We investigated the effect of APOE ε4 status on intrinsic connectivity in an age, gender, and education-matched sample of elderly cognitively normal older adults. The major findings were that APOE ε4 carriers show (1) diminished connectivity of the posterior DMN, and (2) a relative increase in connectivity in the SN.
The DMN and SN are widely distributed anti-correlated neuroanatomical networks (15
). The DMN is consistently shown to have relatively more activity when individuals are at rest, i.e., not performing cognitive tasks (34
). The SN is involved in cognitive control functions such as attention, working memory, and response selection (35
) as well as uncertainty, pain and other homeostatic challenges (29
). When individuals engage in cognitively demanding tasks, the DMN deactivates as activity in the SN becomes more pronounced (38
). The right fronto-insular cortex, which is a network hub of the SN, plays a critical role in switching between task negative and task positive networks (39
The DMN and SN are in a dynamic balance during resting states. Recent literature comparing AD with other dementias emphasizes the unique relationship between the DMN and SN and how they differ (16
). The DMN and SN have disease specificity, hence we interrogated both networks. Our results suggest that there is a disruption in the balance between the DMN and SN is observable even in cognitively normal asymptomatic APOE ε4 carriers. One possible interpretation, although speculative, is that a reduction in the inhibitory control of the posterior DMN may result in an aberrant relative increase in the SN, and that this may represent a loss of the ability to appropriately regulate functional networks in clinically asymptomatic individuals.
Sheline et al. recently reported on functional connectivity changes of the DMN in APOE ε4 carriers vs. non-carriers (14
). All of their subjects were PiB negative which allowed for isolation of the effect of APOE status. They placed a single seed in the precuneus and similar to our results with a posterior cingulate cortex seed, they found a decrease in connectivity in regions of the posterior DMN, including the left hippocampus, left parahippocampus and middle temporal cortex in the APOE ε4 carriers relative to non-carriers. Unlike their study however, we also specifically interrogated the SN with a second seed placed in the anterior cingulate gyrus.. Another difference is that on average, our APOE ε4 carriers are 20 years older than their sample.
Several fMRI task activation studies show enhanced activation of brain regions in older APOE ε4 carriers vs. non-carriers during cognitive tasks (40
). One of these studies used a cohort similar in age to ours and found that the APOE ε4 carriers showed greater activation during a verbal paired-associate learning task than the non-carriers in multiple regions in the right hemisphere, despite an equivalent level of memory function and comparable brain volume (43
). Han and Bondi (44
) revised the apolipoprotein E compensatory mechanism recruitment hypothesis and proposed that APOE ε4 carriers compensate for cognitive declines later in life by invoking additional brain regions to perform cognitive tasks with a predilection for increases in right hemisphere activity. They further suggest that frontal-executive cognitive processes might mediate these compensatory mechanisms. Our results indicate a relative increase in the SN, but suggest that rather than compensation per se, this “increase” in resting state connectivity occurs in the context of decreased posterior default mode network connectivity and thus may represent disruption of the balance between these two networks(15
The primary biologic effect of APOE ε4 appears to be an increase in brain burden Aß. Although our subjects were clinically normal, resting state MR shows that there are subclinical consequences which are evident even in cognitively normal elderly individuals (7
). Our results reflect changes in resting state connectivity that may be a direct result of higher amyloid burden in APOE ε4 carriers who are more likely to harbor clinically silent amyloid plaques and who are more likely to develop AD in the future(9
Based on the observation that regions of the DMN that are metabolically active in young adults also show a striking correlation with the pattern of amyloid deposition in older adults with AD, Buckner et al. suggested that the areas of enhanced metabolism may provide regional conditions that are conducive to amyloid deposition (4
). Fillipini and colleagues (12
) show that connectivity within the DMN is increased in young adult APOE ε4 carriers (i.e., mean age 28 years) relative to non-carriers, thus potentially setting the stage for earlier deposition of amyloid in regions of the DMN in carriers of the APOE ε4 allele. We propose that after an initial phase of increased resting metabolism in young adulthood, APOE ε4 carriers show a more rapid decline in DMN connectivity than APOE ε4 non-carriers as they age. Future studies of the resting state in APOE ε4 carriers and non-carriers throughout middle adulthood will ultimately provide a better understanding of the trajectory of the DMN over the life span and the age at which these declines begin to occur.
Our study has several strengths. We have a fairly large sample size of thoroughly evaluated and well characterized individuals. Our groups are matched on age, gender, and education, effectively ruling out these variables as potential explanations for the group differences observed in resting state connectivity. Secondly, we performed both ICA and seed-based analyses, strengthening our results. Finally, results from our VBM analysis confirm that the group differences are not due to relatively greater loss of gray matter density in the APOE ε4 carriers.
Our cohort consists of older individuals. The changes we describe may not generalize to changes in connectivity in younger cohorts. Although nearly all our patients are derived from a population-based sample, they represent a subset of individuals who are willing to undergo neuroimaging studies. This could potentially limit the generalizability of our findings. Finally, although studies clearly document an association between APOE ε4 status and amyloid, we do not have imaging evidence of amyloidosis to confirm a direct relationship.