**2.9 The ageing brain**

One of the reasons that the AD neuropathological diagnostic criteria are a probability scale is the occurrence of both plaques and NFTs, either independently or together, in a proportion of aged subjects without dementia. Diffuse plaques are seen in as many as 30% of all brains examined (Braak and Braak, 1997; Davis *et al.*, 1999). A similar percentage of cognitively normal individuals have tau-positive neuritic pathology (Knopman *et al.,* 2003) although tau pathology confined to the hippocampal formation appears to be seen in most, if not all, aged brains (Troncoso *et al.,* 1996). As discussed above the quantity of AD pathology tends to correlate relatively closely to the level of dementia and many researchers consider that the presence of mild pathology is representative of preclinical AD (Price *et al.,* 2009). Dementia then occurs when the quantity of AD pathology crosses a particular threshold. Two issues with this idea are that some individuals with A will not develop dementia prior to death (incidental AD pathology) and these A clinicopathological correlations tend to breakdown in the oldest old (>90 years of age) (Kril, 2009).

As will be discussed further below, the common occurrence of incidental AD and AD-type pathology in nondemented controls could also be a factor in the small effect sizes and lack of reproducibility seen in AD association studies to date (Sutherland *et al.*, 2011b).
