This study provides evidence that function of the posteromedial cortices is more impaired in carriers of the APOE ε4 allele, compared to non-carriers, across a range of cognitive ability. Failure of memory-related deactivation in these key regions of the default network was evident even among healthy elderly individuals who carry the APOE ε4 allele. Furthermore, magnitude of BOLD fMRI signal of the left posteromedial cortical region, which showed significant ε4-related dysfunction, was related to verbal episodic memory performance, even within the range of cognitively normal older subjects. These findings suggest that fMRI activity in the posteromedial cortical areas of the default network is modulated by two major risk factors for AD – that is, presence of APOE ε4 allele and incipient episodic memory impairment.
Previous studies have reported evidence of impaired fMRI deactivation in subjects with MCI compared to healthy elderly3,4
and in ε4 carriers compared to non-carriers27
. The present study investigated the entire continuum from cognitively intact subjects at genetic risk for AD to subjects with cognitive impairment (CDR 0.5) to those with clinical AD, and found that the ε4 allele was associated with more impaired activity of regions of the default network throughout the course of the disease. Furthermore, ε4 carriers without any clinical impairment, demonstrated impaired fMRI activity in the same posteromedial cortical regions, which were found to differentiate AD patients from healthy older subjects.
Our finding of dysfunction of the posteromedial cortices in cognitively normal elderly individuals at genetic risk for AD is consistent with previous FDG-PET results of abnormal resting-state metabolism in ε4 carriers versus non-carriers11,12
and a recent fMRI study27
. Furthermore, molecular PET imaging using a tracer called [11
C]Pittsburgh Compound B, or PIB, has recently provided in vivo
evidence that the posteromedial cortices are among the earliest sites of amyloid β (Aβ) plaque accumulation – one of the pathological hallmarks of AD.28,29
ε4 is known to increase brain's vulnerability to Aβ pathology,30,31
and even before formation of Aβ plaques, to induce neurotoxicity of soluble Aβ oligomers.32-34
Both the increased Aβ plaque deposition and impaired synaptic transmission due to Aβ oligomers in ε4 carriers provide potential biological mechanisms for the posteromedial cortical dysfunction observed in this fMRI study. It remains unknown how amyloid pathology results in decreased resting glucose metabolism as observed with PET and inability to effectively modulate the neuronal activity in these postermedial cortical regions as demonstrated with fMRI. It may be that regions which show evidence of decreased metabolism at rest are unable to respond with further decrease in activity during goal-directed task performance to support, for example, memory encoding.35,36
Given the strong inter-connectivity between the posteromedial and medial temporal cortices,37
it is also possible that impaired posteromedial cortical function in the ε4 carriers versus non-carriers reflects remote effects of more pronounced neurofibrillary tangle pathology in the medial temporal regions of the ε4 carriers.28,31,38,39
The same posteromedial regions vulnerable to hypometabolism during rest and impaired fMRI response pattern during goal-directed cognitive tasks have been proposed as key components of the default network40
and of large-scale memory networks41
.The cognitive operations supported by the posteromedial cortices are, however, not fully understood. In young subjects, the default network regions typically show deactivation during most goal-oriented cognitive tasks, however, new fMRI studies suggest that the posteromedial cortices may have a specific role in memory formation and retrieval. There is recent fMRI evidence that deactivation of the posteromedial cortices during encoding supports successful memory formation,35,36
and that the same posteromedial cortices which are deactivated during successful encoding, are activated during memory retrieval.42
Furthermore, fMRI studies suggest that retrieval-related activity of these regions is impaired in MCI.43
Our current study is in agreement with the hypothesis that greater fMRI deactivation during encoding is related to better memory ability, even when measured via delayed recall as in standard neuropsychological tests, both within cognitively intact older individuals and across a spectrum of clinical impairment. Interestingly, both right and left posteromedial cortical activity was significantly compromised in the ε4 carriers but only magnitude of the left posteromedial fMRI signal correlated with verbal memory measures.
In this study, up-regulation of the posteromedial cortical fMRI activity in subjects at risk for AD was observed in the context of a wide-spread network of brain areas demonstrating increased fMRI activity in ε4 carriers compared to non-carriers. Among these regions, similar to posteromedial cortices, the ventral anterior cingulum is often considered as part of the default network, and typically demonstrates deactivation during externally directed cognitive tasks, such as intentional encoding.40,41
Other regions which showed increased fMRI activity in ε4 carriers, however, are parts of attentional and working memory networks, which typically activate during demanding memory tasks. Similar to our study, increased lateral prefrontal activity in ε4 carriers has been reported in previous fMRI studies44,45
and has been interpreted to be compensatory in nature46
. It is also possible that early AD pathology, more likely to be present in the ε4 carriers, is associated with widespread cortical irritability or chronic up-regulation of neuronal activity.47
Our study has several limitations which need to be addressed in future studies. We analyzed fMRI data from elderly subjects spanning a wide cognitive range and stratified by the APOE
ε4 allele status. There were, however, relatively small numbers of ε4 carriers within each clinical subgroup. We did not have detailed data available on the family history of AD for all of the subjects. Recent fMRI studies have interestingly suggested complex interactions between cognitive performance, APOE
genotype and family history effects on fMRI activity.48,49
In this study, we did not perform a whole-brain structural voxel-based morphometric analysis between the study groups, although we did use the gray matter volumes as covariates in the functional data analyses. It is worth noting that task-related BOLD fMRI is always a relative measure investigating the net difference between two cognitive conditions – that is, there is not a quantitative zero baseline from which BOLD signal would vary up or down.50,51
It is also possible that some of the observed differences between groups were due to different cognitive strategies, that is the nature of the encoding task may have been more challenging or emotionally taxing to the subjects who have dementia or are concerned that they may have a memory problem. Patients with greater cognitive impairment may also be in a different cognitive state during the fixation baseline condition, which is also an issue in resting functional connectivity MRI studies. Nevertheless, we observed consistent alterations in posteromedial cortical activity related to both the presence of the ε4 allele and performance on an episodic memory task, even among clinically normal subjects. Further clinical follow-up will be necessary to determine if these healthy older subjects will progress to demonstrate cognitive impairment and eventual clinical dementia. Finally, there may be alterations in BOLD fMRI activity that are related to neurovascular coupling or vascular factors.52-54
Future studies may incorporate arterial spin labeling or gadolinium dynamic contrast perfusion MRI techniques to determine if, for example, regional alterations in the baseline blood flow are responsible for some of the observed relative differences between ε4 carriers and non-carriers.
In conclusion, our findings suggest that abnormal fMRI response pattern in the posteromedial cortices may be an early indicator of brain dysfunction and is related to risk factors for developing AD. Functional imaging of the posteromedial cortices may provide a sensitive technique to track alterations in neural activity due to evolving AD pathology, identify subjects at risk for developing AD, and potentially monitor response to disease-modifying therapy.