Nongenetic Risk Factors For Alzheimers Disease

Age is clearly the most important risk factor for AD. Alois Alzheimer originally described this disorder as a form of premature aging.58 Many studies have implicated low education as a risk factor for cognitive impairment in elderly people.59,60 Although Filley et al61 and Beard et al62 did not find that education provides protection against dementia, it must be recalled that their subjects had relatively high schooling levels. Education may enhance brain reserve by increasing synaptic density in the neo-cortical association cortex.63 Individuals with higher levels of education may have greater brain capacity (i.e. more cortical synapses) than individuals with lower levels of education, and thus have more resistance to the deterioration caused by the progressive synaptic and neuronal loss associated with aging than do less educated individuals.24

Our study in Wadi Ara confirmed an association between education and dementia. However, these factors could only partly explain the very high rates of dementia observed by us in this Arab population. Most of the elderly Arab population in Wadi Ara received no formal education (illiteracy rate >70%), and therefore we used illiteracy or literacy for analysis in the contingency tables but a continuous variable (number of school years) in the logistic regression model. Thus, it is possible to suggest that the protective effect of education is non-linear, with a marked effect related to low schooling and a minimal additional effect beyond 6-8 years in school.22

One confounding factor that should be discussed as being responsible for the correlation between education and dementia is smoking. In most developed countries, smoking is more frequent in lower socio-economic classes. The higher prevalence of dementia among less educated groups is, therefore, the reverse of what would be expected if smoking were protective. In addition, people who had more school years usually belong to higher social classes and are more likely to take better care of their health in general, e.g. blood pressure control and hyperlipi-demia. These in turn may affect the development of dementia.

The relationship of smoking to dementia is complex. Epidemiological studies have established a negative association between cigarette smoking and the prevalence of DAT.64 In these studies, the risk of DAT in non-smokers has generally been about twice that of smokers. This negative association has been interpreted as suggesting that cigarette smoking exerts a biological neuroprotective influence against the development of AD.65 Before accepting this seemingly counterintuitive interpretation, however, we should remember the golden rule of statistics: association alone, no matter how significant, does not, cannot, and will not ever mean causation.66,67 Moreover, other epidemiological studies found nonsignificant negative correlations between DAT and smoking.68,69 Ford et al70 also reported that the prevalence of cognitive impairment was lower among smokers than among non-smokers, but logistic regression, adjusted for age, income, and gender, showed this difference to be non-significant (OR = 0.73; 95% CI 0.42-1.29). For several reasons, it is difficult to generalize concerning the studies carried out to date. Case-control studies have often included cases from hospital series and may not represent dementia cases in the general population.

Moreover, prevalence studies are susceptible to survival bias if demented patients who smoked had a relatively higher mortality than non-demented smokers. This would produce an image of a protective effect of smoking against DAT. Cases referred to a memory clinic may be more likely to have other diseases (perhaps due to smoking) and thus poorer survival than healthy controls. Population-based studies on prevalent cases may have similar biases due to shorter survival of smokers. Population-based prospective studies focusing on smoking in relation to cognitive impairment failed to confirm the protective effect of smoking on the occurrence of DAT.68,71,72

Thus most previous studies which suggested a protective effect of smoking on AD were case-control studies based on prevalent cases. In contrast, the findings of several incidence studies suggest that smoking is a risk factor for the development of DAT (Tables 35.4 and 35.5).

Several studies suggest an association between head injury and AD,73,74 but these observations have remained inconsistent because most studies have been cross-sectional. The risk of AD and dementia increased with severity of head injury.75 The observed dose-response pattern may support a causal effect of head injury in the pathogenesis of AD and dementia.

Epidemiological studies have suggested that female gender is an independent risk factor for AD,76 even allowing for the increased proportion of women in the older, at-risk population, which is caused by their relative longevity, with a female/male prevalence ratio in DAT of 2 :1.76 In our study we also observed a higher prevalence of dementia among females, with a female/male prevalence ratio in DAT of 1.7:1 (Table 35.6). Possible explanations for the higher prevalence of DAT among women could include unrecognized environmental influences, hormonal effects such as late effects of the menopause, or the use of estrogens by

Table 35.4 Association between smoking and DAT in prevalence studies in different countries

Prevalence studies

OR (95% CI)

Cleveland, Ohio, USA70

Manhattan, USA110

Rotterdam, The Netherlands64

Stockholm, Sweden72

Wadi Ara (first prevalence study, 1995)

Wadi Ara (second prevalence study, 2000)

OR 0.73 (95% CI = 0.4-1.3), NS RR 0.7 (95% CI = 0.5-1.1), protective effect OR 0.8 (95% CI = 0.6-1.0), protective effect OR 0.6 (95% Cl = 0.4-1.0), protective effect OR 0.7 (95% CI = 0.4-1.2), NS OR 0.88 (95% CI = 0.5-1.5), NS

Table 35.5 Association between smoking and DAT in different incidence studies in different countries

Incidence studies

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