A more fundamental challenge to understanding the role of vascular factors in AD is the limited interface between risk factor outcome research and research into underlying causal pathways. AD can be considered as, in eect, two disorders – rst, a process of nerve cell death with particular appearances at a cellular level, which can only be observed at autopsy, and 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, it is important to bear in mind that sizeable numbers of people have signicant Alzheimer pathology with no clinical evidence of dementia and/or preserved cognitive function (Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study, 2001; Jack et al., 2014). Furthermore, these pathological changes more poorly predict dementia in later old age despite similar associations with cerebral atrophy (Savva et al., 2009), suggesting that links between ‘traditional’ pathologies and cognitive decline are more complex than originally envisaged.