elderly; (2) vascular and cerebrovascular disease precipitating AD; (3) an additive or synergistic (AD + vascular) pathogenesis of dementia; and (4) misclassification of vascular dementia as AD.11 12 At this moment, the question about the primary and secondary pathology in AD is unlikely to be answered. The mechanisms linking vascular risk factors to AD remain unclear. Atherosclerosis has been postulated as one common mechanism mediating the association between AD and various vascular risk factors. However, statistical models have failed to demonstrate an important mediating role for atherosclerosis as one common factor. Either the measures of extracranial atherosclerosis are not suitable as proxies for intracranial atherosclerosis, or there are other mechanisms whereby cardiovascular risk factors are associated with AD. METHODOLOGICAL ISSUES A brief overview has been given of the current knowledge of prevalence, incidence, and risk factors of dementia. Although v5 NEUROLOGY IN PRACTICE www.jnnp.com copyright. on December 4, 2021 by guest. Protected by http://jnnp.bmj.com/ J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2005.082867 on 16 November 2005. Downloaded from progress in understanding dementia is being made, the basic mechanisms causing the majority of dementias are still not known, and satisfying therapeutic options are as yet not available. Studies of dementia are hampered by certain methodological issues inherent to the disorder. These methodological issues may influence the results of studies and be partly responsible for variability in results across studies. Without intending to give a complete overview of the methodological issues associated with the study of dementia, we would like to address briefly four important issues here. Diagnostic procedure The most important problem with respect to studying dementia and AD is defining the outcome. As yet, there is no single diagnostic test for AD or most of the other types of dementia. The diagnosis of AD is based on clinical criteria, and can be graded as possible, probable, or definite. Several sets of criteria are available, of which the criteria of the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer’s Disease and Related Disorders Association (ADRDA), dating from 1984, are the most commonly used.13 The diagnostic work-up of dementia is time and cost intensive. In large population based studies, it is impossible to assess every subject with a complete diagnostic work-up. Using medical records to identify cases would lead to an underestimation of the number of individuals with dementia, as many of the cases of dementia are never diagnosed in a formal setting. Therefore, large population based studies usually employ a stepwise approach to identify cases. Most studies use one of two possible stepwise approaches. (1) All subjects are assessed using a screening test. Only those performing below a certain cut off level receive an extensive assessment. A drawback of this approach is the low sensitivity of screening tests. Subjects who are demented but score above cut-off on the screening test are missed. These may include mild cases, and individuals with good cognitive reserve due to, for example, high educational level. (2) A subsample, stratified by certain characteristics such as age, sex, and performance on a screening test, receives an extensive diagnostic assessment. Results are extrapolated to the entire sample. Inherent to this approach is the fact that not all cases will receive an extensive assessment, which may result in lack of precision. The use of different criteria to diagnose dementia, and the variable approaches to operationalise these criteria in large samples, can result in highly varying estimates of frequency. The difficulty of diagnosing mild dementia can lead to an additional problem in incidence studies, as cases that are very mild and therefore not recognised at baseline may be wrongly counted as incident cases at follow up, resulting in biased estimates.14 Insidious onset A second—and related—methodological problem inherent to dementia is the insidious onset of the disorder. Neuropathological changes,