM-Corp-Site-Icons-39TMM-Corp-Site-Icons-40TMM-Corp-Site-Icons-41TMM-Corp-Site-Icons-42TMM-Corp-Site-Icons-43TMM-Corp-Site-Icons-44TMM-Corp-Site-Icons-45TMM-Corp-Site-Icons-46TMM-Corp-Site-Icons-47TMM-Corp-Site-Icons-48TMM-Corp-Site-Icons-49TMM-Corp-Site-Icons-50TMM-Corp-Site-Icons-51TMM-Corp-Site-Icons-52TMM-Corp-Site-Icons-53TMM-Corp-Site-Icons-54TMM-Corp-Site-Icons-55TMM-Corp-Site-Icons-56TMM-Corp-Site-Icons-57TMM-Corp-Site-Icons-58TMM-Corp-Site-Icons-59TMM-Corp-Site-Icons-60TMM-Corp-Site-Icons-61TMM-Corp-Site-Icons-62TMM-Corp-Site-Icons-63TMM-Corp-Site-Icons-64TMM-Corp-Site-Icons-65TMM-Corp-Site-Icons-66TMM-Corp-Site-Icons-67TMM-Corp-Site-Icons-68TMM-Corp-Site-Icons-69TMM-Corp-Site-Icons-70TMM-Corp-Site-Icons-71TMM-Corp-Site-Icons-72