Brain imaging studies with structural MRI have shown that atrophy associated with AD usually appears first in medial temporal lobe (MTL) structures, and research in recent years has repeatedly found the entorhinal cortex (EC) in this region to be primarily affected by neurofibrillary tangles and neuritic plaques (Blackwell et al., 2004; Bobinski et al., 1999; C.R Jack et al., 2004; Chan et al., 2001; Killiany et al., 2000; C. J. Morris, Csernansky, & Price, 2002; Mosconi et al., 2004; Salmon et al., 1999). The EC forms part of the anterior parahippocampal region, and receives projections from the association cortices. Studies have shown that up to 30-60% of neurons are lost in the earliest stages of AD (Gomez-isla, J, & D, 1996; Killiany et al., 2002). Furthermore, neuronal loss in this region is believed to precede documentable memory problems by 10 or more years, and the subclinical stages of the illness may extend over several decades (Forstl & Kurz, 1999; Nagy et al., 1999).
The enthorhinal and adjacent perirhinal cortices are believed to be important structures in the formation of associative learning, especially for arbitrarily related items (Blackwell et al., 2004; Fowler et al., 2002; Weintrob, Saling, Berkovic, Berlangieri, & Reutens, 2002). The tendency to forget the location of objects in pre-clinical stages of AD might be attributable to EC atrophy (Blackwell et al., 2004; Killiany et al., 2002). Recent studies have been successful in demonstrating the difficulty of AD patients in forming and maintaining an arbitrary association between items and locations, and these will be reviewed in the section concerned with early detection of AD.