Etiology And Risk Factors

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The main risk factor for most forms of dementia is advanced age, with prevalence roughly doubling every five years over the age of 65 years. Onset before this age is very unusual and, in the case of AD, often suggests a genetic cause. Single gene mutations at one of three loci (beta amyloid precursor protein, presenilinl and presenilin2) account for most of these cases. For late-onset AD both environmental (lifestyle) and genetic factors are important. A common genetic polymorphism, the apolipoprotein E (apoE) gene e4 allele greatly increases risk of going on to suffer from dementia; up to 25% of the population have one or two copies (4, 5). However, it is not uncommon for one identical twin to suffer from dementia and the other not. This implies a strong influence of the environment (6). Evidence from cross-sectional and case-control studies suggests associations between AD and limited education (7) and head injury (8, 9), which, however, are only partly supported by longitudinal (follow-up) studies (10). Depression is a risk factor in short-term longitudinal studies, but this may be because depression is an early presenting symptom rather than a cause of dementia (11). Recent research suggests that vascular disease predisposes to AD as well as to VaD (12). Smoking seems to increase the risk for AD as well as VaD (13). Long-term follow-up studies show that high blood pressure (14, 15) and high cholesterol levels (15) in middle age each increase the risk of going on to develop AD in later life.

Reports from epidemiological studies of protective effects of certain prescribed medication, non-steroidal anti-inflammatory drugs, hormone replacement therapy (HRT) and cholesterol-lowering therapies are now being investigated in randomized controlled trials. The randomized controlled trial of HRT in postmenopausal women indicated, against expectation, that it increased rather than lowered the incidence of dementia.

Despite many investigations, far too little is still understood about the environmental and lifestyle factors linked to AD and other dementias. It may be that the focus on research in developed countries has limited possibilities to identify risk factors. Prevalence and incidence of AD seem to be much lower in some developing regions (see the section on Epidemiology and burden, below). This may be because some environmental risk factors are much less prevalent in these settings. For example, African men tend to be very healthy from a cardiovascular point of view with low cholesterol, low blood pressure and low incidence of heart disease and stroke. Conversely, some risk factors may only be apparent in developing countries, as they are too infrequent in the developed economies for their effects to be detected; for example, anaemia has been identified as a risk factor in India (16).

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