ABSTRACT
A more fundamental challenge to understanding the role of vascular factors in AD is the limited interface between epidemiological and biological research. Epidemiological research investigates associations between potential risk factors and a specified disorder, accepting that causal processes in between may not be measurable in the population. These causal processes can be represented as a ‘black box’ between exposure and outcome. Biological research on the other hand focuses on potential causal processes within the ‘box’. However, in the absence of tissue biopsies (which are impractical in dementia research), findings at a molecular or cellular level cannot be linked directly to clinical symptoms/syndromes observed in life. Because of this lack of connection, AD has become in effect two disorders – one a process of nerve cell death with particular features at a cellular level that can only be observed at autopsy, the second a clinical disorder characterized by its symptoms and clinical course. AD the pathological disorder is likely to be have been present for a decade or two before AD the clinical disorder becomes apparent. However, large numbers of people with significant levels of AD pathology show no clinical evidence of dementia (Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study, 2001). Diagnostic criteria for AD as a clinical disorder attempt to predict the presence of AD pathology by the time of death (McKhann et al., 1984). However, these criteria poorly reflect mixed disease (Holmes et al., 1999), which will become increasingly common with population ageing.
