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The studies discussed above provide strong support that the PCC is a key brain area to study in order to better understand the sequence of brain changes associated with AD. As proposed in Section 1.2, one strategy which could enhance understanding of this sequence, is to study this brain region in young APOE-E4 carriers. Notably, several of the neuroimaging methods applied in AD have already been used to study PCC metabolism and function in young APOE-E4 carriers.

Similar to the findings from the FDG-PET studies of glucose metabolism in AD patients, the PCC of young APOE-E4 carriers also shows glucose hypometabolism. In an FDG-PET study of 12 APOE-E4 heterozygote carriers compared to 15 non-carriers, where the mean age of the participants was 31 years (range 20-39 years), glucose metabolism during rest was found to be lower in the PCC of the young E4 carriers compared with the

non-carriers (Reiman et al., 2004). This PCC area of the glucose hypometabolism in the young APOE-E4 carriers had close correspondence with that found in AD patients, although it covered a smaller area (see Figure 1.10).

Figure 1.10: Both AD patients (on the left) and young APOE-E4 carriers (on the right) have decreased glucose metabolism in the PCC area (shown in blue) (image adapted from

Reiman et al., 2012).

In addition, and similar to the altered PCC and DN activity seen during rest in AD and MCI patients, resting state PCC activity in young healthy APOE-E4 carriers is also altered. Filippini et al., (2009) investigated the activity of the DN during the resting state in young APOE-E4 carriers compared to non-carriers (mean age 29 years, range 18-39 years), and detected a higher level of activity in the PCC/retrosplenial cortex, hippocampus and anterior cingulate areas in the young APOE-E4 carriers (see Figure 1.11) (Filippini, MacIntosh, et al., 2009).

Figure 1.11: Brain regions that show a higher level of activity during the resting state in

APOE-E4 carriers compared to non-carriers. The red/yellow area towards the back of the

brain in the image on the right shows the higher level of activity in the PCC/RSC in the young E4 carriers (image taken from Filippini et al., 2009).

As well as alterations in task-free (resting state) PCC activity in young APOE-E4 carriers, task-induced PCC activity also shows critical differences. To maximise the sensitivity to detect any early alterations in brain activity in young APOE-E4 carriers, a recent study in our lab applied cognitive paradigms sensitive to behavioural changes in AD to test task-induced fMRI activity in the PCC of young APOE-E4 carriers compared to non-carriers (mean age 19 years) (Shine, Hodgetts, Postans, Lawrence, & Graham, 2015). The paradigms included were a working memory task and an oddity perception task, both of which contrasted different stimuli conditions, with the prediction that APOE-E4 carriers would be particularly affected when undertaking perception and short-term memory for scenes, compared to non-scene stimuli. This hypothesis was based on evidence that AD patients show a category-sensitive impairment on scene oddity (A. C. H. Lee et al., 2006; A. C. H. Lee, Levi, Davies, Hodges, & Graham, 2007) and on scene short– term memory conditions (Bird et al., 2010; Pengas, Patterson, et al., 2010). Furthermore the focus on the scene categories of the two paradigms here also stems from the recent account in the memory literature that different cognitive domains (e.g. memory, perception and working memory) rely on the same underlying category-specific representations in the brain. Importantly, the representations for complex scenes are proposed to form a scaffold for memory (Graham, Barense, & Lee, 2010). Since memory, scene perception and scene working memory impairments are evident in AD, it was hypothesised that the scene category may be particularly sensitive to detect any alterations in activity in the young APOE-E4 carriers.

To test this, Shine et al., (2015) first compared activity elicited in young APOE-E4 carriers and non-carriers during a 1-back working memory task for the experimental conditions of scenes, faces, objects and scrambled objects versus the baseline condition of rest. This revealed that young APOE-E4 carriers showed a reduced level of deactivation in PCC for the contrast scenes>rest compared to non-carriers, and this was specific to the scene condition as there was no difference between carriers and non- carriers for the other conditions vs rest (see Figure 1.12 A and B). Using this same PCC area as a region-of-interest (ROI), activity elicited during odd-one-out judgements for scenes, faces and objects (against a baseline size discrimination condition, see Figure 1.12C) was compared across APOE-E4 carriers and non-carriers. Young APOE-E4 carriers again showed a smaller degree of deactivation compared to baseline for the scene condition (see Figure 1.12D). Consistent with evidence of a failure to deactivate the PCC/DN in AD and MCI (as discussed in Section 1.4.2) the authors proposed that these findings could provide evidence of a similar difficulty deactivating the PCC during scene

perception and memory tasks, especially those sensitive to the very earliest behavioural impairments in AD (A. C. H. Lee et al., 2006, 2007).

Figure 1.12: Investigation of PCC activity in young APOE-E4 carriers vs non-carriers during a working memory task and a perception task. (A) The design of the working memory paradigm. Participants were shown a series of scenes, faces, objects and scrambled objects,

and were asked to press a response button when the item was identical to that one trial previously (i.e. 1-back working memory task). When activity during each category was contrasted with rest, and compared between the APOE-E4 carriers and non-carriers, this

revealed the brain region shown in (B) to have higher activity in the carriers during the scene condition only. There were no activity differences between groups for the three other stimuli conditions. (C) The design of the oddity perception task. Participants were shown either three scenes, faces, objects, or squares. Two of the images were the same but

from a different viewpoint, and the third image was the odd-one-out. Participants were asked to select the odd one out. (D) The BOLD percent signal change in the same ROI as identified in the scene working memory task when each stimuli category in the odd-one- out task was compared to the baseline condition of size. This revealed a more positive level

of activity that was specific to scenes in the young E4 carriers, whereas there was no significant differences in activity for the other conditions of faces or objects between APOE-