for these differences, but it is also conceivable that the variable estimates reflect real geographical differences. There are substantial differences in possible risk factors for dementia between regions. Such chronic disease risk factor variation is thought to be responsible for the wide variation seen in other diseases of older age such as cancer and cardiovascular disease (for example, differences between North and South Europe). Given the available evidence for risk factors of dementia and the pronounced variation in vascular risk factors across regions, there could be parallel variation in the incidence of dementia. In fact, the pooled analysis of eight European studies mentioned above suggests a geographical dissociation, with higher incidence rates being found among the oldest old of northwestern countries than among southern countries.6 To assess variation in incidence within country, the Medical Research Council cognitive function and ageing study (MRC CFAS) compared incidence rates among five sites with different risk patterns and mortality rates.8 As reported before, incidence was observed to rise with age, particularly above the age of 75, and continued to increase for both males and females into the oldest age groups. However, there was no convincing evidence for variation across sites, and incidence rates did not reflect the variations in the prevalence of possible risk factors in these sites. RISK FACTORS The estimates of frequency of dementia are important by themselves, as they underline the extent of the health care problem as created by dementia. Although important for health care planners, the frequency of disease in itself is not the most important issue. Rather, we need to gain insight into the mechanisms that cause dementia, to be able to develop therapeutic agents that can slow down or even cure these diseases. Risk factors are studied to find out the basic mechanisms leading to dementia. By influencing these risk factors we hope to be able to modify the course of the disease. Studies on risk factors for dementia have mainly focused on AD, as it is the most frequent cause of dementia. Age is the most well known risk factor for dementia. Studies of prevalence and incidence of dementia and AD have consistently shown an almost exponential increase with advancing age, in that estimates of both prevalence and incidence double with every five year increase in age. In addition, female sex has repeatedly been shown to be associated with an increased risk of AD, especially at old age.6 7 Other risk factors for AD include genetic and vascular factors. Genetic risk factors Only a small proportion of all individuals with dementia suffers from a familial form of dementia, caused by an autosomal dominant mutation. Mutations in several genes (including Ab precursor protein, presenilin 1, and presenilin 2) have been shown to cause AD, but these genetic forms of AD account for less than 5% of all cases. The largest proportion of AD cases is therefore ‘‘sporadic’’. However, genetic factors also seem to influence non-familial cases of AD. The ‘‘common disease/common variant’’ hypothesis postulates that common disorders, such as AD, are also governed by common DNA variants.9 These variants significantly increase disease risk but are neither necessary nor sufficient to actually cause a specific disorder. Rather, these risk genes display intricate patterns of interaction with each other as well as with non-genetic variables, modifying the risk for a disease. To date, only one such factor has been identified in AD. The apoliprotein E gene presents in three allelic forms (e2, e3, and e4), of which the e4 allele is a risk factor for AD.10 APOE e4 itself is neither necessary nor sufficient to cause AD, but instead operates as a genetic risk modifier. The well known effect of age on AD is modified by APOE, as age of onset is lower in APOE e4 positives.7 In addition, it has been suggested that APOE interacts with vascular risk factors. Vascular risk factors There is abundant evidence that vascular factors play a role in AD. Vascular risk factors such as hypertension, diabetes mellitus, smoking, and heart disease all have been shown to be associated with AD.11 Explanations for these associations include: (1) the coincidence of common disorders in the